Maintenance of long-term adaptation of synaptic transmission requires axonal transport following induction in an identified crayfish motoneuron.

PubMed

Nguyen, P V; Atwood, H L

1992-03-01

Motoneurons can adapt to altered levels of electrical activity by effecting semi-permanent changes in their neuromuscular synaptic physiology. In the present study, we tested the hypothesis that maintenance of activity-dependent long-term adaptation of synaptic transmission in a crayfish abdominal extensor motoneuron (phasic axon 3) required axonal transport following induction. Intact crayfish were chronically wired for periodic in vivo stimulation of axon 3. Periodic unilateral stimulation for 3-5 consecutive days (2 h/day) induced long-term adaptation (LTA) of neuromuscular synaptic transmission in axon 3. Initial EPSP amplitudes (measured at 0.1 Hz) were significantly reduced to approximately 40% of contralateral control amplitudes over a 7-day poststimulation period. Additionally, synaptic depression during 5 Hz test stimulation of axon 3 was significantly less in chronically stimulated neurons: excitatory postsynaptic potential (EPSP) amplitudes measured after 20 min of 5 Hz test stimulation (final EPSPs) were significantly larger in conditioned neurons than in unstimulated controls. The depression of initial EPSP amplitudes persisted for 7 days postinduction, while the increased synaptic stamina persisted for 4 days but was absent at 7 days postinduction. Axotomy of axon 3 following induction of LTA had no effect on long-term maintenance of the activity-induced reduction in initial EPSP amplitudes. Initial EPSP amplitudes in conditioned, axotomized neurons were still reduced to 42% of control amplitudes over the 7-day postinduction period. In contrast, postinduction axotomy of axon 3 elicited an accelerated decay of the enhanced synaptic stamina. Following axotomy, final EPSP amplitudes were significantly larger in conditioned neurons for only 1 day poststimulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Antidepressants Rescue Stress-Induced Disruption of Synaptic Plasticity via Serotonin Transporter-Independent Inhibition of L-Type Calcium Channels.

PubMed

Normann, Claus; Frase, Sibylle; Haug, Verena; von Wolff, Gregor; Clark, Kristin; Münzer, Patrick; Dorner, Alexandra; Scholliers, Jonas; Horn, Max; Vo Van, Tanja; Seifert, Gabriel; Serchov, Tsvetan; Biber, Knut; Nissen, Christoph; Klugbauer, Norbert; Bischofberger, Josef

2017-10-19

Long-term synaptic plasticity is a basic ability of the brain to dynamically adapt to external stimuli and regulate synaptic strength and ultimately network function. It is dysregulated by behavioral stress in animal models of depression and in humans with major depressive disorder. Antidepressants have been shown to restore disrupted synaptic plasticity in both animal models and humans; however, the underlying mechanism is unclear. We examined modulation of synaptic plasticity by selective serotonin reuptake inhibitors (SSRIs) in hippocampal brain slices from wild-type rats and serotonin transporter (SERT) knockout mice. Recombinant voltage-gated calcium (Ca 2+ ) channels in heterologous expression systems were used to determine the modulation of Ca 2+ channels by SSRIs. We tested the behavioral effects of SSRIs in the chronic behavioral despair model of depression both in the presence and in the absence of SERT. SSRIs selectively inhibited hippocampal long-term depression. The inhibition of long-term depression by SSRIs was mediated by a direct block of voltage-activated L-type Ca 2+ channels and was independent of SERT. Furthermore, SSRIs protected both wild-type and SERT knockout mice from behavioral despair induced by chronic stress. Finally, long-term depression was facilitated in animals subjected to the behavioral despair model, which was prevented by SSRI treatment. These results showed that antidepressants protected synaptic plasticity and neuronal circuitry from the effects of stress via a modulation of Ca 2+ channels and synaptic plasticity independent of SERT. Thus, L-type Ca 2+ channels might constitute an important signaling hub for stress response and for pathophysiology and treatment of depression. Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Learning induces the translin/trax RNase complex to express activin receptors for persistent memory.

PubMed

Park, Alan Jung; Havekes, Robbert; Fu, Xiuping; Hansen, Rolf; Tudor, Jennifer C; Peixoto, Lucia; Li, Zhi; Wu, Yen-Ching; Poplawski, Shane G; Baraban, Jay M; Abel, Ted

2017-09-20

Long-lasting forms of synaptic plasticity and memory require de novo protein synthesis. Yet, how learning triggers this process to form memory is unclear. Translin/trax is a candidate to drive this learning-induced memory mechanism by suppressing microRNA-mediated translational silencing at activated synapses. We find that mice lacking translin/trax display defects in synaptic tagging, which requires protein synthesis at activated synapses, and long-term memory. Hippocampal samples harvested from these mice following learning show increases in several disease-related microRNAs targeting the activin A receptor type 1C (ACVR1C), a component of the transforming growth factor-β receptor superfamily. Furthermore, the absence of translin/trax abolishes synaptic upregulation of ACVR1C protein after learning. Finally, synaptic tagging and long-term memory deficits in mice lacking translin/trax are mimicked by ACVR1C inhibition. Thus, we define a new memory mechanism by which learning reverses microRNA-mediated silencing of the novel plasticity protein ACVR1C via translin/trax.

Memantine alters striatal plasticity inducing a shift of synaptic responses toward long-term depression.

PubMed

Mancini, Maria; Ghiglieri, Veronica; Bagetta, Vincenza; Pendolino, Valentina; Vannelli, Anna; Cacace, Fabrizio; Mineo, Desireé; Calabresi, Paolo; Picconi, Barbara

2016-02-01

Memantine is an open channel blocker that antagonizes NMDA receptors reducing the inappropriate calcium (Ca(2+)) influx occurring in presence of moderately increased glutamate levels. At the same time, memantine has the ability to preserve the transient physiological activation of NMDA receptor, essential for learning and memory formation at synaptic level. In the present study we investigated the effects exerted by memantine on striatal synaptic plasticity in rat striatal spiny projection neurons (SPNs). In vitro application of memantine in striatal slices elicited a disruption of long-term potentiation (LTP) induction and maintenance, and revealed, in the majority of the recorded neurons, a long-term depression (LTD), whose amplitude was concentration-dependent (0.3-10 μM). Interestingly, preincubation with the dopamine (DA) D2 receptor antagonist sulpiride (10 μM) prevented memantine-induced LTD and restored LTP. Moreover, the DA D2 agonist quinpirole (10 μM), similarly to memantine, induced LTD in a subgroup of SPNs. In addition, memantine-induced LTD was also prevented by the CB1 endocannabinoid receptor antagonist AM 251 (1 μM). These results suggest that the actions exerted by memantine on striatal synaptic plasticity, and in particular the induction of LTD observed in SPNs, could be attributed to its ability to activate DA D2 receptors. By contrast, blockade of NMDA receptor is not involved in memantine-induced LTD since APV (30 μM) and MK801 (10 μM), two NMDA receptor antagonists, failed to induce this form of synaptic plasticity. Our data indicate that memantine could be used as treatment of neurological disorders in which DA D2 receptor represents a possible therapeutic target. Copyright © 2015 Elsevier Ltd. All rights reserved.

Demonstration of Synaptic Behaviors and Resistive Switching Characterizations by Proton Exchange Reactions in Silicon Oxide

PubMed Central

Chang, Yao-Feng; Fowler, Burt; Chen, Ying-Chen; Zhou, Fei; Pan, Chih-Hung; Chang, Ting-Chang; Lee, Jack C.

2016-01-01

We realize a device with biological synaptic behaviors by integrating silicon oxide (SiOx) resistive switching memory with Si diodes. Minimal synaptic power consumption due to sneak-path current is achieved and the capability for spike-induced synaptic behaviors is demonstrated, representing critical milestones for the use of SiO2–based materials in future neuromorphic computing applications. Biological synaptic behaviors such as long-term potentiation (LTP), long-term depression (LTD) and spike-timing dependent plasticity (STDP) are demonstrated systematically using a comprehensive analysis of spike-induced waveforms, and represent interesting potential applications for SiOx-based resistive switching materials. The resistive switching SET transition is modeled as hydrogen (proton) release from (SiH)2 to generate the hydrogen bridge defect, and the RESET transition is modeled as an electrochemical reaction (proton capture) that re-forms (SiH)2. The experimental results suggest a simple, robust approach to realize programmable neuromorphic chips compatible with large-scale CMOS manufacturing technology. PMID:26880381

Demonstration of Synaptic Behaviors and Resistive Switching Characterizations by Proton Exchange Reactions in Silicon Oxide

NASA Astrophysics Data System (ADS)

Chang, Yao-Feng; Fowler, Burt; Chen, Ying-Chen; Zhou, Fei; Pan, Chih-Hung; Chang, Ting-Chang; Lee, Jack C.

2016-02-01

We realize a device with biological synaptic behaviors by integrating silicon oxide (SiOx) resistive switching memory with Si diodes. Minimal synaptic power consumption due to sneak-path current is achieved and the capability for spike-induced synaptic behaviors is demonstrated, representing critical milestones for the use of SiO2-based materials in future neuromorphic computing applications. Biological synaptic behaviors such as long-term potentiation (LTP), long-term depression (LTD) and spike-timing dependent plasticity (STDP) are demonstrated systematically using a comprehensive analysis of spike-induced waveforms, and represent interesting potential applications for SiOx-based resistive switching materials. The resistive switching SET transition is modeled as hydrogen (proton) release from (SiH)2 to generate the hydrogen bridge defect, and the RESET transition is modeled as an electrochemical reaction (proton capture) that re-forms (SiH)2. The experimental results suggest a simple, robust approach to realize programmable neuromorphic chips compatible with large-scale CMOS manufacturing technology.

Opposite long-term synaptic effects of 17β-estradiol and 5α-dihydrotestosterone and localization of their receptors in the medial vestibular nucleus of rats.

PubMed

Grassi, Silvarosa; Scarduzio, Mariangela; Panichi, Roberto; Dall'Aglio, Cecilia; Boiti, Cristiano; Pettorossi, Vito E

2013-08-01

In brainstem slices of male rats, we examined in single neurons of the medial vestibular nucleus (MVN) the effect of exogenous administration of estrogenic (17β-estradiol, E2) and androgenic (5α-dihydrotestosterone, DHT) steroids on the synaptic response to vestibular afferent stimulation. By whole cell patch clamp recordings we showed that E2 induced synaptic long-term potentiation (LTP) that was cancelled by the subsequent administration of DHT. Conversely, DHT induced synaptic long-term depression (LTD) that was partially reversed by E2. The electrophysiological findings were supported by immunohistochemical analysis showing the presence of estrogen (ER: α and β) and androgen receptors (AR) in the MVN neurons. We found that a large number of neurons were immunoreactive for ERα, ERβ, and AR and most of them co-localized ERβ and AR. We also showed the presence of P450-aromatase (ARO) in the MVN neurons, clearly proving that E2 can be locally synthesized in the MVN. On the whole, these results demonstrate a role of estrogenic and androgenic signals in modulating vestibular synaptic plasticity and suggest that the enhancement or depression of vestibular synaptic response may depend on the local conversion of T into E2 or DHT. Copyright © 2013 Elsevier Inc. All rights reserved.

Piracetam prevents memory deficit induced by postnatal propofol exposure in mice.

PubMed

Wang, Yuan-Lin; Li, Feng; Chen, Xin

2016-05-15

Postnatal propofol exposure impairs hippocampal synaptic development and memory. However, the effective agent to alleviate the impairments was not verified. In this study, piracetam, a positive allosteric modulator of AMPA receptor was administered following a seven-day propofol regime. Two months after propofol administration, hippocampal long-term potentiation (LTP) and long-term memory decreased, while intraperitoneal injection of piracetam at doses of 100mg/kg and 50mg/kg following last propofol exposure reversed the impairments of memory and LTP. Mechanically, piracetam reversed propofol exposure-induced decrease of BDNF and phosphorylation of mTor. Similar as piracetam, BDNF supplementary also ameliorated propofol-induced abnormalities of synaptic plasticity-related protein expressions, hippocampal LTP and long-term memory. These results suggest that piracetam prevents detrimental effects of propofol, likely via activating BDNF synthesis. Copyright © 2016 Elsevier B.V. All rights reserved.

Neurogranin restores amyloid β-mediated synaptic transmission and long-term potentiation deficits.

PubMed

Kaleka, Kanwardeep Singh; Gerges, Nashaat Z

2016-03-01

Amyloid β (Aβ) is widely considered one of the early causes of cognitive deficits observed in Alzheimer's disease. Many of the deficits caused by Aβ are attributed to its disruption of synaptic function represented by its blockade of long-term potentiation (LTP) and its induction of synaptic depression. Identifying pathways that reverse these synaptic deficits may open the door to new therapeutic targets. In this study, we explored the possibility that Neurogranin (Ng)-a postsynaptic calmodulin (CaM) targeting protein that enhances synaptic function-may rescue Aβ-mediated deficits in synaptic function. Our results show that Ng is able to reverse synaptic depression and LTP deficits induced by Aβ. Furthermore, Ng's restoration of synaptic transmission is through the insertion of GluA1-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptors (AMPARs). These restorative effects of Ng are dependent on the interaction of Ng and CaM and CaM-dependent activation of CaMKII. Overall, this study identifies a novel mechanism to rescue synaptic deficits induced by Aβ oligomers. It also suggests Ng and CaM signaling as potential therapeutic targets for Alzheimer's disease as well as important tools to further explore the pathophysiology underlying the disease. Copyright © 2015 Elsevier Inc. All rights reserved.

Out with the old and in with the new: Synaptic mechanisms of extinction in the amygdala

PubMed Central

Maren, Stephen

2014-01-01

Considerable research indicates that long-term synaptic plasticity in the amygdala underlies the acquisition of emotional memories, including those learned during Pavlovian fear conditioning. Much less is known about the synaptic mechanisms involved in other forms of associative learning, including extinction, that update fear memories. Extinction learning might reverse conditioning-related changes (e.g., depotentiation) or induce plasticity at inhibitory synapses (e.g., long-term potentiation) to suppress conditioned fear responses. Either mechanism must account for fear recovery phenomena after extinction, as well as savings of extinction after fear recovery. PMID:25312830

Acute and Chronic Effects of Ethanol on Learning-Related Synaptic Plasticity

PubMed Central

Zorumski, Charles F.; Mennerick, Steven; Izumi, Yukitoshi

2014-01-01

Alcoholism is associated with acute and long-term cognitive dysfunction including memory impairment, resulting in substantial disability and cost to society. Thus, understanding how ethanol impairs cognition is essential for developing treatment strategies to dampen its adverse impact. Memory processing is thought to involve persistent, use-dependent changes in synaptic transmission, and ethanol alters the activity of multiple signaling molecules involved in synaptic processing, including modulation of the glutamate and gamma-aminobutyric acid (GABA) transmitter systems that mediate most fast excitatory and inhibitory transmission in the brain. Effects on glutamate and GABA receptors contribute to ethanol-induced changes in long-term potentiation (LTP) and long-term depression (LTD), forms of synaptic plasticity thought to underlie memory acquisition. In this paper, we review the effects of ethanol on learning-related forms of synaptic plasticity with emphasis on changes observed in the hippocampus, a brain region that is critical for encoding contextual and episodic memories. We also include studies in other brain regions as they pertain to altered cognitive and mental function. Comparison of effects in the hippocampus to other brain regions is instructive for understanding the complexities of ethanol’s acute and long-term pharmacological consequences. PMID:24447472

Correlating Fluorescence and High-Resolution Scanning Electron Microscopy (HRSEM) for the study of GABAA receptor clustering induced by inhibitory synaptic plasticity.

PubMed

Orlando, Marta; Ravasenga, Tiziana; Petrini, Enrica Maria; Falqui, Andrea; Marotta, Roberto; Barberis, Andrea

2017-10-23

Both excitatory and inhibitory synaptic contacts display activity dependent dynamic changes in their efficacy that are globally termed synaptic plasticity. Although the molecular mechanisms underlying glutamatergic synaptic plasticity have been extensively investigated and described, those responsible for inhibitory synaptic plasticity are only beginning to be unveiled. In this framework, the ultrastructural changes of the inhibitory synapses during plasticity have been poorly investigated. Here we combined confocal fluorescence microscopy (CFM) with high resolution scanning electron microscopy (HRSEM) to characterize the fine structural rearrangements of post-synaptic GABA A Receptors (GABA A Rs) at the nanometric scale during the induction of inhibitory long-term potentiation (iLTP). Additional electron tomography (ET) experiments on immunolabelled hippocampal neurons allowed the visualization of synaptic contacts and confirmed the reorganization of post-synaptic GABA A R clusters in response to chemical iLTP inducing protocol. Altogether, these approaches revealed that, following the induction of inhibitory synaptic potentiation, GABA A R clusters increase in size and number at the post-synaptic membrane with no other major structural changes of the pre- and post-synaptic elements.

Different synaptic stimulation patterns influence the local androgenic and estrogenic neurosteroid availability triggering hippocampal synaptic plasticity in the male rat.

PubMed

Di Mauro, Michela; Tozzi, Alessandro; Calabresi, Paolo; Pettorossi, Vito Enrico; Grassi, Silvarosa

2017-02-01

Electrophysiological recordings were used to investigate the role of the local synthesis of 17β-estradiol (E2) and 5α-dihydrotestosterone (DHT) on synaptic long-term effects induced in the hippocampal CA1 region of male rat slices. Long-term depression (LTD) and long-term potentiation (LTP), induced by different stimulation patterns, were examined under the block of the DHT synthesis by finasteride (FIN), and the E2 synthesis by letrozole (LET). We used low frequency stimulation (LFS) for LTD, high frequency stimulation (HFS) for LTP, and intermediate patterns differing in duration or frequency. We found that FIN reverted the LFS-LTD into LTP and enhanced LTP induced by intermediate and HFSs. These effects were abolished by exogenous DHT at concentration higher than the basal one, suggesting a stimulus dependent increase in DHT availability. No effect on the synaptic responses was observed giving DHT alone. Moreover, we found that the inhibition of E2 synthesis influenced the HFS-LTP by reducing its amplitude, and the exogenous E2 either enhanced HFS-LTP or reverted the LFS-LTD into LTP. The equivalence of the E2 concentration for rescuing the full HFS-LTP under LET and reverting the LFS-LTD into LTP suggests an enhancement of the endogenous E2 availability that is specifically driven by the HFS. No effect of FIN or LET was observed on the responses to stimuli that did not induce either LTD or LTP. This study provides evidence that the E2 and DHT availability combined with specific stimulation patterns is determinant for the sign and amplitude of the long-term effects. © 2016 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

A repetitive intracortical microstimulation pattern induces long-lasting synaptic depression in brain slices of the rat primary somatosensory cortex.

PubMed

Heusler, P; Cebulla, B; Boehmer, G; Dinse, H R

2000-12-01

Repetitive intracortical microstimulation (ICMS) applied to the rat primary somatosensory cortex (SI) in vivo was reported to induce reorganization of receptive fields and cortical maps. The present study was designed to examine the effect of such an ICMS pattern applied to layer IV of brain slices containing SI on the efficacy of synaptic input to layer II/III. Effects of ICMS on the synaptic strength was quantified for the first synaptic component (s1) of cortical field potentials (FPs) recorded from layer II/III of SI. FPs were evoked by stimulation in layer IV. The pattern of ICMS was identical to that used in vivo. However, stimulation intensity had to be raised to induce an alteration of synaptic strength. In brain slices superfused with standard ACSF, repetitive ICMS induced a short-lasting (60 min) reduction of the amplitude (-37%) and the slope (-61%) of s1 evoked from the ICMS site, while the amplitude and the slope of s1 evoked from a control stimulation site in cortical layer IV underwent a slow onset increase (13% and 50%, respectively). In brain slices superfused with ACSF containing 1.25 microM bicuculline, ICMS induced an initial strong reduction of the amplitude (-50%) and the slope (-79%) of s1 evoked from the ICMS site. These effects decayed to a sustained level of depression by -30% (amplitude) and -60% (slope). In contrast to experiments using standard ACSF, s1 evoked from the control site was not affected by ICMS. The presynaptic volley was not affected in either of the two groups of experiments. A conventional high frequency stimulation (HFS) protocol induced input-specific long-term potentiation (LTP) of the amplitude and slope of s1 (25% and 76%, respectively). Low frequency stimulation (LFS) induced input-specific long-term depression (LTD) of the amplitude and slope of s1 (24% and 30%, respectively). Application of common forms of conditioning stimulation (HFS and LFS) resulted in LTP or LTD of s1, indicating normal susceptibility of the brain slices studied to the induction of common forms of synaptic plasticity. Therefore, the effects of repetitive ICMS on synaptic FP components were considered ICMS-specific forms of short-lasting (standard ACSF) or long-lasting synaptic depression (ACSF containing bicuculline), the latter resembling neocortical LTD. Results of this study suggest that synaptic depression of excitatory mechanisms are involved in the cortical reorganization induced by repetitive ICMS in vivo. An additional contribution of an ICMS-induced modification of inhibitory mechanisms to cortical reorganization is discussed.

Chelation of hippocampal zinc enhances long-term potentiation and synaptic tagging/capture in CA1 pyramidal neurons of aged rats: implications to aging and memory.

PubMed

Shetty, Mahesh Shivarama; Sharma, Mahima; Sajikumar, Sreedharan

2017-02-01

Aging is associated with decline in cognitive functions, prominently in the memory consolidation and association capabilities. Hippocampus plays a crucial role in the formation and maintenance of long-term associative memories, and a significant body of evidence shows that impairments in hippocampal function correlate with aging-related memory loss. A number of studies have implicated alterations in hippocampal synaptic plasticity, such as long-term potentiation (LTP), in age-related cognitive decline although exact mechanisms underlying are not completely clear. Zinc deficiency and the resultant adverse effects on cognition have been well studied. However, the role of excess of zinc in synaptic plasticity, especially in aging, is not addressed well. Here, we have investigated the hippocampal zinc levels and the impairments in synaptic plasticity, such as LTP and synaptic tagging and capture (STC), in the CA1 region of acute hippocampal slices from 82- to 84-week-old male Wistar rats. We report increased zinc levels in the hippocampus of aged rats and also deficits in the tetani-induced and dopaminergic agonist-induced late-LTP and STC. The observed deficits in synaptic plasticity were restored upon chelation of zinc using a cell-permeable chelator. These data suggest that functional plasticity and associativity can be successfully established in aged neural networks by chelating zinc with cell-permeable chelating agents. © 2016 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

PKMζ Inhibition Reverses Learning-Induced Increases in Hippocampal Synaptic Strength and Memory during Trace Eyeblink Conditioning

PubMed Central

Madroñal, Noelia; Gruart, Agnès; Sacktor, Todd C.; Delgado-García, José M.

2010-01-01

A leading candidate in the process of memory formation is hippocampal long-term potentiation (LTP), a persistent enhancement in synaptic strength evoked by the repetitive activation of excitatory synapses, either by experimental high-frequency stimulation (HFS) or, as recently shown, during actual learning. But are the molecular mechanisms for maintaining synaptic potentiation induced by HFS and by experience the same? Protein kinase Mzeta (PKMζ), an autonomously active atypical protein kinase C isoform, plays a key role in the maintenance of LTP induced by tetanic stimulation and the storage of long-term memory. To test whether the persistent action of PKMζ is necessary for the maintenance of synaptic potentiation induced after learning, the effects of ZIP (zeta inhibitory peptide), a PKMζ inhibitor, on eyeblink-conditioned mice were studied. PKMζ inhibition in the hippocampus disrupted both the correct retrieval of conditioned responses (CRs) and the experience-dependent persistent increase in synaptic strength observed at CA3-CA1 synapses. In addition, the effects of ZIP on the same associative test were examined when tetanic LTP was induced at the hippocampal CA3-CA1 synapse before conditioning. In this case, PKMζ inhibition both reversed tetanic LTP and prevented the expected LTP-mediated deleterious effects on eyeblink conditioning. Thus, PKMζ inhibition in the CA1 area is able to reverse both the expression of trace eyeblink conditioned memories and the underlying changes in CA3-CA1 synaptic strength, as well as the anterograde effects of LTP on associative learning. PMID:20454458

Synaptic Activation of Ribosomal Protein S6 Phosphorylation Occurs Locally in Activated Dendritic Domains

ERIC Educational Resources Information Center

Pirbhoy, Patricia Salgado; Farris, Shannon; Steward, Oswald

2016-01-01

Previous studies have shown that induction of long-term potentiation (LTP) induces phosphorylation of ribosomal protein S6 (rpS6) in postsynaptic neurons, but the functional significance of rpS6 phosphorylation is poorly understood. Here, we show that synaptic stimulation that induces perforant path LTP triggers phosphorylation of rpS6 (p-rpS6)…

Status Epilepticus Impairs Synaptic Plasticity in Rat Hippocampus and Is Followed by Changes in Expression of NMDA Receptors.

PubMed

Postnikova, T Y; Zubareva, O E; Kovalenko, A A; Kim, K K; Magazanik, L G; Zaitsev, A V

2017-03-01

Cognitive deficits and memory loss are frequent in patients with temporal lobe epilepsy. Persistent changes in synaptic efficacy are considered as a cellular substrate underlying memory processes. Electrophysiological studies have shown that the properties of short-term and long-term synaptic plasticity in the cortex and hippocampus may undergo substantial changes after seizures. However, the neural mechanisms responsible for these changes are not clear. In this study, we investigated the properties of short-term and long-term synaptic plasticity in rat hippocampal slices 24 h after pentylenetetrazole (PTZ)-induced status epilepticus. We found that the induction of long-term potentiation (LTP) in CA1 pyramidal cells is reduced compared to the control, while short-term facilitation is increased. The experimental results do not support the hypothesis that status epilepticus leads to background potentiation of hippocampal synapses and further LTP induction becomes weaker due to occlusion, as the dependence of synaptic responses on the strength of input stimulation was not different in the control and experimental animals. The decrease in LTP can be caused by impairment of molecular mechanisms of neuronal plasticity, including those associated with NMDA receptors and/or changes in their subunit composition. Real-time PCR demonstrated significant increases in the expression of GluN1 and GluN2A subunits 3 h after PTZ-induced status epilepticus. The overexpression of obligate GluN1 subunit suggests an increase in the total number of NMDA receptors in the hippocampus. A 3-fold increase in the expression of the GluN2B subunit observed 24 h after PTZ-induced status epilepticus might be indicative of an increase in the proportion of GluN2B-containing NMDA receptors. Increased expression of the GluN2B subunit may be a cause for reducing the magnitude of LTP at hippocampal synapses after status epilepticus.

Synaptic plasticity in the hippocampal area CA1-subiculum projection: implications for theories of memory.

PubMed

O'Mara, S M; Commins, S; Anderson, M

2000-01-01

This paper reviews investigations of synaptic plasticity in the major, and underexplored, pathway from hippocampal area CA1 to the subiculum. This brain area is the major synaptic relay for the majority of hippocampal area CA1 neurons, making the subiculum the last relay of the hippocampal formation prior to the cortex. The subiculum thus has a very major role in mediating hippocampal-cortical interactions. We demonstrate that the projection from hippocampal area CA1 to the subiculum sustains plasticity on a number of levels. We show that this pathway is capable of undergoing both long-term potentiation (LTP) and paired-pulse facilitation (PPF, a short-term plastic effect). Although we failed to induce long-term depression (LTD) of this pathway with low-frequency stimulation (LFS) and two-pulse stimulation (TPS), both protocols can induce a "late-developing" potentiation of synaptic transmission. We further demonstrate that baseline synaptic transmission can be dissociated from paired-pulse stimulation of the same pathway; we also show that it is possible, using appropriate protocols, to change PPF to paired-pulse depression, thus revealing subtle and previously undescribed mechanisms which regulate short-term synaptic plasticity. Finally, we successfully recorded from individual subicular units in the freely-moving animal, and provide a description of the characteristics of such neurons in a pellet-chasing task. We discuss the implications of these findings in relation to theories of the biological consolidation of memory.

Long-Term, Fructose-Induced Metabolic Syndrome-Like Condition Is Associated with Higher Metabolism, Reduced Synaptic Plasticity and Cognitive Impairment in Octodon degus.

PubMed

Rivera, Daniela S; Lindsay, Carolina B; Codocedo, Juan F; Carreño, Laura E; Cabrera, Daniel; Arrese, Marco A; Vio, Carlos P; Bozinovic, Francisco; Inestrosa, Nibaldo C

2018-04-13

There has been a progressive increase in the incidence of fructose-induced metabolic disorders, such as metabolic syndrome (MetS). Moreover, novel evidence reported negative effects of high-fructose diets in brain function. This study was designed to evaluate for the first time the effects of long-term fructose consumption (LT-FC) on the normal ageing process in a long-lived animal model rodent, Octodon degus or degu. Moreover, we could replicate human sugar consumption behaviour over time, leading us to understand then the possible mechanisms by which this MetS-like condition could affect cognitive abilities. Our results support that 28 months (from pup to adulthood) of a 15% solution of fructose induced clinical conditions similar to MetS which includes an insulin-resistance scenario together with elevated basal metabolic rate and non-alcoholic fatty liver disease. Additionally, we extended our analysis to evaluate the impact of this MetS-like condition on the functional and cognitive brain processes. Behavioural test suggests that fructose-induced MetS-like condition impair hippocampal-dependent and independent memory performance. Moreover, we also reported several neuropathological events as impaired hippocampal redox balance, together with synaptic protein loss. These changes might be responsible for the alterations in synaptic plasticity and transmitter release observed in these cognitively impaired animals. Our results indicate that LT-FC induced several facets of MetS that eventually could trigger brain disorders, in particular, synaptic dysfunction and reduced cognition.

Long-term potentiation and depression after unilateral labyrinthectomy in the medial vestibular nucleus of rats.

PubMed

Pettorossi, Vito Enrico; Dutia, Mayank; Frondaroli, Adele; Dieni, Cristina; Grassi, Silvarosa

2003-01-01

We previously demonstrated in rat brainstem slices that high-frequency stimulation (HFS) of the vestibular afferents induces long-term potentiation (LTP) in the ventral part (Vp) of the medial vestibular nucleus (MVN) and long-term depression (LTD) in the dorsal part (Dp). Both LTP and LTD depend on N-methyl-D-aspartate receptor activation, which increases synaptic efficacy; however, in the Dp, LTP reverses to LTD because of the activation of gamma-aminobutyric acid-ergic neurons. Here we show that the probability of inducing long-term effects in the MVN of rat brainstem slices is altered after unilateral labyrinthectomy (UL). In fact, LTP occurs less frequently in the ventral contra-lesional side compared with sham-operated rats. In the dorsal ipsi-lesional side, LTD is reduced and LTP enhanced, while the opposite occurs in the dorsal contra-lesional side. These changes in synaptic plasticity may be useful for re-balancing the tonic discharge of the MVN of the two sides during vestibular compensation, and for enhancing the dynamic responses of the deafferented MVN neurons in the long term.

A single amino acid difference between the intracellular domains of amyloid precursor protein and amyloid-like precursor protein 2 enables induction of synaptic depression and block of long-term potentiation.

PubMed

Trillaud-Doppia, Emilie; Paradis-Isler, Nicolas; Boehm, Jannic

2016-07-01

Alzheimer disease (AD) is initially characterized as a disease of the synapse that affects synaptic transmission and synaptic plasticity. While amyloid-beta and tau have been traditionally implicated in causing AD, recent studies suggest that other factors, such as the intracellular domain of the amyloid-precursor protein (APP-ICD), can also play a role in the development of AD. Here, we show that the expression of APP-ICD induces synaptic depression, while the intracellular domain of its homolog amyloid-like precursor protein 2 (APLP2-ICD) does not. We are able to show that this effect by APP-ICD is due to a single alanine vs. proline difference between APP-ICD and APLP2-ICD. The alanine in APP-ICD and the proline in APLP2-ICD lie directly behind a conserved caspase cleavage site. Inhibition of caspase cleavage of APP-ICD prevents the induction of synaptic depression. Finally, we show that the expression of APP-ICD increases and facilitates long-term depression and blocks induction of long-term potentiation. The block in long-term potentiation can be overcome by mutating the aforementioned alanine in APP-ICD to the proline of APLP2. Based on our results, we propose the emergence of a new APP critical domain for the regulation of synaptic plasticity and in consequence for the development of AD. Copyright © 2016 Elsevier Inc. All rights reserved.

Synaptic long-term potentiation and depression in the rat medial vestibular nuclei depend on neural activation of estrogenic and androgenic signals.

PubMed

Scarduzio, Mariangela; Panichi, Roberto; Pettorossi, Vito Enrico; Grassi, Silvarosa

2013-01-01

Estrogenic and androgenic steroids can be synthesised in the brain and rapidly modulate synaptic transmission and plasticity through direct interaction with membrane receptors for estrogens (ERs) and androgens (ARs). We used whole cell patch clamp recordings in brainstem slices of male rats to explore the influence of ER and AR activation and local synthesis of 17β-estradiol (E2) and 5α-dihydrotestosterone (DHT) on the long-term synaptic changes induced in the neurons of the medial vestibular nucleus (MVN). Long-term depression (LTD) and long-term potentiation (LTP) caused by different patterns of high frequency stimulation (HFS) of the primary vestibular afferents were assayed under the blockade of ARs and ERs or in the presence of inhibitors for enzymes synthesizing DHT (5α-reductase) and E2 (P450-aromatase) from testosterone (T). We found that LTD is mediated by interaction of locally produced androgens with ARs and LTP by interaction of locally synthesized E2 with ERs. In fact, the AR block with flutamide prevented LTD while did not affect LTP, and the blockade of ERs with ICI 182,780 abolished LTP without influencing LTD. Moreover, the block of P450-aromatase with letrozole not only prevented the LTP induction, but inverted LTP into LTD. This LTD is likely due to the local activation of androgens, since it was abolished under blockade of ARs. Conversely, LTD was still induced in the presence of finasteride the inhibitor of 5α-reductase demonstrating that T is able to activate ARs and induce LTD even when DHT is not synthesized. This study demonstrates a key and opposite role of sex neurosteroids in the long-term synaptic changes of the MVN with a specific role of T-DHT for LTD and of E2 for LTP. Moreover, it suggests that different stimulation patterns can lead to LTD or LTP by specifically activating the enzymes involved in the synthesis of androgenic or estrogenic neurosteroids.

Group 1 mGluR-dependent synaptic long-term depression: mechanisms and implications for circuitry and disease.

PubMed

Lüscher, Christian; Huber, Kimberly M

2010-02-25

Many excitatory synapses express Group 1, or Gq coupled, metabotropic glutamate receptors (Gp1 mGluRs) at the periphery of their postsynaptic density. Activation of Gp1 mGluRs typically occurs in response to strong activity and triggers long-term plasticity of synaptic transmission in many brain regions, including the neocortex, hippocampus, midbrain, striatum, and cerebellum. Here we focus on mGluR-induced long-term synaptic depression (LTD) and review the literature that implicates Gp1 mGluRs in the plasticity of behavior, learning, and memory. Moreover, recent studies investigating the molecular mechanisms of mGluR-LTD have discovered links to mental retardation, autism, Alzheimer's disease, Parkinson's disease, and drug addiction. We discuss how mGluRs lead to plasticity of neural circuits and how the understanding of the molecular mechanisms of mGluR plasticity provides insight into brain disease.

Enhancement of synaptic transmission induced by BDNF in cultured cortical neurons

NASA Astrophysics Data System (ADS)

He, Jun; Gong, Hui; Zeng, Shaoqun; Li, Yanling; Luo, Qingming

2005-03-01

Brain-derived neurotrophic factor (BDNF), like other neurotrophins, has long-term effects on neuronal survival and differentiation; furthermore, BDNF has been reported to exert an acute potentiation of synaptic activity and are critically involved in long-term potentiation (LTP). We found that BDNF rapidly induced potentiation of synaptic activity and an increase in the intracellular Ca2+ concentration in cultured cortical neurons. Within minutes of BDNF application to cultured cortical neurons, spontaneous firing rate was dramatically increased as were the frequency and amplitude of excitatory spontaneous postsynaptic currents (EPSCs). Fura-2 recordings showed that BDNF acutely elicited an increase in intracellular calcium concentration ([Ca2+]c). This effect was partially dependent on [Ca2+]o; The BDNF-induced increase in [Ca2+]c can not be completely blocked by Ca2+-free solution. It was completely blocked by K252a and partially blocked by Cd2+ and TTX. The results demonstrate that BDNF can enhances synaptic transmission and that this effect is accompanied by a rise in [Ca2+]c that requires two route: the release of Ca2+ from intracellular calcium stores and influx of extracellular Ca2+ through voltage-dependent Ca2+ channels in cultured cortical neurons.

Postsynaptic N-type or P/Q-type calcium channels mediate long-term potentiation by group I metabotropic glutamate receptors in the trigeminal oralis.

PubMed

Weon, Haein; Kim, Tae Wan; Youn, Dong-Ho

2017-11-01

Both N-type and P/Q-type voltage-gated Ca 2+ channels (VGCCs) are involved in the induction of long-term potentiation (LTP), the long-lasting increase of synaptic strength, in the central nervous system. To provide further information on the roles of N-type and P/Q-type VGCCs in the induction of LTP at excitatory synapses of trigeminal primary afferents in the spinal trigeminal subnucleus oralis (Vo), we investigated whether they contribute to the induction of LTP by activation of group I metabotropic glutamate receptors (mGluRs). (S)-3,5-Dihydroxyphenylglycine (DHPG; 10μM for 5min), the group I mGluR agonist, was used to induce LTP of excitatory postsynaptic currents that were evoked in the Vo neurons by stimulating the trigeminal track. Weak blockade of the N-type or P/Q-type VGCCs by ω-conotoxin GVIA or ω-agatoxin IVA, respectively, which inhibited only 20-40% of Ca 2+ currents recorded in isolated trigeminal ganglion neurons but had no effect on the basal excitatory synaptic transmission, completely blocked the induction of LTP. In contrast, stronger blockade of the channels, which inhibited >50% of Ca 2+ currents and about 30% of basal synaptic transmission, resulted in the development of long-term depression (LTD), the long-lasting decrease of synaptic strength. Interestingly, the postsynaptic mechanism of DHPG-induced LTP, which was determined by paired-pulse ratio, disappeared when LTP was blocked, or LTD occurred, while a presynaptic mechanism still remained. Our data suggest that postsynaptic N-type and P/Q-type VGCCs mediate the DHPG-induced LTP at the trigeminal afferent synapses in the Vo. Copyright © 2017 Elsevier Inc. All rights reserved.

mGluR long-term depression regulates GluA2 association with COPII vesicles and exit from the endoplasmic reticulum.

PubMed

Pick, Joseph E; Khatri, Latika; Sathler, Matheus F; Ziff, Edward B

2017-01-17

mGluR long-term depression (mGluR-LTD) is a form of synaptic plasticity induced at excitatory synapses by metabotropic glutamate receptors (mGluRs). mGluR-LTD reduces synaptic strength and is relevant to learning and memory, autism, and sensitization to cocaine; however, the mechanism is not known. Here we show that activation of Group I mGluRs in medium spiny neurons induces trafficking of GluA2 from the endoplasmic reticulum (ER) to the synapse by enhancing GluA2 binding to essential COPII vesicle proteins, Sec23 and Sec13. GluA2 exit from the ER further depends on IP3 and Ryanodine receptor-controlled Ca 2+ release as well as active translation. Synaptic insertion of GluA2 is coupled to removal of high-conducting Ca 2+ -permeable AMPA receptors from synapses, resulting in synaptic depression. This work demonstrates a novel mechanism in which mGluR signals release AMPA receptors rapidly from the ER and couple ER release to GluA2 synaptic insertion and GluA1 removal. © 2016 The Authors.

Glutamate Receptor GluA1 Subunit Is Implicated in Capsaicin Induced Modulation of Amygdala LTP but Not LTD

ERIC Educational Resources Information Center

Gebhardt, Christine; Albrecht, Doris

2018-01-01

Capsaicin has been shown to modulate synaptic plasticity in various brain regions including the amygdala. Whereas in the lateral amygdala the modulatory effect of capsaicin on long-term potentiation (LA-LTP) is mediated by TRPV1 channels, we have recently shown that capsaicin-induced enhancement of long term depression (LA-LTD) is mediated by…

TBI-Induced Formation of Toxic Tau and Its Biochemical Similarities to Tau in AD Brains

DTIC Science & Technology

2016-10-01

onto wild-type mice markedly reduces 1) memory including contextual fear memory and spatial memory, and 2) long-term potentiation, a type of...TERMS Tau, contextual fear memory, spatial memory, synaptic plasticity, traumatic brain injury, Alzheimer’s disease 16. SECURITY CLASSIFICATION OF: 17...mechanism leading to TBI and AD. 2 KEYWORDS Tau, contextual fear memory, spatial memory, synaptic plasticity, traumatic brain injury, Alzheimer’s

Characterization of stress-induced suppression of long-term potentiation in the hippocampal CA1 field of freely moving rats.

PubMed

Hirata, Riki; Togashi, Hiroko; Matsumoto, Machiko; Yamaguchi, Taku; Izumi, Takeshi; Yoshioka, Mitsuhiro

2008-08-21

Several lines of evidence have shown that exposure to stress impairs long-term potentiation (LTP) in the CA1 field of the hippocampus, but the detailed mechanisms for this effect remain to be clarified. The present study elucidated the synaptic mechanism of stress-induced LTP suppression in conscious, freely moving rats using electrophysiological approaches. Open field stress (i.e., novel environment stress) and elevated platform stress (i.e., uncontrollable stress) were employed. Basal synaptic transmission was significantly reduced during exposure to elevated platform stress but not during exposure to open field stress. LTP induction was blocked by elevated platform stress but not influenced by open field stress. Significant increases in serum corticosterone levels were observed in the elevated platform stress group compared with the open field stress group. Furthermore, LTP suppression induced by elevated platform stress was prevented by pretreatment with an anxiolytic drug diazepam (1 mg/kg, i.p.). These results suggest that stress-induced LTP suppression depends on the relative intensity of the stressor. The inhibitory synaptic response induced by an intense psychological stress, such as elevated platform stress, may be attributable to LTP impairment in the CA1 field of the hippocampus.

Levodopa-induced plasticity: a double-edged sword in Parkinson's disease?

PubMed Central

Calabresi, Paolo; Ghiglieri, Veronica; Mazzocchetti, Petra; Corbelli, Ilenia; Picconi, Barbara

2015-01-01

The long-term replacement therapy with the dopamine (DA) precursor 3,4-dihydroxy-l-phenylalanine (L-DOPA) is a milestone in the treatment of Parkinson's disease (PD). Although this drug precursor can be metabolized into the active neurotransmitter DA throughout the brain, its therapeutic benefit is due to restoring extracellular DA levels within the dorsal striatum, which lacks endogenous DA as a consequence of the neurodegenerative process induced by the disease. In the early phases of PD, L-DOPA treatment is able to restore both long-term depression (LTD) and long-term potentiation (LTP), two major forms of corticostriatal synaptic plasticity that are altered by dopaminergic denervation. However, unlike physiological DA transmission, this therapeutic approach in the advanced phase of the disease leads to abnormal peaks of DA, non-synaptically released, which are supposed to trigger behavioural sensitization, namely L-DOPA-induced dyskinesia. This condition is characterized by a loss of synaptic depotentiation, an inability to reverse previously induced LTP. In the advanced stages of PD, L-DOPA can also induce non-motor fluctuations with cognitive dysfunction and neuropsychiatric symptoms such as compulsive behaviours and impulse control disorders. Although the mechanisms underlying the role of L-DOPA in both motor and behavioural symptoms are still incompletely understood, recent data from electrophysiological and imaging studies have increased our understanding of the function of the brain areas involved and of the mechanisms implicated in both therapeutic and adverse actions of L-DOPA in PD patients. PMID:26009763

Activation of Muscarinic M1 Acetylcholine Receptors Induces Long-Term Potentiation in the Hippocampus

PubMed Central

Dennis, Siobhan H.; Pasqui, Francesca; Colvin, Ellen M.; Sanger, Helen; Mogg, Adrian J.; Felder, Christian C.; Broad, Lisa M.; Fitzjohn, Steve M.; Isaac, John T.R.; Mellor, Jack R.

2016-01-01

Muscarinic M1 acetylcholine receptors (M1Rs) are highly expressed in the hippocampus, and their inhibition or ablation disrupts the encoding of spatial memory. It has been hypothesized that the principal mechanism by which M1Rs influence spatial memory is by the regulation of hippocampal synaptic plasticity. Here, we use a combination of recently developed, well characterized, selective M1R agonists and M1R knock-out mice to define the roles of M1Rs in the regulation of hippocampal neuronal and synaptic function. We confirm that M1R activation increases input resistance and depolarizes hippocampal CA1 pyramidal neurons and show that this profoundly increases excitatory postsynaptic potential-spike coupling. Consistent with a critical role for M1Rs in synaptic plasticity, we now show that M1R activation produces a robust potentiation of glutamatergic synaptic transmission onto CA1 pyramidal neurons that has all the hallmarks of long-term potentiation (LTP): The potentiation requires NMDA receptor activity and bi-directionally occludes with synaptically induced LTP. Thus, we describe synergistic mechanisms by which acetylcholine acting through M1Rs excites CA1 pyramidal neurons and induces LTP, to profoundly increase activation of CA1 pyramidal neurons. These features are predicted to make a major contribution to the pro-cognitive effects of cholinergic transmission in rodents and humans. PMID:26472558

Effects of long-term salicylate administration on synaptic ultrastructure and metabolic activity in the rat CNS

PubMed Central

Yi, Bin; Hu, Shousen; Zuo, Chuantao; Jiao, Fangyang; Lv, Jingrong; Chen, Dongye; Ma, Yufei; Chen, Jianyong; Mei, Ling; Wang, Xueling; Huang, Zhiwu; Wu, Hao

2016-01-01

Tinnitus is associated with neural hyperactivity in the central nervous system (CNS). Salicylate is a well-known ototoxic drug, and we induced tinnitus in rats using a model of long-term salicylate administration. The gap pre-pulse inhibition of acoustic startle test was used to infer tinnitus perception, and only rats in the chronic salicylate-treatment (14 days) group showed evidence of experiencing tinnitus. After small animal positron emission tomography scans were performed, we found that the metabolic activity of the inferior colliculus (IC), the auditory cortex (AC), and the hippocampus (HP) were significantly higher in the chronic treatment group compared with saline group (treated for 14 days), which was further supported by ultrastructural changes at the synapses. The alterations all returned to baseline 14 days after the cessation of salicylate-treatment (wash-out group), indicating that these changes were reversible. These findings indicate that long-term salicylate administration induces tinnitus, enhanced neural activity and synaptic ultrastructural changes in the IC, AC, and HP of rats due to neuroplasticity. Thus, an increased metabolic rate and synaptic transmission in specific areas of the CNS may contribute to the development of tinnitus. PMID:27068004

Structural synaptic plasticity in the hippocampus induced by spatial experience and its implications in information processing.

PubMed

Carasatorre, M; Ramírez-Amaya, V; Díaz Cintra, S

2016-10-01

Long-lasting memory formation requires that groups of neurons processing new information develop the ability to reproduce the patterns of neural activity acquired by experience. Changes in synaptic efficiency let neurons organise to form ensembles that repeat certain activity patterns again and again. Among other changes in synaptic plasticity, structural modifications tend to be long-lasting which suggests that they underlie long-term memory. There is a large body of evidence supporting that experience promotes changes in the synaptic structure, particularly in the hippocampus. Structural changes to the hippocampus may be functionally implicated in stabilising acquired memories and encoding new information. Copyright © 2012 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

A synaptic device built in one diode-one resistor (1D-1R) architecture with intrinsic SiOx-based resistive switching memory

NASA Astrophysics Data System (ADS)

Chang, Yao-Feng; Fowler, Burt; Chen, Ying-Chen; Zhou, Fei; Pan, Chih-Hung; Chang, Kuan-Chang; Tsai, Tsung-Ming; Chang, Ting-Chang; Sze, Simon M.; Lee, Jack C.

2016-04-01

We realize a device with biological synaptic behaviors by integrating silicon oxide (SiOx) resistive switching memory with Si diodes to further minimize total synaptic power consumption due to sneak-path currents and demonstrate the capability for spike-induced synaptic behaviors, representing critical milestones for the use of SiO2-based materials in future neuromorphic computing applications. Biological synaptic behaviors such as long-term potentiation, long-term depression, and spike-timing dependent plasticity are demonstrated systemically with comprehensive investigation of spike waveform analyses and represent a potential application for SiOx-based resistive switching materials. The resistive switching SET transition is modeled as hydrogen (proton) release from the (SiH)2 defect to generate the hydrogenbridge defect, and the RESET transition is modeled as an electrochemical reaction (proton capture) that re-forms (SiH)2. The experimental results suggest a simple, robust approach to realize programmable neuromorphic chips compatible with largescale complementary metal-oxide semiconductor manufacturing technology.

Contributions of Bcl-xL to acute and long term changes in bioenergetics during neuronal plasticity.

PubMed

Jonas, Elizabeth A

2014-08-01

Mitochondria manufacture and release metabolites and manage calcium during neuronal activity and synaptic transmission, but whether long term alterations in mitochondrial function contribute to the neuronal plasticity underlying changes in organism behavior patterns is still poorly understood. Although normal neuronal plasticity may determine learning, in contrast a persistent decline in synaptic strength or neuronal excitability may portend neurite retraction and eventual somatic death. Anti-death proteins such as Bcl-xL not only provide neuroprotection at the neuronal soma during cell death stimuli, but also appear to enhance neurotransmitter release and synaptic growth and development. It is proposed that Bcl-xL performs these functions through its ability to regulate mitochondrial release of bioenergetic metabolites and calcium, and through its ability to rapidly alter mitochondrial positioning and morphology. Bcl-xL also interacts with proteins that directly alter synaptic vesicle recycling. Bcl-xL translocates acutely to sub-cellular membranes during neuronal activity to achieve changes in synaptic efficacy. After stressful stimuli, pro-apoptotic cleaved delta N Bcl-xL (ΔN Bcl-xL) induces mitochondrial ion channel activity leading to synaptic depression and this is regulated by caspase activation. During physiological states of decreased synaptic stimulation, loss of mitochondrial Bcl-xL and low level caspase activation occur prior to the onset of long term decline in synaptic efficacy. The degree to which Bcl-xL changes mitochondrial membrane permeability may control the direction of change in synaptic strength. The small molecule Bcl-xL inhibitor ABT-737 has been useful in defining the role of Bcl-xL in synaptic processes. Bcl-xL is crucial to the normal health of neurons and synapses and its malfunction may contribute to neurodegenerative disease. Copyright © 2013. Published by Elsevier B.V.

Long-term modifications of synaptic efficacy in the human inferior and middle temporal cortex

NASA Technical Reports Server (NTRS)

Chen, W. R.; Lee, S.; Kato, K.; Spencer, D. D.; Shepherd, G. M.; Williamson, A.

1996-01-01

The primate temporal cortex has been demonstrated to play an important role in visual memory and pattern recognition. It is of particular interest to investigate whether activity-dependent modification of synaptic efficacy, a presumptive mechanism for learning and memory, is present in this cortical region. Here we address this issue by examining the induction of synaptic plasticity in surgically resected human inferior and middle temporal cortex. The results show that synaptic strength in the human temporal cortex could undergo bidirectional modifications, depending on the pattern of conditioning stimulation. High frequency stimulation (100 or 40 Hz) in layer IV induced long-term potentiation (LTP) of both intracellular excitatory postsynaptic potentials and evoked field potentials in layers II/III. The LTP induced by 100 Hz tetanus was blocked by 50-100 microM DL-2-amino-5-phosphonovaleric acid, suggesting that N-methyl-D-aspartate receptors were responsible for its induction. Long-term depression (LTD) was elicited by prolonged low frequency stimulation (1 Hz, 15 min). It was reduced, but not completely blocked, by DL-2-amino-5-phosphonovaleric acid, implying that some other mechanisms in addition to N-methyl-DL-aspartate receptors were involved in LTD induction. LTD was input-specific, i.e., low frequency stimulation of one pathway produced LTD of synaptic transmission in that pathway only. Finally, the LTP and LTD could reverse each other, suggesting that they can act cooperatively to modify the functional state of cortical network. These results suggest that LTP and LTD are possible mechanisms for the visual memory and pattern recognition functions performed in the human temporal cortex.

Neo-synthesis of estrogenic or androgenic neurosteroids determine whether long-term potentiation or depression is induced in hippocampus of male rat.

PubMed

Di Mauro, Michela; Tozzi, Alessandro; Calabresi, Paolo; Pettorossi, Vito Enrico; Grassi, Silvarosa

2015-01-01

Estrogenic and androgenic steroids synthesized in the brain may rapidly modulate synaptic plasticity interacting with specific membrane receptors. We explored by electrophysiological recordings in hippocampal slices of male rat the influence of 17β-estradiol (E2) and 5α-dihydrotestosterone (DHT) neo-synthesis on the synaptic changes induced in the CA1 region. Induction of long-term depression (LTD) and depotentiation (DP) by low frequency stimulation (LFS, 15 min-1 Hz) and of long-term potentiation (LTP) by high frequency stimulation (HFS, 1 s-100 Hz), medium (MFS, 1 s-50 Hz), or weak (WFS, 1 s-25 Hz) frequency stimulation was assayed under inhibitors of enzymes converting testosterone (T) into DHT (5α-reductase) and T into E2 (P450-aromatase). We found that LFS-LTD depends on DHT synthesis, since it was fully prevented under finasteride, an inhibitor of DHT synthesis, and rescued by exogenous DHT, while the E2 synthesis was not involved. Conversely, the full development of HFS-LTP requires the synthesis of E2, as demonstrated by the LTP reduction observed under letrozole, an inhibitor of E2 synthesis, and its full rescue by exogenous E2. For intermediate stimulation protocols DHT, but not E2 synthesis, was involved in the production of a small LTP induced by WFS, while the E2 synthesis was required for the MFS-dependent LTP. Under the combined block of DHT and E2 synthesis all stimulation frequencies induced partial LTP. Overall, these results indicate that DHT is required for converting the partial LTP into LTD whereas E2 is needed for the full expression of LTP, evidencing a key role of the neo-synthesis of sex neurosteroids in determining the direction of synaptic long-term effects.

Zif268/Egr1 gain of function facilitates hippocampal synaptic plasticity and long-term spatial recognition memory.

PubMed

Penke, Zsuzsa; Morice, Elise; Veyrac, Alexandra; Gros, Alexandra; Chagneau, Carine; LeBlanc, Pascale; Samson, Nathalie; Baumgärtel, Karsten; Mansuy, Isabelle M; Davis, Sabrina; Laroche, Serge

2014-01-05

It is well established that Zif268/Egr1, a member of the Egr family of transcription factors, is critical for the consolidation of several forms of memory; however, it is as yet uncertain whether increasing expression of Zif268 in neurons can facilitate memory formation. Here, we used an inducible transgenic mouse model to specifically induce Zif268 overexpression in forebrain neurons and examined the effect on recognition memory and hippocampal synaptic transmission and plasticity. We found that Zif268 overexpression during the establishment of memory for objects did not change the ability to form a long-term memory of objects, but enhanced the capacity to form a long-term memory of the spatial location of objects. This enhancement was paralleled by increased long-term potentiation in the dentate gyrus of the hippocampus and by increased activity-dependent expression of Zif268 and selected Zif268 target genes. These results provide novel evidence that transcriptional mechanisms engaging Zif268 contribute to determining the strength of newly encoded memories.

Bidirectional modulation of hippocampal synaptic plasticity by Dopaminergic D4-receptors in the CA1 area of hippocampus.

PubMed

Navakkode, Sheeja; Chew, Katherine C M; Tay, Sabrina Jia Ning; Lin, Qingshu; Behnisch, Thomas; Soong, Tuck Wah

2017-11-14

Long-term potentiation (LTP) is the persistent increase in the strength of the synapses. However, the neural networks would become saturated if there is only synaptic strenghthening. Synaptic weakening could be facilitated by active processes like long-term depression (LTD). Molecular mechanisms that facilitate the weakening of synapses and thereby stabilize the synapses are also important in learning and memory. Here we show that blockade of dopaminergic D4 receptors (D4R) promoted the formation of late-LTP and transformed early-LTP into late-LTP. This effect was dependent on protein synthesis, activation of NMDA-receptors and CaMKII. We also show that GABA A -receptor mediated mechanisms are involved in the enhancement of late-LTP. We could show that short-term plasticity and baseline synaptic transmission were unaffected by D4R inhibition. On the other hand, antagonizing D4R prevented both early and late forms of LTD, showing that activation of D4Rs triggered a dual function. Synaptic tagging experiments on LTD showed that D4Rs act as plasticity related proteins rather than the setting of synaptic tags. D4R activation by PD 168077 induced a slow-onset depression that was protein synthesis, NMDAR and CaMKII dependent. The D4 receptors, thus exert a bidirectional modulation of CA1 pyramidal neurons by restricting synaptic strengthening and facilitating synaptic weakening.

Possible relationship between the stress-induced synaptic response and metaplasticity in the hippocampal CA1 field of freely moving rats.

PubMed

Hirata, Riki; Matsumoto, Machiko; Judo, Chika; Yamaguchi, Taku; Izumi, Takeshi; Yoshioka, Mitsuhiro; Togashi, Hiroko

2009-07-01

Hippocampal long-term potentiation (LTP) is suppressed not only by stress paradigms but also by low frequency stimulation (LFS) prior to LTP-inducing high frequency stimulation (HFS; tetanus), termed metaplasticity. These synaptic responses are dependent on N-methyl-D-aspartate receptors, leading to speculations about the possible relationship between metaplasticity and stress-induced LTP impairment. However, the functional significance of metaplasticity has been unclear. The present study elucidated the electrophysiological and neurochemical profiles of metaplasticity in the hippocampal CA1 field, with a focus on the synaptic response induced by the emotional stress, contextual fear conditioning (CFC). The population spike amplitude in the CA1 field was decreased during exposure to CFC, and LTP induction was suppressed after CFC in conscious rats. The synaptic response induced by CFC was mimicked by LFS, i.e., LFS impaired the synaptic transmission and subsequent LTP. Plasma corticosterone levels were increased by both CFC and LFS. Extracellular levels of gamma-aminobutyric acid (GABA), but not glutamate, in the hippocampus increased during exposure to CFC or LFS. Furthermore, electrical stimulation of the medial prefrontal cortex (mPFC), which caused decreases in freezing behavior during exposure to CFC, counteracted the LTP impairment induced by LFS. These findings suggest that metaplasticity in the rat hippocampal CA1 field is related to the neural basis of stress experience-dependent fear memory, and that hippocampal synaptic response associated stress-related processes is under mPFC regulation.

Synaptic Impairment in Layer 1 of the Prefrontal Cortex Induced by Repeated Stress During Adolescence is Reversed in Adulthood

PubMed Central

Negrón-Oyarzo, Ignacio; Dagnino-Subiabre, Alexies; Muñoz Carvajal, Pablo

2015-01-01

Chronic stress is a risk factor for the development of psychiatric disorders, some of which involve dysfunction of the prefrontal cortex (PFC). There is a higher prevalence of these chronic stress-related psychiatric disorders during adolescence, when the PFC has not yet fully matured. In the present work we studied the effect of repeated stress during adolescence on synaptic function in the PFC in adolescence and adulthood. To this end, adolescent Sprague-Dawley rats were subjected to seven consecutive days of restraint stress. Afterward, both synaptic transmission and short- and long-term synaptic plasticity were evaluated in layer 1 of medial-PFC (mPFC) slices from adolescent and adult rats. We found that repeated stress significantly reduced the amplitude of evoked field excitatory post-synaptic potential (fEPSP) in the mPFC. Isolation of excitatory transmission reveled that lower-amplitude fEPSPs were associated with a reduction in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated transmission. We also found that repeated stress significantly decreased long-term depression (LTD). Interestingly, AMPA/kainate receptor-mediated transmission and LTD were recovered in adult animals that experienced a three-week stress-free recovery period. The data indicates that the changes in synaptic transmission and plasticity in the mPFC induced by repeated stress during adolescence are reversed in adulthood after a stress-free period. PMID:26617490

Synaptic Impairment in Layer 1 of the Prefrontal Cortex Induced by Repeated Stress During Adolescence is Reversed in Adulthood.

PubMed

Negrón-Oyarzo, Ignacio; Dagnino-Subiabre, Alexies; Muñoz Carvajal, Pablo

2015-01-01

Chronic stress is a risk factor for the development of psychiatric disorders, some of which involve dysfunction of the prefrontal cortex (PFC). There is a higher prevalence of these chronic stress-related psychiatric disorders during adolescence, when the PFC has not yet fully matured. In the present work we studied the effect of repeated stress during adolescence on synaptic function in the PFC in adolescence and adulthood. To this end, adolescent Sprague-Dawley rats were subjected to seven consecutive days of restraint stress. Afterward, both synaptic transmission and short- and long-term synaptic plasticity were evaluated in layer 1 of medial-PFC (mPFC) slices from adolescent and adult rats. We found that repeated stress significantly reduced the amplitude of evoked field excitatory post-synaptic potential (fEPSP) in the mPFC. Isolation of excitatory transmission reveled that lower-amplitude fEPSPs were associated with a reduction in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated transmission. We also found that repeated stress significantly decreased long-term depression (LTD). Interestingly, AMPA/kainate receptor-mediated transmission and LTD were recovered in adult animals that experienced a three-week stress-free recovery period. The data indicates that the changes in synaptic transmission and plasticity in the mPFC induced by repeated stress during adolescence are reversed in adulthood after a stress-free period.

Low-frequency stimulation cancels the high-frequency-induced long-lasting effects in the rat medial vestibular nuclei.

PubMed

Grassi, S; Pettorossi, V E; Zampolini, M

1996-05-15

In rat brainstem slices, we investigated the effects of low-frequency stimulation (LFS) of the primary vestibular afferents on the amplitude of the field potentials evoked in the medial vestibular nuclei (MVN). LFS induced long-term effects, the sign of which depended on whether the vestibular neurons were previously conditioned by HFS. In unconditioned slices, LFS evoked modifications of the responses that were similar to those observed after HFS but had a smaller extension. In fact, LFS caused long-lasting potentiation of the N1 wave in the MVN ventral portion (Vp) and long-lasting depression of the N2 wave in the MVN dorsal portion (Dp), whereas it provoked small and variable effects on the N1 wave. By contrast, when the synaptic transmission was already conditioned, LFS influenced the synaptic responses oppositely, reducing or annulling the HFS long-term effects. This phenomenon was specifically induced by LFS, because HFS was not able to cause it. The involvement of NMDA receptors in mediating the LFS long-term effects was supported by the fact that AP-5 prevented their induction. In addition, the annulment of HFS long-term effects by LFS was also demonstrated by the shift in the latency of the evoked unitary potentials after LFS. In conclusion, we suggest that the reduction of the previously induced conditioning could represent a cancellation mechanism, useful to quickly adapt the vestibular system to continuous different needs and to avoid saturation.

Synaptic depression in the CA1 region of freely behaving mice is highly dependent on afferent stimulation parameters

PubMed Central

Goh, Jinzhong J.; Manahan-Vaughan, Denise

2012-01-01

Persistent synaptic plasticity has been subjected to intense study in the decades since it was first described. Occurring in the form of long-term potentiation (LTP) and long-term depression (LTD), it shares many cellular and molecular properties with hippocampus-dependent forms of persistent memory. Recent reports of both LTP and LTD occurring endogenously under specific learning conditions provide further support that these forms of synaptic plasticity may comprise the cellular correlates of memory. Most studies of synaptic plasticity are performed using in vitro or in vivo preparations where patterned electrical stimulation of afferent fibers is implemented to induce changes in synaptic strength. This strategy has proven very effective in inducing LTP, even under in vivo conditions. LTD in vivo has proven more elusive: although LTD occurs endogenously under specific learning conditions in both rats and mice, its induction has not been successfully demonstrated with afferent electrical stimulation alone. In this study we screened a large spectrum of protocols that are known to induce LTD either in hippocampal slices or in the intact rat hippocampus, to clarify if LTD can be induced by sole afferent stimulation in the mouse CA1 region in vivo. Low frequency stimulation at 1, 2, 3, 5, 7, or 10 Hz given in the range of 100 through 1800 pulses produced, at best, short-term depression (STD) that lasted for up to 60 min. Varying the administration pattern of the stimuli (e.g., 900 pulses given twice at 5 min intervals), or changing the stimulation intensity did not improve the persistency of synaptic depression. LTD that lasts for at least 24 h occurs under learning conditions in mice. We conclude that a coincidence of factors, such as afferent activity together with neuromodulatory inputs, play a decisive role in the enablement of LTD under more naturalistic (e.g., learning) conditions. PMID:23355815

Effects of metabotropic glutamate receptor block on the synaptic transmission and plasticity in the rat medial vestibular nuclei.

PubMed

Grassi, S; Malfagia, C; Pettorossi, V E

1998-11-01

In rat brainstem slices, we investigated the possible role of metabotropic glutamate receptors in modulating the synaptic transmission within the medial vestibular nuclei, under basal and plasticity inducing conditions. We analysed the effect of the metabotropic glutamate receptor antagonist (R,S)-alpha-methyl-4-carboxyphenylglycine on the amplitude of the field potentials and latency of unitary potentials evoked in the ventral portion of the medial vestibular nuclei by primary vestibular afferent stimulation, and on the induction and maintenance of long-term potentiation, after high-frequency stimulation. Two effects were observed, consisting of a slight increase of the field potentials and reduction of unit latency during the drug infusion, and a further long-lasting development of these modifications after the drug wash-out. The long-term effect depended on N-methyl-D-aspartate receptor activation, as D,L-2-amino-5-phosphonopentanoic acid prevented its development. We suggest that (R,S)-alpha-methyl-4carboxyphenylglycine enhances the vestibular responses and induces N-methyl-D-aspartate-dependent long-term potentiation by increasing glutamate release, through the block of presynaptic metabotropic glutamate receptors which actively inhibit it. The block of these receptors was indirectly supported by the fact that the agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid reduced the vestibular responses and blocked the induction of long-term potentiation by high-frequency stimulation. The simultaneous block of metabotropic glutamate receptors facilitating synaptic plasticity, impedes the full expression of the long-term effect throughout the (R,S)-alpha-methyl-4-carboxyphenylglycine infusion. The involvement of such a facilitatory mechanism in the potentiation is supported by its reversible reduction following a second (R,S)-alpha-methyl-4-carboxyphenylglycine infusion. The drug also reduced the expression of potentiation induced by high-frequency stimulation. Conversely the electrical long-term potentiation was still induced, but it was occluded by the previous drug potentiation. We conclude that metabotropic glutamate receptors play a dual functional role in the medial vestibular nuclei, consisting in the inhibition of glutamate release under basal conditions, and the facilitation of N-methyl-D-aspartate-dependent plasticity phenomena.

Locus Coeruleus Stimulation Facilitates Long-Term Depression in the Dentate Gyrus That Requires Activation of β-Adrenergic Receptors

PubMed Central

Hansen, Niels; Manahan-Vaughan, Denise

2015-01-01

Synaptic plasticity comprises a cellular mechanism through which the hippocampus most likely enables memory formation. Neuromodulation, related to arousal, is a key aspect in information storage. The activation of locus coeruleus (LC) neurons by novel experience leads to noradrenaline release in the hippocampus at the level of the dentate gyrus (DG). We explored whether synaptic plasticity in the DG is influenced by activation of the LC via electrical stimulation. Coupling of test-pulses that evoked stable basal synaptic transmission in the DG with stimulation of the LC induced β-adrenoreceptor-dependent long-term depression (LTD) at perforant path–DG synapses in adult rats. Furthermore, persistent LTD (>24 h) induced by perforant path stimulation also required activation of β-adrenergic receptors: Whereas a β-adrenergic receptor antagonist (propranolol) prevented, an agonist (isoproterenol) strengthened the persistence of LTD for over 24 h. These findings support the hypothesis that persistent LTD in the DG is modulated by β-adrenergic receptors. Furthermore, LC activation potently facilitates DG LTD. This suggests in turn that synaptic plasticity in the DG is tightly regulated by activity in the noradrenergic system. This may reflect the role of the LC in selecting salient information for subsequent synaptic processing in the hippocampus. PMID:24464942

Critical Role of Endoplasmic Reticulum Stress in Chronic Intermittent Hypoxia-Induced Deficits in Synaptic Plasticity and Long-Term Memory

PubMed Central

Xu, Lin-Hao; Xie, Hui; Shi, Zhi-Hui; Du, Li-Da; Wing, Yun-Kwok; Li, Albert M.

2015-01-01

Abstract Aims: This study examined the role of endoplasmic reticulum (ER) stress in mediating chronic intermittent hypoxia (IH)-induced neurocognitive deficits. We designed experiments to demonstrate that ER stress is initiated in the hippocampus under chronic IH and determined its role in apoptotic cell death, impaired synaptic structure and plasticity, and memory deficits. Results: Two weeks of IH disrupted ER fine structure and upregulated ER stress markers, glucose-regulated protein 78, caspase-12, and C/EBP homologous protein, in the hippocampus, which could be suppressed by ER stress inhibitors, tauroursodeoxycholic acid (TUDCA) and 4-phenylbutyric acid. Meanwhile, ER stress induced apoptosis via decreased Bcl-2, promoted reactive oxygen species production, and increased malondialdehyde formation and protein carbonyl, as well as suppressed mitochondrial function. These effects were largely prevented by ER stress inhibitors. On the other hand, suppression of oxidative stress could reduce ER stress. In addition, the length of the synaptic active zone and number of mature spines were reduced by IH. Long-term recognition memory and spatial memory were also impaired, which was accompanied by reduced long-term potentiation in the Schaffer collateral pathway. These effects were prevented by coadministration of the TUDCA. Innovation and Conclusion: These results show that ER stress plays a critical role in underlying memory deficits in obstructive sleep apnea (OSA)-associated IH. Attenuators of ER stress may serve as novel adjunct therapeutic agents for ameliorating OSA-induced neurocognitive impairment. Antioxid. Redox Signal. 23, 695–710. PMID:25843188

Group 1 mGluR-dependent synaptic long-term depression (mGluR-LTD): mechanisms and implications for circuitry & disease

PubMed Central

Lüscher, Christian; Huber, Kimberly M.

2010-01-01

Many excitatory synapses express Group 1, or Gq coupled, metabotropic glutamate receptors (Gp1 mGluRs) at the periphery of their postsynaptic density. Activation of Gp1 mGluRs typically occurs in response to strong activity and triggers long-term plasticity of synaptic transmission in many brain regions including the neocortex, hippocampus, midbrain, striatum and cerebellum. Here we focus on mGluR-induced long-term synaptic depression (LTD) and review the literature that implicates Gp1 mGluRs in the plasticity of behavior, learning and memory. Moreover, recent studies investigating the molecular mechanisms of mGluR-LTD have discovered links to mental retardation, autism, Alzheimer’s disease, Parkinson’s disease and drug addiction. We discuss how mGluRs lead to plasticity of neural circuits and how the understanding of the molecular mechanisms of mGluR plasticity provides insight into brain disease. PMID:20188650

Cyclic estrogenic fluctuation influences synaptic transmission of the medial vestibular nuclei in female rats.

PubMed

Pettorossi, Vito E; Frondaroli, Adele; Grassi, Silvarosa

2011-04-01

The estrous cycle in female rats influences the basal synaptic responsiveness and plasticity of the medial vestibular nucleus (MVN) neurons through different levels of circulating 17β-estradiol (cE(2)). The aim of this study was to verify, in the female rat, whether cyclic fluctuations of cE(2) influence long-term synaptic effects induced by high frequency afferent stimulation (HFS) in the MVN, since we found that HFS in the male rat induces fast long-term potentiation (fLTP), which depends on the neural synthesis of E(2) (nE(2)) from testosterone (T). We analyzed the field potential (FP) evoked in the MVN by vestibular afferent stimulation, under basal conditions, and after HFS, in brainstem slices of female rats during high levels (proestrus, PE) and low levels (diestrus, DE) of cE(2). Selective blocking agents of converting T enzymes were used. Unlike in the male rat, HFS induced three effects: fLTP through T conversion into E(2), and slow LTP (sLTP) and long-term depression (LTD), through T conversion into DHT. The occurrence of these effects depended on the estrous cycle phase: the frequency of fLTP was higher in DE, and those of sLTP and LTD were higher in PE. Conversely, the basal FP was also higher in PE than in DE.

Effects of Lipoic Acid on High-Fat Diet-Induced Alteration of Synaptic Plasticity and Brain Glucose Metabolism: A PET/CT and 13C-NMR Study.

PubMed

Liu, Zhigang; Patil, Ishan; Sancheti, Harsh; Yin, Fei; Cadenas, Enrique

2017-07-14

High-fat diet (HFD)-induced obesity is accompanied by insulin resistance and compromised brain synaptic plasticity through the impairment of insulin-sensitive pathways regulating neuronal survival, learning, and memory. Lipoic acid is known to modulate the redox status of the cell and has insulin mimetic effects. This study was aimed at determining the effects of dietary administration of lipoic acid on a HFD-induced obesity model in terms of (a) insulin signaling, (b) brain glucose uptake and neuronal- and astrocytic metabolism, and (c) synaptic plasticity. 3-Month old C57BL/6J mice were divided into 4 groups exposed to their respective treatments for 9 weeks: (1) normal diet, (2) normal diet plus lipoic acid, (3) HFD, and (4) HFD plus lipoic acid. HFD resulted in higher body weight, development of insulin resistance, lower brain glucose uptake and glucose transporters, alterations in glycolytic and acetate metabolism in neurons and astrocytes, and ultimately synaptic plasticity loss evident by a decreased long-term potentiation (LTP). Lipoic acid treatment in mice on HFD prevented several HFD-induced metabolic changes and preserved synaptic plasticity. The metabolic and physiological changes in HFD-fed mice, including insulin resistance, brain glucose uptake and metabolism, and synaptic function, could be preserved by the insulin-like effect of lipoic acid.

Synaptic Long-Term Potentiation and Depression in the Rat Medial Vestibular Nuclei Depend on Neural Activation of Estrogenic and Androgenic Signals

PubMed Central

Scarduzio, Mariangela; Panichi, Roberto; Pettorossi, Vito Enrico; Grassi, Silvarosa

2013-01-01

Estrogenic and androgenic steroids can be synthesised in the brain and rapidly modulate synaptic transmission and plasticity through direct interaction with membrane receptors for estrogens (ERs) and androgens (ARs). We used whole cell patch clamp recordings in brainstem slices of male rats to explore the influence of ER and AR activation and local synthesis of 17β-estradiol (E2) and 5α-dihydrotestosterone (DHT) on the long-term synaptic changes induced in the neurons of the medial vestibular nucleus (MVN). Long-term depression (LTD) and long-term potentiation (LTP) caused by different patterns of high frequency stimulation (HFS) of the primary vestibular afferents were assayed under the blockade of ARs and ERs or in the presence of inhibitors for enzymes synthesizing DHT (5α-reductase) and E2 (P450-aromatase) from testosterone (T). We found that LTD is mediated by interaction of locally produced androgens with ARs and LTP by interaction of locally synthesized E2 with ERs. In fact, the AR block with flutamide prevented LTD while did not affect LTP, and the blockade of ERs with ICI 182,780 abolished LTP without influencing LTD. Moreover, the block of P450-aromatase with letrozole not only prevented the LTP induction, but inverted LTP into LTD. This LTD is likely due to the local activation of androgens, since it was abolished under blockade of ARs. Conversely, LTD was still induced in the presence of finasteride the inhibitor of 5α-reductase demonstrating that T is able to activate ARs and induce LTD even when DHT is not synthesized. This study demonstrates a key and opposite role of sex neurosteroids in the long-term synaptic changes of the MVN with a specific role of T-DHT for LTD and of E2 for LTP. Moreover, it suggests that different stimulation patterns can lead to LTD or LTP by specifically activating the enzymes involved in the synthesis of androgenic or estrogenic neurosteroids. PMID:24265837

Different Compartments of Apical CA1 Dendrites Have Different Plasticity Thresholds for Expressing Synaptic Tagging and Capture

ERIC Educational Resources Information Center

Sajikumar, Sreedharan; Korte, Martin

2011-01-01

The consolidation process from short- to long-term memory depends on the type of stimulation received from a specific neuronal network and on the cooperativity and associativity between different synaptic inputs converging onto a specific neuron. We show here that the plasticity thresholds for inducing LTP are different in proximal and distal…

Pannexin 1 regulates bidirectional hippocampal synaptic plasticity in adult mice.

PubMed

Ardiles, Alvaro O; Flores-Muñoz, Carolina; Toro-Ayala, Gabriela; Cárdenas, Ana M; Palacios, Adrian G; Muñoz, Pablo; Fuenzalida, Marco; Sáez, Juan C; Martínez, Agustín D

2014-01-01

The threshold for bidirectional modification of synaptic plasticity is known to be controlled by several factors, including the balance between protein phosphorylation and dephosphorylation, postsynaptic free Ca(2+) concentration and NMDA receptor (NMDAR) composition of GluN2 subunits. Pannexin 1 (Panx1), a member of the integral membrane protein family, has been shown to form non-selective channels and to regulate the induction of synaptic plasticity as well as hippocampal-dependent learning. Although Panx1 channels have been suggested to play a role in excitatory long-term potentiation (LTP), it remains unknown whether these channels also modulate long-term depression (LTD) or the balance between both types of synaptic plasticity. To study how Panx1 contributes to excitatory synaptic efficacy, we examined the age-dependent effects of eliminating or blocking Panx1 channels on excitatory synaptic plasticity within the CA1 region of the mouse hippocampus. By using different protocols to induce bidirectional synaptic plasticity, Panx1 channel blockade or lack of Panx1 were found to enhance LTP, whereas both conditions precluded the induction of LTD in adults, but not in young animals. These findings suggest that Panx1 channels restrain the sliding threshold for the induction of synaptic plasticity and underlying brain mechanisms of learning and memory.

Pannexin 1 regulates bidirectional hippocampal synaptic plasticity in adult mice

PubMed Central

Ardiles, Alvaro O.; Flores-Muñoz, Carolina; Toro-Ayala, Gabriela; Cárdenas, Ana M.; Palacios, Adrian G.; Muñoz, Pablo; Fuenzalida, Marco; Sáez, Juan C.; Martínez, Agustín D.

2014-01-01

The threshold for bidirectional modification of synaptic plasticity is known to be controlled by several factors, including the balance between protein phosphorylation and dephosphorylation, postsynaptic free Ca2+ concentration and NMDA receptor (NMDAR) composition of GluN2 subunits. Pannexin 1 (Panx1), a member of the integral membrane protein family, has been shown to form non-selective channels and to regulate the induction of synaptic plasticity as well as hippocampal-dependent learning. Although Panx1 channels have been suggested to play a role in excitatory long-term potentiation (LTP), it remains unknown whether these channels also modulate long-term depression (LTD) or the balance between both types of synaptic plasticity. To study how Panx1 contributes to excitatory synaptic efficacy, we examined the age-dependent effects of eliminating or blocking Panx1 channels on excitatory synaptic plasticity within the CA1 region of the mouse hippocampus. By using different protocols to induce bidirectional synaptic plasticity, Panx1 channel blockade or lack of Panx1 were found to enhance LTP, whereas both conditions precluded the induction of LTD in adults, but not in young animals. These findings suggest that Panx1 channels restrain the sliding threshold for the induction of synaptic plasticity and underlying brain mechanisms of learning and memory. PMID:25360084

A Model of Bidirectional Synaptic Plasticity: From Signaling Network to Channel Conductance

ERIC Educational Resources Information Center

Castellani, Gastone C.; Quinlan, Elizabeth M.; Bersani, Ferdinando; Cooper, Leon N.; Shouval, Harel Z.

2005-01-01

In many regions of the brain, including the mammalian cortex, the strength of synaptic transmission can be bidirectionally regulated by cortical activity (synaptic plasticity). One line of evidence indicates that long-term synaptic potentiation (LTP) and long-term synaptic depression (LTD), correlate with the phosphorylation/dephosphorylation of…

Gravin orchestrates PKA and β2-adrenergic receptor signaling critical for synaptic plasticity and memory

PubMed Central

Havekes, Robbert; Canton, David A.; Park, Alan J.; Huang, Ted; Nie, Ting; Day, Jonathan P.; Guercio, Leonardo A.; Grimes, Quinn; Luczak, Vincent; Gelman, Irwin H.; Baillie, George S.; Scott, John D.; Abel, Ted

2012-01-01

A kinase-anchoring proteins (AKAPs) organize compartmentalized pools of Protein Kinase A (PKA) to enable localized signaling events within neurons. However, it is unclear which of the many expressed AKAPs in neurons target PKA to signaling complexes important for long-lasting forms of synaptic plasticity and memory storage. In the forebrain, the anchoring protein gravin recruits a signaling complex containing PKA, PKC, calmodulin, and PDE4D to the β2-adrenergic receptor. Here, we show that mice lacking the α-isoform of gravin have deficits in PKA-dependent long-lasting forms of hippocampal synaptic plasticity including β2-adrenergic receptor-mediated plasticity, and selective impairments of long-term memory storage. Further, both hippocampal β2-adrenergic receptor phosphorylation by PKA, and learning-induced activation of ERK, are attenuated in the CA1 region of the hippocampus in mice lacking gravin-α. We conclude that gravin compartmentalizes a significant pool of PKA that regulates learning-induced β2-adrenergic receptor signaling and ERK activation in the hippocampus in vivo, organizing molecular interactions between glutamatergic and noradrenergic signaling pathways for long-lasting synaptic plasticity, and memory storage. PMID:23238728

Synaptic activity regulates AMPA receptor trafficking through different recycling pathways

PubMed Central

Zheng, Ning; Jeyifous, Okunola; Munro, Charlotte; Montgomery, Johanna M; Green, William N

2015-01-01

Changes in glutamatergic synaptic strength in brain are dependent on AMPA-type glutamate receptor (AMPAR) recycling, which is assumed to occur through a single local pathway. In this study, we present evidence that AMPAR recycling occurs through different pathways regulated by synaptic activity. Without synaptic stimulation, most AMPARs recycled in dynamin-independent endosomes containing the GTPase, Arf6. Few AMPARs recycled in dynamin-dependent endosomes labeled by transferrin receptors (TfRs). AMPAR recycling was blocked by alterations in the GTPase, TC10, which co-localized with Arf6 endosomes. TC10 mutants that reduced AMPAR recycling had no effect on increased AMPAR levels with long-term potentiation (LTP) and little effect on decreased AMPAR levels with long-term depression. However, internalized AMPAR levels in TfR-containing recycling endosomes increased after LTP, indicating increased AMPAR recycling through the dynamin-dependent pathway with synaptic plasticity. LTP-induced AMPAR endocytosis is inconsistent with local recycling as a source of increased surface receptors, suggesting AMPARs are trafficked from other sites. DOI: http://dx.doi.org/10.7554/eLife.06878.001 PMID:25970033

Activation of α7 nicotinic acetylcholine receptors persistently enhances hippocampal synaptic transmission and prevents Aß-mediated inhibition of LTP in the rat hippocampus.

PubMed

Ondrejcak, Tomas; Wang, Qinwen; Kew, James N C; Virley, David J; Upton, Neil; Anwyl, Roger; Rowan, Michael J

2012-02-29

Nicotinic acetylcholine receptors mediate fast cholinergic modulation of glutamatergic transmission and synaptic plasticity. Here we investigated the effects of subtype selective activation of the α7 nicotinic acetylcholine receptors on hippocampal transmission and the inhibition of synaptic long-term potentiation by the Alzheimer's disease associated amyloid ß-protein (Aß). The α7 nicotinic acetylcholine receptor agonist "compound A" ((R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-(2-pyridyl))thiophene-2-carboxamide) induced a rapid-onset persistent enhancement of synaptic transmission in the dentate gyrus in vitro. Consistent with a requirement for activation of α7 nicotinic acetylcholine receptors, the type II α7-selective positive allosteric modulator PheTQS ((3aR, 4S, 9bS)-4-(4-methylphenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide) potentiated, and the antagonist methyllycaconitine (MLA) prevented the persistent enhancement. Systemic injection of the agonist also induced a similar MLA-sensitive persistent enhancement of synaptic transmission in the CA1 area in vivo. Remarkably, although compound A did not affect control long-term potentiation (LTP) in vitro, it prevented the inhibition of LTP by Aß1-42 and this effect was inhibited by MLA. These findings strongly indicate that activation of α7 nicotinic acetylcholine receptors is sufficient to persistently enhance hippocampal synaptic transmission and to overcome the inhibition of LTP by Aß. Copyright © 2011 Elsevier B.V. All rights reserved.

Genetic deletion of melanin-concentrating hormone neurons impairs hippocampal short-term synaptic plasticity and hippocampal-dependent forms of short-term memory.

PubMed

Le Barillier, Léa; Léger, Lucienne; Luppi, Pierre-Hervé; Fort, Patrice; Malleret, Gaël; Salin, Paul-Antoine

2015-11-01

The cognitive role of melanin-concentrating hormone (MCH) neurons, a neuronal population located in the mammalian postero-lateral hypothalamus sending projections to all cortical areas, remains poorly understood. Mainly activated during paradoxical sleep (PS), MCH neurons have been implicated in sleep regulation. The genetic deletion of the only known MCH receptor in rodent leads to an impairment of hippocampal dependent forms of memory and to an alteration of hippocampal long-term synaptic plasticity. By using MCH/ataxin3 mice, a genetic model characterized by a selective deletion of MCH neurons in the adult, we investigated the role of MCH neurons in hippocampal synaptic plasticity and hippocampal-dependent forms of memory. MCH/ataxin3 mice exhibited a deficit in the early part of both long-term potentiation and depression in the CA1 area of the hippocampus. Post-tetanic potentiation (PTP) was diminished while synaptic depression induced by repetitive stimulation was enhanced suggesting an alteration of pre-synaptic forms of short-term plasticity in these mice. Behaviorally, MCH/ataxin3 mice spent more time and showed a higher level of hesitation as compared to their controls in performing a short-term memory T-maze task, displayed retardation in acquiring a reference memory task in a Morris water maze, and showed a habituation deficit in an open field task. Deletion of MCH neurons could thus alter spatial short-term memory by impairing short-term plasticity in the hippocampus. Altogether, these findings could provide a cellular mechanism by which PS may facilitate memory encoding. Via MCH neuron activation, PS could prepare the day's learning by increasing and modulating short-term synaptic plasticity in the hippocampus. © 2015 Wiley Periodicals, Inc.

Announced reward counteracts the effects of chronic social stress on anticipatory behavior and hippocampal synaptic plasticity in rats.

PubMed

Kamal, Amer; Van der Harst, Johanneke E; Kapteijn, Chantal M; Baars, Annemarie J M; Spruijt, Berry M; Ramakers, Geert M J

2010-04-01

Chronic stress causes insensitivity to rewards (anhedonia) in rats, reflected by the absence of anticipatory behavior for a sucrose-reward, which can be reversed by antidepressant treatment or repeated announced transfer to an enriched cage. It was, however, not clear whether the highly rewarding properties of the enriched cage alone caused this reversal or whether the anticipation of this reward as such had an additional effect. Therefore, the present study compared the consequences of the announcement of a reward to the mere effect of a reward alone with respect to their efficacy to counteract the consequences of chronic stress. Two forms of synaptic plasticity, long-term potentiation and long-term depression were investigated in area CA1 of the hippocampus. This was done in socially stressed rats (induced by defeat and subsequent long-term individual housing), socially stressed rats that received a reward (short-term enriched housing) and socially stressed rats to which this reward was announced by means of a stimulus that was repeatedly paired to the reward. The results were compared to corresponding control rats. We show that announcement of enriched housing appeared to have had an additional effect compared to the enriched housing per se as indicated by a significant higher amount of LTP. In conclusion, announced short-term enriched housing has a high and long-lasting counteracting efficacy on stress-induced alterations of hippocampal synaptic plasticity. This information is important for counteracting the consequences of chronic stress in both human and captive rats.

WASP-1, a canonical Wnt signaling potentiator, rescues hippocampal synaptic impairments induced by Aβ oligomers.

PubMed

Vargas, Jessica Y; Ahumada, Juan; Arrázola, Macarena S; Fuenzalida, Marco; Inestrosa, Nibaldo C

2015-02-01

Amyloid-β (Aβ) oligomers are a key factor in Alzheimer's disease (AD)-associated synaptic dysfunction. Aβ oligomers block the induction of hippocampal long-term potentiation (LTP) in rodents. The activation of Wnt signaling prevents Aβ oligomer-induced neurotoxic effects. The compound WASP-1 (Wnt-activating small molecule potentiator-1), has been described as a synergist of the ligand Wnt-3a, enhancing the activation of Wnt/β-catenin signaling. Herein, we report that WASP-1 administration successfully rescued Aβ-induced synaptic impairments both in vitro and in vivo. The activation of canonical Wnt/β-catenin signaling by WASP-1 increased synaptic transmission and rescued hippocampal LTP impairments induced by Aβ oligomers. Additionally, intra-hippocampal administration of WASP-1 to the double transgenic APPswe/PS1dE9 mouse model of AD prevented synaptic protein loss and reduced tau phosphorylation levels. Moreover, we found that WASP-1 blocked Aβ aggregation in vitro and reduced pathological tau phosphorylation in vivo. These results indicate that targeting canonical Wnt signaling with WASP-1 could have value for treating AD. Copyright © 2014 Elsevier Inc. All rights reserved.

Neurotrophin-3 restores synaptic plasticity in the striatum of a mouse model of Huntington's disease.

PubMed

Gómez-Pineda, Victor G; Torres-Cruz, Francisco M; Vivar-Cortés, César I; Hernández-Echeagaray, Elizabeth

2018-04-01

Neurotrophin-3 (NT-3) is expressed in the mouse striatum; however, it is not clear the NT-3 role in striatal physiology. The expression levels of mRNAs and immune localization of the NT-3 protein and its receptor TrkC are altered in the striatum following damage induced by an in vivo treatment with 3-nitropropionic acid (3-NP), a mitochondrial toxin used to mimic the histopathological hallmarks of Huntington's disease (HD). The aim of this study was to evaluate the role of NT-3 on corticostriatal synaptic transmission and its plasticity in both the control and damaged striatum. Corticostriatal population spikes were electrophysiologically recorded and striatal synaptic plasticity was induced by high-frequency stimulation. Further, the phosphorylation status of Trk receptors was tested under conditions that imitated electrophysiological experiments. NT-3 modulates both synaptic transmission and plasticity in the striatum; nonetheless, synaptic plasticity was modified by the 3-NP treatment, where instead of producing striatal long-term depression (LTD), long-term potentiation (LTP) was obtained. Moreover, the administration of NT-3 in the recording bath restored the plasticity observed under control conditions (LTD) in this model of striatal degeneration. NT-3 modulates corticostriatal transmission through TrkB stimulation and restores striatal LTD by signaling through its TrkC receptor. © 2018 John Wiley & Sons Ltd.

Diversity of neuropsin (KLK8)-dependent synaptic associativity in the hippocampal pyramidal neuron

PubMed Central

Ishikawa, Yasuyuki; Tamura, Hideki; Shiosaka, Sadao

2011-01-01

Abstract Hippocampal early (E-) long-term potentiation (LTP) and long-term depression (LTD) elicited by a weak stimulus normally fades within 90 min. Late (L-) LTP and LTD elicited by strong stimuli continue for >180 min and require new protein synthesis to persist. If a strong tetanus is applied once to synaptic inputs, even a weak tetanus applied to another synaptic input can evoke persistent LTP. A synaptic tag is hypothesized to enable the capture of newly synthesized synaptic molecules. This process, referred to as synaptic tagging, is found between not only the same processes (i.e. E- and L-LTP; E- and L-LTD) but also between different processes (i.e. E-LTP and L-LTD; E-LTD and L-LTP) induced at two independent synaptic inputs (cross-tagging). However, the mechanisms of synaptic tag setting remain unclear. In our previous study, we found that synaptic associativity in the hippocampal Schaffer collateral pathway depended on neuropsin (kallikrein-related peptidase 8 or KLK8), a plasticity-related extracellular protease. In the present study, we investigated how neuropsin participates in synaptic tagging and cross-tagging. We report that neuropsin is involved in synaptic tagging during LTP at basal and apical dendritic inputs. Moreover, neuropsin is involved in synaptic tagging and cross-tagging during LTP at apical dendritic inputs via integrin β1 and calcium/calmodulin-dependent protein kinase II signalling. Thus, neuropsin is a candidate molecule for the LTP-specific tag setting and regulates the transformation of E- to L-LTP during both synaptic tagging and cross-tagging. PMID:21646406

IGF1-Dependent Synaptic Plasticity of Mitral Cells in Olfactory Memory during Social Learning.

PubMed

Liu, Zhihui; Chen, Zijun; Shang, Congping; Yan, Fei; Shi, Yingchao; Zhang, Jiajing; Qu, Baole; Han, Hailin; Wang, Yanying; Li, Dapeng; Südhof, Thomas C; Cao, Peng

2017-07-05

During social transmission of food preference (STFP), mice form long-term memory of food odors presented by a social partner. How does the brain associate a social context with odor signals to promote memory encoding? Here we show that odor exposure during STFP, but not unconditioned odor exposure, induces glomerulus-specific long-term potentiation (LTP) of synaptic strength selectively at the GABAergic component of dendrodendritic synapses of granule and mitral cells in the olfactory bulb. Conditional deletion of synaptotagmin-10, the Ca 2+ sensor for IGF1 secretion from mitral cells, or deletion of IGF1 receptor in the olfactory bulb prevented the socially relevant GABAergic LTP and impaired memory formation after STFP. Conversely, the addition of IGF1 to acute olfactory bulb slices elicited the GABAergic LTP in mitral cells by enhancing postsynaptic GABA receptor responses. Thus, our data reveal a synaptic substrate for a socially conditioned long-term memory that operates at the level of the initial processing of sensory information. Copyright © 2017 Elsevier Inc. All rights reserved.

Muscarinic Long-Term Enhancement of Tonic and Phasic GABAA Inhibition in Rat CA1 Pyramidal Neurons

PubMed Central

Domínguez, Soledad; Fernández de Sevilla, David; Buño, Washington

2016-01-01

Acetylcholine (ACh) regulates network operation in the hippocampus by controlling excitation and inhibition in rat CA1 pyramidal neurons (PCs), the latter through gamma-aminobutyric acid type-A receptors (GABAARs). Although, the enhancing effects of ACh on GABAARs have been reported (Dominguez et al., 2014, 2015), its role in regulating tonic GABAA inhibition has not been explored in depth. Therefore, we aimed at determining the effects of the activation of ACh receptors on responses mediated by synaptic and extrasynaptic GABAARs. Here, we show that under blockade of ionotropic glutamate receptors ACh, acting through muscarinic type 1 receptors, paired with post-synaptic depolarization induced a long-term enhancement of tonic GABAA currents (tGABAA) and puff-evoked GABAA currents (pGABAA). ACh combined with depolarization also potentiated IPSCs (i.e., phasic inhibition) in the same PCs, without signs of interactions of synaptic responses with pGABAA and tGABAA, suggesting the contribution of two different GABAA receptor pools. The long-term enhancement of GABAA currents and IPSCs reduced the excitability of PCs, possibly regulating plasticity and learning in behaving animals. PMID:27833531

[Effects of rapamycin on amyloid β-protein induced impairments of working memory and synaptic plasticity in rats].

PubMed

Hao, Ming; Tong, Jia-qing; Zhang, Jun; Wu, Mei-na; Qi, Jin-shun

2016-01-01

The present study investigated the effects of rapamycin on Aβ1-42-induced deficits in working memory and synaptic plasticity. After bilateral hippocampal injection of Aβ1-42 and rapamycinin rats, spontaneous alternation in Y-maze and in vivo hippocampal long-term potentiation (LTP) of rats were recorded. All data were analized by two-way repeated measures analysis of variance (ANOVA). (Hippocampal injection of Aβ1-42 alone impaired working memory of rats; (2) Rapamycin did not affect working memory of rats, but alleviated Aβ1-42-induced working memory deficits, compared with Aβ1-42 alone group; (Aβ1-42 remarkably suppressed in vivo hippocampal LTP of fEPSPs in the CA1 region; (4) Pretreatment with rapamycin prevented Aβ1-42-induced suppression of LTP. These data indicates that rapamycin could protect against Aβ1-42-induced impairments in working memory and synaptic plasticity in rats.

Synaptic plasticity in the medial vestibular nuclei: role of glutamate receptors and retrograde messengers in rat brainstem slices.

PubMed

Grassi, S; Pettorossi, V E

2001-08-01

The analysis of cellular-molecular events mediating synaptic plasticity within vestibular nuclei is an attempt to explain the mechanisms underlying vestibular plasticity phenomena. The present review is meant to illustrate the main results, obtained in vitro, on the mechanisms underlying long-term changes in synaptic strength within the medial vestibular nuclei. The synaptic plasticity phenomena taking place at the level of vestibular nuclei could be useful for adapting and consolidating the efficacy of vestibular neuron responsiveness to environmental requirements, as during visuo-vestibular recalibration and vestibular compensation. Following a general introduction on the most salient features of vestibular compensation and visuo-vestibular adaptation, which are two plastic events involving neuronal circuitry within the medial vestibular nuclei, the second and third sections describe the results from rat brainstem slice studies, demonstrating the possibility to induce long-term potentiation and depression in the medial vestibular nuclei, following high frequency stimulation of the primary vestibular afferents. In particular the mechanisms sustaining the induction and expression of vestibular long-term potentiation and depression, such as the role of various glutamate receptors and retrograde messengers have been described. The relevant role of the interaction between the platelet-activating factor, acting as a retrograde messenger, and the presynaptic metabotropic glutamate receptors, in determining the full expression of vestibular long-term potentiation is also underlined. In addition, the mechanisms involved in vestibular long-term potentiation have been compared with those leading to long-term potentiation in the hippocampus to emphasize the most significant differences emerging from vestibular studies. The fourth part, describes recent results demonstrating the essential role of nitric oxide, another retrograde messenger, in the induction of vestibular potentiation. Finally the fifth part suggests the possible functional significance of different action times of the two retrograde messengers and metabotropic glutamate receptors, which are involved in mediating the presynaptic mechanism sustaining vestibular long-term potentiation.

Dysregulation of synaptic plasticity precedes appearance of morphological defects in a Pten conditional knockout mouse model of autism.

PubMed

Takeuchi, Koichi; Gertner, Michael J; Zhou, Jing; Parada, Luis F; Bennett, Michael V L; Zukin, R Suzanne

2013-03-19

The phosphoinositide signaling system is a crucial regulator of neural development, cell survival, and plasticity. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) negatively regulates phosphatidylinositol 3-kinase signaling and downstream targets. Nse-Cre Pten conditional knockout mice, in which Pten is ablated in granule cells of the dentate gyrus and pyramidal neurons of the hippocampal CA3, but not CA1, recapitulate many of the symptoms of humans with inactivating PTEN mutations, including progressive hypertrophy of the dentate gyrus and deficits in hippocampus-based social and cognitive behaviors. However, the impact of Pten loss on activity-dependent synaptic plasticity in this clinically relevant mouse model of Pten inactivation remains unclear. Here, we show that two phosphatidylinositol 3-kinase- and protein synthesis-dependent forms of synaptic plasticity, theta burst-induced long-term potentiation and metabotropic glutamate receptor (mGluR)-dependent long-term depression, are dysregulated at medial perforant path-to-dentate gyrus synapses of young Nse-Cre Pten conditional knockout mice before the onset of visible morphological abnormalities. In contrast, long-term potentiation and mGluR-dependent long-term depression are normal at CA3-CA1 pyramidal cell synapses at this age. Our results reveal that deletion of Pten in dentate granule cells dysregulates synaptic plasticity, a defect that may underlie abnormal social and cognitive behaviors observed in humans with Pten inactivating mutations and potentially other autism spectrum disorders.

Neo-synthesis of estrogenic or androgenic neurosteroids determine whether long-term potentiation or depression is induced in hippocampus of male rat

PubMed Central

Di Mauro, Michela; Tozzi, Alessandro; Calabresi, Paolo; Pettorossi, Vito Enrico; Grassi, Silvarosa

2015-01-01

Estrogenic and androgenic steroids synthesized in the brain may rapidly modulate synaptic plasticity interacting with specific membrane receptors. We explored by electrophysiological recordings in hippocampal slices of male rat the influence of 17β-estradiol (E2) and 5α-dihydrotestosterone (DHT) neo-synthesis on the synaptic changes induced in the CA1 region. Induction of long-term depression (LTD) and depotentiation (DP) by low frequency stimulation (LFS, 15 min-1 Hz) and of long-term potentiation (LTP) by high frequency stimulation (HFS, 1 s-100 Hz), medium (MFS, 1 s-50 Hz), or weak (WFS, 1 s-25 Hz) frequency stimulation was assayed under inhibitors of enzymes converting testosterone (T) into DHT (5α-reductase) and T into E2 (P450-aromatase). We found that LFS-LTD depends on DHT synthesis, since it was fully prevented under finasteride, an inhibitor of DHT synthesis, and rescued by exogenous DHT, while the E2 synthesis was not involved. Conversely, the full development of HFS-LTP requires the synthesis of E2, as demonstrated by the LTP reduction observed under letrozole, an inhibitor of E2 synthesis, and its full rescue by exogenous E2. For intermediate stimulation protocols DHT, but not E2 synthesis, was involved in the production of a small LTP induced by WFS, while the E2 synthesis was required for the MFS-dependent LTP. Under the combined block of DHT and E2 synthesis all stimulation frequencies induced partial LTP. Overall, these results indicate that DHT is required for converting the partial LTP into LTD whereas E2 is needed for the full expression of LTP, evidencing a key role of the neo-synthesis of sex neurosteroids in determining the direction of synaptic long-term effects. PMID:26483631

Histone Deacetylase Inhibition Induces Odor Preference Memory Extension and Maintains Enhanced AMPA Receptor Expression in the Rat Pup Model

ERIC Educational Resources Information Center

Bhattacharya, Sriya; Mukherjee, Bandhan; Doré, Jules J. E.; Yuan, Qi; Harley, Carolyn W.; McLean, John H.

2017-01-01

Histone deacetylase (HDAC) plays a role in synaptic plasticity and long-term memory formation. We hypothesized that trichostatin-A (TSA), an HDAC inhibitor, would promote long-term odor preference memory and maintain enhanced GluA1 receptor levels that have been hypothesized to support memory. We used an early odor preference learning model in…

TH-9 (a theophylline derivative) induces long-lasting enhancement in excitatory synaptic transmission in the rat hippocampus that is occluded by frequency-dependent plasticity in vitro.

PubMed

Nashawi, H; Bartl, T; Bartl, P; Novotny, L; Oriowo, M A; Kombian, S B

2012-09-18

Dementia, especially Alzheimer's disease, is a rapidly increasing medical condition that presents with enormous challenge for treatment. It is characterized by impairment in memory and cognitive function often accompanied by changes in synaptic transmission and plasticity in relevant brain regions such as the hippocampus. We recently synthesized TH-9, a conjugate racetam-methylxanthine compound and tested if it had potential for enhancing synaptic function and possibly, plasticity, by examining its effect on hippocampal fast excitatory synaptic transmission and plasticity. Field excitatory postsynaptic potentials (fEPSPs) were recorded in the CA1 hippocampal area of naïve juvenile male Sprague-Dawley rats using conventional electrophysiological recording techniques. TH-9 caused a concentration-dependent, long-lasting enhancement in fEPSPs. This effect was blocked by adenosine A1, acetylcholine (muscarinic and nicotinic) and glutamate (N-methyl-d-aspartate) receptor antagonists but not by a γ-aminobutyric acid receptor type B (GABA(B)) receptor antagonist. The TH-9 effect was also blocked by enhancing intracellular cyclic adenosine monophosphate and inhibiting protein kinase A. Pretreatment with TH-9 did not prevent the induction of long-term potentiation (LTP) or long-term depression (LTD). Conversely, induction of LTP or LTD completely occluded the ability of TH-9 to enhance fEPSPs. Thus, TH-9 utilizes cholinergic and adenosinergic mechanisms to cause long-lasting enhancement in fEPSPs which were occluded by LTP and LTD. TH-9 may therefore employ similar or convergent mechanisms with frequency-dependent synaptic plasticities to produce the observed long-lasting enhancement in synaptic transmission and may thus, have potential for use in improving memory. Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.

Robust short-term memory without synaptic learning.

PubMed

Johnson, Samuel; Marro, J; Torres, Joaquín J

2013-01-01

Short-term memory in the brain cannot in general be explained the way long-term memory can--as a gradual modification of synaptic weights--since it takes place too quickly. Theories based on some form of cellular bistability, however, do not seem able to account for the fact that noisy neurons can collectively store information in a robust manner. We show how a sufficiently clustered network of simple model neurons can be instantly induced into metastable states capable of retaining information for a short time (a few seconds). The mechanism is robust to different network topologies and kinds of neural model. This could constitute a viable means available to the brain for sensory and/or short-term memory with no need of synaptic learning. Relevant phenomena described by neurobiology and psychology, such as local synchronization of synaptic inputs and power-law statistics of forgetting avalanches, emerge naturally from this mechanism, and we suggest possible experiments to test its viability in more biological settings.

Endocannabinoid-Dependent Long-Term Potentiation of Synaptic Transmission at Rat Barrel Cortex.

PubMed

Maglio, Laura Eva; Noriega-Prieto, José Antonio; Maraver, Maria Jesús; Fernández de Sevilla, David

2018-05-01

Brain-derived neurotrophic factor (BDNF) plays a critical role in modulating plasticity in sensory cortices. Indeed, a BDNF-dependent long-term potentiation (LTP) at distal basal excitatory synapses of Layer 5 pyramidal neurons (L5PNs) has been demonstrated in disinhibited rat barrel cortex slices. Although it is well established that this LTP requires the pairing of excitatory postsynaptic potentials (PSPs) with Ca2+ spikes, its induction when synaptic inhibition is working remains unexplored. Here we show that low-frequency stimulation at basal dendrites of L5PNs is able to trigger a PSP followed by an action potential (AP) and a slow depolarization (termed PSP-Ca2+ response) in thalamocortical slices without blocking synaptic inhibition. We demonstrate that AP barrage-mediated release of endocannabinoids (eCBs) from the recorded L5PNs induces PSP-Ca2+ response facilitation and BDNF-dependent LTP. Indeed, this LTP requires the type 1 cannabinoid receptors activation, is prevented by postsynaptic intracellular 1,2-bis(2-aminophenoxy) ethane-N,N,N,N'-tetraacetic acid (BAPTA) or the anandamide membrane transporter inhibitor AM404, and only occurs in L5PNs neurons showing depolarization-induced suppression of inhibition. Additionally, electrical stimulation at the posteromedial thalamic nucleus induced similar response and LTP. These results reveal a novel form of eCB-dependent LTP at L5PNs that could be relevant in the processing of sensory information in the barrel cortex.

Hippocampal dendritic spines modifications induced by perinatal asphyxia.

PubMed

Saraceno, G E; Castilla, R; Barreto, G E; Gonzalez, J; Kölliker-Frers, R A; Capani, F

2012-01-01

Perinatal asphyxia (PA) affects the synaptic function and morphological organization. In previous works, we have shown neuronal and synaptic changes in rat neostriatum subjected to hypoxia leading to long-term ubi-protein accumulation. Since F-actin is highly concentrated in dendritic spines, modifications in its organization could be related with alterations induced by hypoxia in the central nervous system (CNS). In the present study, we investigate the effects of PA on the actin cytoskeleton of hippocampal postsynaptic densities (PSD) in 4-month-old rats. PSD showed an increment in their thickness and in the level of ubiquitination. Correlative fluorescence-electron microscopy photooxidation showed a decrease in the number of F-actin-stained spines in hippocampal excitatory synapses subjected to PA. Although western blot analysis also showed a slight decrease in β-actin in PSD in PA animals, the difference was not significant. Taken together, this data suggests that long-term actin cytoskeleton might have role in PSD alterations which would be a spread phenomenon induced by PA.

Hippocampal Dendritic Spines Modifications Induced by Perinatal Asphyxia

PubMed Central

Saraceno, G. E.; Castilla, R.; Barreto, G. E.; Gonzalez, J.; Kölliker-Frers, R. A.; Capani, F.

2012-01-01

Perinatal asphyxia (PA) affects the synaptic function and morphological organization. In previous works, we have shown neuronal and synaptic changes in rat neostriatum subjected to hypoxia leading to long-term ubi-protein accumulation. Since F-actin is highly concentrated in dendritic spines, modifications in its organization could be related with alterations induced by hypoxia in the central nervous system (CNS). In the present study, we investigate the effects of PA on the actin cytoskeleton of hippocampal postsynaptic densities (PSD) in 4-month-old rats. PSD showed an increment in their thickness and in the level of ubiquitination. Correlative fluorescence-electron microscopy photooxidation showed a decrease in the number of F-actin-stained spines in hippocampal excitatory synapses subjected to PA. Although Western Blot analysis also showed a slight decrease in β-actin in PSD in PA animals, the difference was not significant. Taken together, this data suggests that long-term actin cytoskeleton might have role in PSD alterations which would be a spread phenomenon induced by PA. PMID:22645692

Nothing can be coincidence: synaptic inhibition and plasticity in the cerebellar nuclei

PubMed Central

Pugh, Jason R.; Raman, Indira M.

2009-01-01

Many cerebellar neurons fire spontaneously, generating 10–100 action potentials per second even without synaptic input. This high basal activity correlates with information-coding mechanisms that differ from those of cells that are quiescent until excited synaptically. For example, in the deep cerebellar nuclei, Hebbian patterns of coincident synaptic excitation and postsynaptic firing fail to induce long-term increases in the strength of excitatory inputs. Instead, excitatory synaptic currents are potentiated by combinations of inhibition and excitation that resemble the activity of Purkinje and mossy fiber afferents that is predicted to occur during cerebellar associative learning tasks. Such results indicate that circuits with intrinsically active neurons have rules for information transfer and storage that distinguish them from other brain regions. PMID:19178955

Brain Angiotensin II AT1 receptors are involved in the acute and long-term amphetamine-induced neurocognitive alterations.

PubMed

Marchese, Natalia Andrea; Artur de laVillarmois, Emilce; Basmadjian, Osvaldo Martin; Perez, Mariela Fernanda; Baiardi, Gustavo; Bregonzio, Claudia

2016-03-01

Angiotensin II, by activation of its brain AT1-receptors, plays an active role as neuromodulator in dopaminergic transmission. These receptors participate in the development of amphetamine-induced behavioral and dopamine release sensitization. Dopamine is involved in cognitive processes and provides connectivity between brain areas related to these processes. Amphetamine by its mimetic activity over dopamine neurotransmission elicits differential responses after acute administration or after re-exposure following long-term withdrawal periods in different cognitive processes. The purpose of this study is to evaluate the AT1-receptor involvement in the acute and long-term amphetamine-induced alterations in long-term memory and in cellular-related events. Male Wistar rats (250-300 g) were used in this study. Acute effects: Amphetamine (0.5/2.5 mg/kg i.p.) was administered after post-training in the inhibitory avoidance (IA) response. The AT1-receptor blocker Losartan was administered i.c.v. before a single dose of amphetamine (0.5 mg/kg i.p.). Long-term effects: The AT1-receptors blocker Candesartan (3 mg/kg p.o.) was administered for 5 days followed by 5 consecutive days of amphetamine (2.5 mg/kg/day, i.p.). The neuroadaptive changes were evidenced after 1 week of withdrawal by an amphetamine challenge (0.5 mg/kg i.p.). The IA response, the neuronal activation pattern, and the hippocampal synaptic transmission were evaluated. The impairing effect in the IA response of post-training acute amphetamine was partially prevented by Losartan. The long-term changes induced by repeated amphetamine (resistance to acute amphetamine interference in the IA response, neurochemical altered response, and increased hippocampal synaptic transmission) were prevented by AT1-receptors blockade. AT1-receptors are involved in the acute alterations and in the neuroadaptations induced by repeated amphetamine associated with neurocognitive processes.

Synaptic Scaling Enables Dynamically Distinct Short- and Long-Term Memory Formation

PubMed Central

Tetzlaff, Christian; Kolodziejski, Christoph; Timme, Marc; Tsodyks, Misha; Wörgötter, Florentin

2013-01-01

Memory storage in the brain relies on mechanisms acting on time scales from minutes, for long-term synaptic potentiation, to days, for memory consolidation. During such processes, neural circuits distinguish synapses relevant for forming a long-term storage, which are consolidated, from synapses of short-term storage, which fade. How time scale integration and synaptic differentiation is simultaneously achieved remains unclear. Here we show that synaptic scaling – a slow process usually associated with the maintenance of activity homeostasis – combined with synaptic plasticity may simultaneously achieve both, thereby providing a natural separation of short- from long-term storage. The interaction between plasticity and scaling provides also an explanation for an established paradox where memory consolidation critically depends on the exact order of learning and recall. These results indicate that scaling may be fundamental for stabilizing memories, providing a dynamic link between early and late memory formation processes. PMID:24204240

Synaptic scaling enables dynamically distinct short- and long-term memory formation.

PubMed

Tetzlaff, Christian; Kolodziejski, Christoph; Timme, Marc; Tsodyks, Misha; Wörgötter, Florentin

2013-10-01

Memory storage in the brain relies on mechanisms acting on time scales from minutes, for long-term synaptic potentiation, to days, for memory consolidation. During such processes, neural circuits distinguish synapses relevant for forming a long-term storage, which are consolidated, from synapses of short-term storage, which fade. How time scale integration and synaptic differentiation is simultaneously achieved remains unclear. Here we show that synaptic scaling - a slow process usually associated with the maintenance of activity homeostasis - combined with synaptic plasticity may simultaneously achieve both, thereby providing a natural separation of short- from long-term storage. The interaction between plasticity and scaling provides also an explanation for an established paradox where memory consolidation critically depends on the exact order of learning and recall. These results indicate that scaling may be fundamental for stabilizing memories, providing a dynamic link between early and late memory formation processes.

Thidoredxin-2 overexpression fails to rescue chronic high calorie diet induced hippocampal dysfunction.

PubMed

Liu, Yong; Yang, Ying; Dong, Hui; Cutler, Roy G; Strong, Randy; Mattson, Mark P

2016-01-01

A high calorie diet (HCD) can impair hippocampal synaptic plasticity and cognitive function in animal models. Mitochondrial thioredoxin 2 (TRX-2) is critical for maintaining intracellular redox status, but whether it can protect against HCD-induced impairment of synaptic plasticity is unknown. We found that levels of TRX-2 are reduced in the hippocampus of wild type mice maintained for 8 months on a HCD, and that the mice on the HCD exhibit impaired hippocampal synaptic plasticity (long-term potentiation at CA1 synapses) and cognitive function (novel object recognition). Transgenic mice overexpressing human TRX-2 (hTRX-2) exhibit increased resistance to diquat-induced oxidative stress in peripheral tissues. However, neither the HCD nor hTRX-2 overexpression affected levels of lipid peroxidation products (F2 isoprostanes) in the hippocampus, and hTRX-2 transgenic mice were not protected against the adverse effects of the HCD on hippocampal synaptic plasticity and cognitive function. Our findings indicate that TRX-2 overexpression does not mitigate adverse effects of a HCD on synaptic plasticity, and also suggest that oxidative stress may not be a pivotal factor in the impairment of synaptic plasticity and cognitive function caused by HCDs. Published by Elsevier Inc.

Inhibition of AMP-Activated Protein Kinase Signaling Alleviates Impairments in Hippocampal Synaptic Plasticity Induced by Amyloid β

PubMed Central

Ma, Tao; Chen, Yiran; Vingtdeux, Valerie; Zhao, Haitian; Viollet, Benoit; Marambaud, Philippe

2014-01-01

The AMP-activated protein kinase (AMPK) is a Ser/Thr kinase that is activated in response to low-energy states to coordinate multiple signaling pathways to maintain cellular energy homeostasis. Dysregulation of AMPK signaling has been observed in Alzheimer's disease (AD), which is associated with abnormal neuronal energy metabolism. In the current study we tested the hypothesis that aberrant AMPK signaling underlies AD-associated synaptic plasticity impairments by using pharmacological and genetic approaches. We found that amyloid β (Aβ)-induced inhibition of long-term potentiation (LTP) and enhancement of long-term depression were corrected by the AMPK inhibitor compound C (CC). Similarly, LTP impairments in APP/PS1 transgenic mice that model AD were improved by CC treatment. In addition, Aβ-induced LTP failure was prevented in mice with genetic deletion of the AMPK α2-subunit, the predominant AMPK catalytic subunit in the brain. Furthermore, we found that eukaryotic elongation factor 2 (eEF2) and its kinase eEF2K are key downstream effectors that mediate the detrimental effects of hyperactive AMPK in AD pathophysiology. Our findings describe a previously unrecognized role of aberrant AMPK signaling in AD-related synaptic pathophysiology and reveal a potential therapeutic target for AD. PMID:25186765

Mechanisms of Translation Control Underlying Long-lasting Synaptic Plasticity and the Consolidation of Long-term Memory

PubMed Central

Santini, Emanuela; Huynh, Thu N.; Klann, Eric

2018-01-01

The complexity of memory formation and its persistence is a phenomenon that has been studied intensely for centuries. Memory exists in many forms and is stored in various brain regions. Generally speaking, memories are reorganized into broadly distributed cortical networks over time through systems level consolidation. At the cellular level, storage of information is believed to initially occur via altered synaptic strength by processes such as long-term potentiation (LTP). New protein synthesis is required for long-lasting synaptic plasticity as well as for the formation of long-term memory. The mammalian target of rapamycin complex 1 (mTORC1) is a critical regulator of cap-dependent protein synthesis and is required for numerous forms of long-lasting synaptic plasticity and long-term memory. As such, the study of mTORC1 and protein factors that control translation initiation and elongation have enhanced our understanding of how the process of protein synthesis is regulated during memory formation. Herein we will discuss the molecular mechanisms that regulate protein synthesis as well as pharmacological and genetic manipulations that demonstrate the requirement for proper translational control in long-lasting synaptic plasticity and long-term memory formation. PMID:24484700

Long-term soluble Abeta1-40 activates CaM kinase II in organotypic hippocampal cultures.

PubMed

Tardito, Daniela; Gennarelli, Massimo; Musazzi, Laura; Gesuete, Raffaella; Chiarini, Stefania; Barbiero, Valentina Sara; Rydel, Russell E; Racagni, Giorgio; Popoli, Maurizio

2007-09-01

Recent findings suggested a role for soluble amyloid-beta (Abeta) peptides in Alzheimer's disease associated cognitive decline. We investigated the action of soluble, monomeric Abeta(1-40) on CaM kinase II, a kinase involved in neuroplasticity and cognition. We treated organotypic hippocampal cultures short-term (up to 4h) and long-term (5 days) with Abeta(1-40) (1nM-5microM). Abeta did not induce cell damage, apoptosis or synaptic loss. Short-term treatment down-regulated enzymatic activity of the kinase, by reducing its Thr(286) phosphorylation. In contrast, long-term treatment (1nM-microM) markedly and significantly up-regulated enzymatic activity, with peak stimulation at 10nM (three-fold). Up-regulation of activity was associated with increased expression of the alpha-isoform of CaM kinase II, increased phosphorylation at Thr(286) (activator residue) and decreased phosphorylation at Thr(305-306) (inhibitory residues). We investigated the effect of glutamate on CaM kinase II following exposure to 1 or 10nM Abeta(1-40). As previously reported, glutamate increased CaM kinase II activity. However, the glutamate effect was not altered by pretreatment of slices with Abeta. Short- and long-term Abeta treatment showed opposite effects on CaM kinase II, suggesting that long-term changes are an adaptation to the kinase early down-regulation. The marked effect of Abeta(1-40) on the kinase suggests that semi-physiological and slowly raising peptide concentrations may have a significant impact on synaptic plasticity in the absence of synaptic loss or neuronal cell death.

Disruption of hippocampal–prefrontal cortex activity by dopamine D2R-dependent LTD of NMDAR transmission

PubMed Central

Banks, Paul James; Burroughs, Amelia Caroline; Barker, Gareth Robert Isaac; Brown, Jon Thomas; Warburton, Elizabeth Clea; Bashir, Zafar Iqbal

2015-01-01

Functional connectivity between the hippocampus and prefrontal cortex (PFC) is essential for associative recognition memory and working memory. Disruption of hippocampal–PFC synchrony occurs in schizophrenia, which is characterized by hypofunction of NMDA receptor (NMDAR)-mediated transmission. We demonstrate that activity of dopamine D2-like receptors (D2Rs) leads selectively to long-term depression (LTD) of hippocampal–PFC NMDAR-mediated synaptic transmission. We show that dopamine-dependent LTD of NMDAR-mediated transmission profoundly disrupts normal synaptic transmission between hippocampus and PFC. These results show how dopaminergic activation induces long-term hypofunction of NMDARs, which can contribute to disordered functional connectivity, a characteristic that is a hallmark of psychiatric disorders such as schizophrenia. PMID:26286993

Laminar distribution of cholinergic- and serotonergic-dependent plasticity within kitten visual cortex.

PubMed

Kojic, L; Gu, Q; Douglas, R M; Cynader, M S

2001-02-28

Both cholinergic and serotonergic modulatory projections to mammalian striate cortex have been demonstrated to be involved in the regulation of postnatal plasticity, and a striking alteration in the number and intracortical distribution of cholinergic and serotonergic receptors takes place during the critical period for cortical plasticity. As well, agonists of cholinergic and serotonergic receptors have been demonstrated to facilitate induction of long-term synaptic plasticity in visual cortical slices supporting their involvement in the control of activity-dependent plasticity. We recorded field potentials from layers 4 and 2/3 in visual cortex slices of 60--80 day old kittens after white matter stimulation, before and after a period of high frequency stimulation (HFS), in the absence or presence of either cholinergic or serotonergic agonists. At these ages, the HFS protocol alone almost never induced long-term changes of synaptic plasticity in either layers 2/3 or 4. In layer 2/3, agonist stimulation of m1 receptors facilitated induction of long-term potentiation (LTP) with HFS stimulation, while the activation of serotonergic receptors had only a modest effect. By contrast, a strong serotonin-dependent LTP facilitation and insignificant muscarinic effects were observed after HFS within layer 4. The results show that receptor-dependent laminar stratification of synaptic modifiability occurs in the cortex at these ages. This plasticity may underly a control system gating the experience-dependent changes of synaptic organization within developing visual cortex.

Long-term potentiation in the dentate gyrus in freely moving rats is reinforced by intraventricular application of norepinephrine, but not oxotremorine.

PubMed

Almaguer-Melian, William; Rojas-Reyes, Yeneissy; Alvare, Armando; Rosillo, Juan C; Frey, Julietta U; Bergado, Jorge A

2005-01-01

Growing evidence suggests that processes of synaptic plasticity, such as long-term potentiation (LTP) occurring in one synaptic population, can be modulated by consolidating afferents from other brain structures. We have previously shown that an early-LTP lasting less than 4 h (E-LTP) in the dentate gyrus can be prolonged by stimulating the basolateral amygdala, the septum or the locus coeruleus within a specific time window. Pharmacological experiments have suggested that noradregeneric (NE) and/or cholinergic systems might be involved in these effects. We have therefore investigated whether the direct intraventricular application of agonists for NE- or muscarinic receptors is able to modulate synaptic plasticity. E-LTP was induced at the dentate gyrus of freely moving rats using a mild tetanization protocol that induces only an E-LTP. NE or oxotremorine (OXO) were applied icv 10 min after the tetanus. Results show that low doses of NE (1.5 and 5 nM) effectively prolong LTP. A higher dose (50 nM) was not effective. None of the OXO doses employed (5, 25, and 50 nM) showed similar effects. These results stress the importance of transmitter-specific modulatory influences on the time course of synaptic plasticity, in particular NE whose application mimics the reinforcing effect of directly stimulating limbic structures on LTP.

The Role of Actin Cytoskeleton in Dendritic Spines in the Maintenance of Long-Term Memory.

PubMed

Basu, Sreetama; Lamprecht, Raphael

2018-01-01

Evidence indicates that long-term memory formation involves alterations in synaptic efficacy produced by modifications in neural transmission and morphology. However, it is not clear how such alterations induced by learning, that encode memory, are maintained over long period of time to preserve long-term memory. This is especially intriguing as the half-life of most of the proteins that underlie such changes is usually in the range of hours to days and these proteins may change their location over time. In this review we describe studies that indicate the involvement of dendritic spines in memory formation and its maintenance. These studies show that learning leads to changes in the number and morphology of spines. Disruption in spines morphology or manipulations that lead to alteration in their number after consolidation are associated with impairment in memory maintenance. We further ask how changes in dendritic spines morphology, induced by learning and reputed to encode memory, are maintained to preserve long-term memory. We propose a mechanism, based on studies described in the review, whereby the actin cytoskeleton and its regulatory proteins involved in the initial alteration in spine morphology induced by learning are also essential for spine structural stabilization that maintains long-term memory. In this model glutamate receptors and other synaptic receptors activation during learning leads to the creation of new actin cytoskeletal scaffold leading to changes in spines morphology and memory formation. This new actin cytoskeletal scaffold is preserved beyond actin and its regulatory proteins turnover and dynamics by active stabilization of the level and activity of actin regulatory proteins within these memory spines.

MPTP-meditated hippocampal dopamine deprivation modulates synaptic transmission and activity-dependent synaptic plasticity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhu Guoqi; Chen Ying; Huang Yuying

2011-08-01

Parkinson's disease (PD)-like symptoms including learning deficits are inducible by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Therefore, it is possible that MPTP may disturb hippocampal memory processing by modulation of dopamine (DA)- and activity-dependent synaptic plasticity. We demonstrate here that intraperitoneal (i.p.) MPTP injection reduces the number of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra (SN) within 7 days. Subsequently, the TH expression level in SN and hippocampus and the amount of DA and its metabolite DOPAC in striatum and hippocampus decrease. DA depletion does not alter basal synaptic transmission and changes pair-pulse facilitation (PPF) of field excitatory postsynaptic potentials (fEPSPs) only atmore » the 30 ms inter-pulse interval. In addition, the induction of long-term potentiation (LTP) is impaired whereas the duration of long-term depression (LTD) becomes prolonged. Since both LTP and LTD depend critically on activation of NMDA and DA receptors, we also tested the effect of DA depletion on NMDA receptor-mediated synaptic transmission. Seven days after MPTP injection, the NMDA receptor-mediated fEPSPs are decreased by about 23%. Blocking the NMDA receptor-mediated fEPSP does not mimic the MPTP-LTP. Only co-application of D1/D5 and NMDA receptor antagonists during tetanization resembled the time course of fEPSP potentiation as observed 7 days after i.p. MPTP injection. Together, our data demonstrate that MPTP-induced degeneration of DA neurons and the subsequent hippocampal DA depletion alter NMDA receptor-mediated synaptic transmission and activity-dependent synaptic plasticity. - Highlights: > I.p. MPTP-injection mediates death of dopaminergic neurons. > I.p. MPTP-injection depletes DA and DOPAC in striatum and hippocampus. > I.p. MPTP-injection does not alter basal synaptic transmission. > Reduction of LTP and enhancement of LTD after i.p. MPTP-injection. > Attenuation of NMDA-receptors mediated fEPSPs after i.p. MPTP-injection.« less

Activity-Dependent Inhibitory Gating in Molecular Signaling Cascades Induces a Novel Form of Intermediate-Term Synaptic Facilitation in "Aplysia Californica"

ERIC Educational Resources Information Center

Fischbach, Soren; Kopec, Ashley M.; Carew, Thomas J.

2014-01-01

Mechanistically distinct forms of long-lasting plasticity and memory can be induced by a variety of different training patterns. Although several studies have identified distinct molecular pathways that are engaged during these different training patterns, relatively little work has explored potential interactions between pathways when they are…

Subclinical Doses of ATP-Sensitive Potassium Channel Modulators Prevent Alterations in Memory and Synaptic Plasticity Induced by Amyloid-β.

PubMed

Salgado-Puga, Karla; Rodríguez-Colorado, Javier; Prado-Alcalá, Roberto A; Peña-Ortega, Fernando

2017-01-01

In addition to coupling cell metabolism and excitability, ATP-sensitive potassium channels (KATP) are involved in neural function and plasticity. Moreover, alterations in KATP activity and expression have been observed in Alzheimer's disease (AD) and during amyloid-β (Aβ)-induced pathology. Thus, we tested whether KATP modulators can influence Aβ-induced deleterious effects on memory, hippocampal network function, and plasticity. We found that treating animals with subclinical doses (those that did not change glycemia) of a KATP blocker (Tolbutamide) or a KATP opener (Diazoxide) differentially restrained Aβ-induced memory deficit, hippocampal network activity inhibition, and long-term synaptic plasticity unbalance (i.e., inhibition of LTP and promotion of LTD). We found that the protective effect of Tolbutamide against Aβ-induced memory deficit was strong and correlated with the reestablishment of synaptic plasticity balance, whereas Diazoxide treatment produced a mild protection against Aβ-induced memory deficit, which was not related to a complete reestablishment of synaptic plasticity balance. Interestingly, treatment with both KATP modulators renders the hippocampus resistant to Aβ-induced inhibition of hippocampal network activity. These findings indicate that KATP are involved in Aβ-induced pathology and they heighten the potential role of KATP modulation as a plausible therapeutic strategy against AD.

PROPYLTHIOURACIL (PTU)-INDUCED HYPOTHYROIDISM: EFFECTS ON SYNAPTIC TRANSMISSION AND LONG TERM POTENTIATION IN HIPPOCAMPAL SLICES.

EPA Science Inventory

Concern has been raised over endocrine effects of some classes of environmental chemicals. Severe hypothyroidism during critical periods of brain developmental leads to alterations in hippocampal structure, learning deficits, yet neurophysiological properties of the hippocampus...

Vesicular zinc promotes presynaptic and inhibits postsynaptic long term potentiation of mossy fiber-CA3 synapse

PubMed Central

Pan, Enhui; Zhang, Xiao-an; Huang, Zhen; Krezel, Artur; Zhao, Min; Tin-berg, Christine E.; Lippard, Stephen J.; McNamara, James O.

2011-01-01

The presence of zinc in glutamatergic synaptic vesicles of excitatory neurons of mammalian cerebral cortex suggests that zinc might regulate plasticity of synapses formed by these neurons. Long term potentiation (LTP) is a form of synaptic plasticity that may underlie learning and memory. We tested the hypothesis that zinc within vesicles of mossy fibers (mf) contributes to mf-LTP, a classical form of presynaptic LTP. We synthesized an extracellular zinc chelator with selectivity and kinetic properties suitable for study of the large transient of zinc in the synaptic cleft induced by mf stimulation. We found that vesicular zinc is required for presynaptic mf-LTP. Unexpectedly, vesicular zinc also inhibits a novel form of postsynaptic mf-LTP. Because the mf-CA3 synapse provides a major source of excitatory input to the hippocampus, regulating its efficacy by these dual actions of vesicular zinc is critical to proper function of hippocampal circuitry in health and disease. PMID:21943607

Non-apoptotic function of BAD and BAX in long-term depression of synaptic transmission

PubMed Central

Jiao, Song; Li, Zheng

2011-01-01

Summary It has recently been found that caspases not only function in apoptosis, but are also crucial for non-apoptotic processes such as NMDA receptor-dependent long-term depression (LTD) of synaptic transmission. It remains unknown, however, how caspases are activated and how neurons escape death in LTD. Here we show that caspase-3 is activated by the BAD-BAX cascade for LTD induction. This cascade is required specifically for NMDA receptor-dependent LTD but not for mGluR-LTD, and its activation is sufficient to induce synaptic depression. In contrast to apoptosis, however, BAD is activated only moderately and transiently and BAX is not translocated to mitochondria, resulting in only modest caspase-3 activation. We further demonstrate that the intensity and duration of caspase-3 activation determin whether it leads to cell death or LTD, thus fine-tuning of caspase-3 activation is critical in distinguishing between these two pathways. PMID:21609830

Endogenous Cannabinoids Trigger the Depolarization-Induced Suppression of Excitation in the Lateral Amygdala

ERIC Educational Resources Information Center

Kodirov, Sodikdjon A.; Jasiewicz, Julia; Amirmahani, Parisa; Psyrakis, Dimitrios; Bonni, Kathrin; Wehrmeister, Michael; Lutz, Beat

2010-01-01

The amygdala is a key area of the brain where the emotional memories are stored throughout the lifespan. It is well established that synapses in the lateral nucleus of amygdala (LA) can undergo long-term potentiation, a putative cellular correlate of learning and memory. However, a type of short-term synaptic plasticity, known as…

Narp regulates long-term aversive effects of morphine withdrawal

PubMed Central

Reti, Irving M.; Crombag, Hans S.; Takamiya, Kogo; Sutton, Jeffrey M.; Guo, Ning; Dinenna, Megan L.; Huganir, Richard L.; Holland, Peter C.; Baraban, Jay M.

2008-01-01

Although long-lasting effects of drug withdrawal are thought to play a key role in motivating continued drug use, the mechanisms mediating this type of drug-induced plasticity are unclear. As Narp is an immediate early gene product that is secreted at synaptic sites and binds to AMPA receptors, it has been implicated in mediating enduring forms of synaptic plasticity. In previous studies, we found that Narp is selectively induced by morphine withdrawal in the extended amygdala, a group of limbic nuclei that mediate aversive behavioral responses. Accordingly, in this study, we evaluated whether long-term aversive effects of morphine withdrawal are altered in Narp KO mice. We found that acute physical signs of morphine withdrawal are unaffected by Narp deletion. However, Narp KO mice acquire and sustain more aversive responses to the environment conditioned with morphine withdrawal than WT controls. Paradoxically, Narp KO mice undergo accelerated extinction of this heightened aversive response. Taken together, these studies suggest that Narp modulates both acquisition and extinction of aversive responses to morphine withdrawal and, therefore, may regulate plasticity processes underlying drug addiction. PMID:18729628

Regulation of hippocampal synaptic plasticity by the tyrosine kinase receptor, REK7/EphA5, and its ligand, AL-1/Ephrin-A5.

PubMed

Gao, W Q; Shinsky, N; Armanini, M P; Moran, P; Zheng, J L; Mendoza-Ramirez, J L; Phillips, H S; Winslow, J W; Caras, I W

1998-08-01

The Eph-related tyrosine kinase receptor, REK7/EphA5, mediates the effects of AL-1/Ephrin-A5 and related ligands and is involved in the guidance of retinal, cortical, and hippocampal axons during development. The continued expression of REK7/EphA5 in the adult brain, in particular in areas associated with a high degree of synaptic plasticity such as the hippocampus, raises the question of its function in the mature nervous system. In this report we examined the role of REK7/EphA5 in synaptic remodeling by asking if agents that either block or activate REK7/EphA5 affect synaptic strength in hippocampal slices from adult mouse brain. We show that a REK7/EphA5 antagonist, soluble REK7/EphA5-IgG, impairs the induction of long-term potentiation (LTP) without affecting other synaptic parameters such as normal synaptic transmission or paired-pulse facilitation. In contrast, perfusion with AL-1/Ephrin-A5-IgG, an activator of REK7/EphA5, induces a sustained increase in normal synaptic transmission that partially mimics LTP. The sustained elevation of normal synaptic transmission could be attributable to a long-lasting binding of the AL-1/Ephrin-A5-IgG to the endogenous REK7/EphA5 receptor, as revealed by immunohistochemistry. Furthermore, maximal electrical induction of LTP occludes the potentiating effects of subsequent treatment with AL-1/Ephrin-A5-IgG. Taken together these results implicate REK7/EphA5 in the regulation of synaptic plasticity in the mature hippocampus and suggest that REK7/EphA5 activation is recruited in the LTP induced by tetanization. Copyright 1998 Academic Press.

Early remodeling of the neocortex upon episodic memory encoding

PubMed Central

Bero, Adam W.; Meng, Jia; Cho, Sukhee; Shen, Abra H.; Canter, Rebecca G.; Ericsson, Maria; Tsai, Li-Huei

2014-01-01

Understanding the mechanisms by which long-term memories are formed and stored in the brain represents a central aim of neuroscience. Prevailing theory suggests that long-term memory encoding involves early plasticity within hippocampal circuits, whereas reorganization of the neocortex is thought to occur weeks to months later to subserve remote memory storage. Here we report that long-term memory encoding can elicit early transcriptional, structural, and functional remodeling of the neocortex. Parallel studies using genome-wide RNA sequencing, ultrastructural imaging, and whole-cell recording in wild-type mice suggest that contextual fear conditioning initiates a transcriptional program in the medial prefrontal cortex (mPFC) that is accompanied by rapid expansion of the synaptic active zone and postsynaptic density, enhanced dendritic spine plasticity, and increased synaptic efficacy. To address the real-time contribution of the mPFC to long-term memory encoding, we performed temporally precise optogenetic inhibition of excitatory mPFC neurons during contextual fear conditioning. Using this approach, we found that real-time inhibition of the mPFC inhibited activation of the entorhinal–hippocampal circuit and impaired the formation of long-term associative memory. These findings suggest that encoding of long-term episodic memory is associated with early remodeling of neocortical circuits, identify the prefrontal cortex as a critical regulator of encoding-induced hippocampal activation and long-term memory formation, and have important implications for understanding memory processing in healthy and diseased brain states. PMID:25071187

Cannabinoid Type 1 Receptors Transiently Silence Glutamatergic Nerve Terminals of Cultured Cerebellar Granule Cells

PubMed Central

Ramírez-Franco, Jorge; Bartolomé-Martín, David; Alonso, Beatris; Torres, Magdalena; Sánchez-Prieto, José

2014-01-01

Cannabinoid receptors are the most abundant G protein-coupled receptors in the brain and they mediate retrograde short-term inhibition of neurotransmitter release, as well as long-term depression of synaptic transmission at many excitatory synapses. The induction of presynaptically silent synapses is a means of modulating synaptic strength, which is important for synaptic plasticity. Persistent activation of cannabinoid type 1 receptors (CB1Rs) mutes GABAergic terminals, although it is unclear if CB1Rs can also induce silencing at glutamatergic synapses. Cerebellar granule cells were transfected with VGLUT1-pHluorin to visualise the exo-endocytotic cycle. We found that prolonged stimulation (10 min) of cannabinoid receptors with the agonist HU-210 induces the silencing of previously active synapses. However, the presynaptic silencing induced by HU-210 is transient as it reverses after 20 min. cAMP with forskolin prevented CB1R-induced synaptic silencing, via activation of the Exchange Protein directly Activated by cAMP (Epac). Furthermore, Epac activation accelerated awakening of already silent boutons. Electron microscopy revealed that silencing was associated with synaptic vesicle (SV) redistribution within the nerve terminal, which diminished the number of vesicles close to the active zone of the plasma membrane. Finally, by combining functional and immunocytochemical approaches, we observed a strong correlation between the release capacity of the nerve terminals and RIM1α protein content, but not that of Munc13-1 protein. These results suggest that prolonged stimulation of cannabinoid receptors can transiently silence glutamatergic nerve terminals. PMID:24533119

Chronic Nicotine Exposure Induces a Long-Lasting and Pathway-Specific Facilitation of LTP in the Amygdala

ERIC Educational Resources Information Center

Huang, Yan-You; Kandel, Eric R.; Levine, Amir

2008-01-01

Nicotine, in the form of tobacco, is the most commonly used drug of abuse. In addition to its rewarding properties, nicotine also affects many cognitive and emotional processes that involve several brain regions, including hippocampus and amygdala. Long-term changes in synaptic strength in these brain regions after drug exposure may be importantly…

Proteasome Inhibition Enhances the Induction and Impairs the Maintenance of Late-Phase Long-Term Potentiation

ERIC Educational Resources Information Center

Dong, Chenghai; Upadhya, Sudarshan C.; Ding, Lan; Smith, Thuy K.; Hegde, Ashok N.

2008-01-01

Protein degradation by the ubiquitin-proteasome pathway plays important roles in synaptic plasticity, but the molecular mechanisms by which proteolysis regulates synaptic strength are not well understood. We investigated the role of the proteasome in hippocampal late-phase long-term potentiation (L-LTP), a model for enduring synaptic plasticity.…

Long term potentiation, but not depression, in interlamellar hippocampus CA1.

PubMed

Sun, Duk-Gyu; Kang, Hyeri; Tetteh, Hannah; Su, Junfeng; Lee, Jihwan; Park, Sung-Won; He, Jufang; Jo, Jihoon; Yang, Sungchil; Yang, Sunggu

2018-03-26

Synaptic plasticity in the lamellar CA3 to CA1 circuitry has been extensively studied while interlamellar CA1 to CA1 connections have not yet received much attention. One of our earlier studies demonstrated that axons of CA1 pyramidal neurons project to neighboring CA1 neurons, implicating information transfer along a longitudinal interlamellar network. Still, it remains unclear whether long-term synaptic plasticity is present within this longitudinal CA1 network. Here, we investigate long-term synaptic plasticity between CA1 pyramidal cells, using in vitro and in vivo extracellular recordings and 3D holography glutamate uncaging. We found that the CA1-CA1 network exhibits NMDA receptor-dependent long-term potentiation (LTP) without direction or layer selectivity. By contrast, we find no significant long-term depression (LTD) under various LTD induction protocols. These results implicate unique synaptic properties in the longitudinal projection suggesting that the interlamellar CA1 network could be a promising structure for hippocampus-related information processing and brain diseases.

Muscarinic Receptor-Dependent Long Term Depression in the Perirhinal Cortex and Recognition Memory are Impaired in the rTg4510 Mouse Model of Tauopathy.

PubMed

Scullion, Sarah E; Barker, Gareth R I; Warburton, E Clea; Randall, Andrew D; Brown, Jonathan T

2018-02-26

Neurodegenerative diseases affecting cognitive dysfunction, such as Alzheimer's disease and fronto-temporal dementia, are often associated impairments in the visual recognition memory system. Recent evidence suggests that synaptic plasticity, in particular long term depression (LTD), in the perirhinal cortex (PRh) is a critical cellular mechanism underlying recognition memory. In this study, we have examined novel object recognition and PRh LTD in rTg4510 mice, which transgenically overexpress tau P301L . We found that 8-9 month old rTg4510 mice had significant deficits in long- but not short-term novel object recognition memory. Furthermore, we also established that PRh slices prepared from rTg4510 mice, unlike those prepared from wildtype littermates, could not support a muscarinic acetylcholine receptor-dependent form of LTD, induced by a 5 Hz stimulation protocol. In contrast, bath application of the muscarinic agonist carbachol induced a form of chemical LTD in both WT and rTg4510 slices. Finally, when rTg4510 slices were preincubated with the acetylcholinesterase inhibitor donepezil, the 5 Hz stimulation protocol was capable of inducing significant levels of LTD. These data suggest that dysfunctional cholinergic innervation of the PRh of rTg4510 mice, results in deficits in synaptic LTD which may contribute to aberrant recognition memory in this rodent model of tauopathy.

[Advances in Acupuncture Mechanism Research on the Changes of Synaptic Plasticity: "Pain Memory" for Chronic Pain].

PubMed

Yang, Yi-Ling; Huang, Jian-Peng; Jiang, Li; Liu, Jian-Hua

2017-12-25

Previous studies have shown that there are many common structures between the neural network of pain and memory, and the main structure in the pain network is also part of the memory network. Chronic pain is characterized by recurrent attacks and is associated with persistent ectopic impulse, which causes changes in synaptic structure and function based on nerve activity. These changes may induce long-term potentiation of synaptic transmission, and ultimately lead to changes in the central nervous system to produce "pain memory". Acupuncture is an effective method in treating chronic pain. It has been proven that acupuncture can affect the spinal cord dorsal horn, hippocampus, cingulate gyrus and other related areas. The possible mechanisms of action include opioid-induced analgesia, activation of glial cells, and the expression of brain derived neurotrophic factor (BDNF). In this study, we systematically review the brain structures, stage of "pain memory" and the mechanisms of acupuncture on synaptic plasticity in chronic pain.

A NMDA receptor glycine site partial agonist, GLYX-13, simultaneously enhances LTP and reduces LTD at Schaffer collateral-CA1 synapses in hippocampus.

PubMed

Zhang, Xiao-lei; Sullivan, John A; Moskal, Joseph R; Stanton, Patric K

2008-12-01

N-methyl-D-aspartate glutamate receptors (NMDARs) are a key route for Ca2+ influx into neurons important to both activity-dependent synaptic plasticity and, when uncontrolled, triggering events that cause neuronal degeneration and death. Among regulatory binding sites on the NMDAR complex is a glycine binding site, distinct from the glutamate binding site, which must be co-activated for NMDAR channel opening. We developed a novel glycine site partial agonist, GLYX-13, which is both nootropic and neuroprotective in vivo. Here, we assessed the effects of GLYX-13 on long-term synaptic plasticity and NMDAR transmission at Schaffer collateral-CA1 synapses in hippocampal slices in vitro. GLYX-13 simultaneously enhanced the magnitude of long-term potentiation (LTP) of synaptic transmission, while reducing long-term depression (LTD). GLYX-13 reduced NMDA receptor-mediated synaptic currents in CA1 pyramidal neurons evoked by low frequency Schaffer collateral stimulation, but enhanced NMDAR currents during high frequency bursts of activity, and these actions were occluded by a saturating concentration of the glycine site agonist d-serine. Direct two-photon imaging of Schaffer collateral burst-evoked increases in [Ca2+] in individual dendritic spines revealed that GLYX-13 selectively enhanced burst-induced NMDAR-dependent spine Ca2+ influx. Examining the rate of MK-801 block of synaptic versus extrasynaptic NMDAR-gated channels revealed that GLYX-13 selectively enhanced activation of burst-driven extrasynaptic NMDARs, with an action that was blocked by the NR2B-selective NMDAR antagonist ifenprodil. Our data suggest that GLYX-13 may have unique therapeutic potential as a learning and memory enhancer because of its ability to simultaneously enhance LTP and suppress LTD.

Two organizational effects of pubertal testosterone in male rats: transient social memory and a shift away from long-term potentiation following a tetanus in hippocampal CA1.

PubMed

Hebbard, Pamela C; King, Rebecca R; Malsbury, Charles W; Harley, Carolyn W

2003-08-01

The organizational role of pubertal androgen receptor (AR) activation in synaptic plasticity in hippocampal CA1 and in social memory was assessed. Earlier data suggest pubertal testosterone reduces adult hippocampal synaptic plasticity. Four groups were created following gonadectomy at the onset of puberty: rats given testosterone; rats given testosterone but with the AR antagonist flutamide, present during puberty; rats given testosterone at the end of puberty; and rats given cholesterol at the end of puberty. A tetanus normally inducing long-term potentiation (LTP) was used to stimulate CA1 in the urethane-anesthetized adults during the dark phase of their cycle. Social memory was assessed prior to electrophysiology. Social memory for a juvenile rat at 120 min was seen only in rats not exposed to AR activation during puberty. Pubertal AR activation may induce the reduced social memory of male rats. Early CA1 LTP occurred following tetanus in rats with no pubertal testosterone. Short-term potentiation occurred in rats exposed to pubertal testosterone. Unexpectedly, rats with pubertal AR activation developed long-term depression (LTD). The same pattern was seen in normal male rats. Lack of LTP during the dark phase is consistent with other data on circadian modulation of CA1 LTP. No correlations were seen among social memory scores and CA1 plasticity measures. These data argue for two organizational effects of pubertal testosterone: (1) CA1 synaptic plasticity shifts away from potentiation toward depression; (2) social memory is reduced. Enduring effects of pubertal androgen on limbic circuits may contribute to reorganized behaviors in the postpubertal period.

Short-term exposure to enriched environment rescues chronic stress-induced impaired hippocampal synaptic plasticity, anxiety, and memory deficits.

PubMed

Bhagya, Venkanna Rao; Srikumar, Bettadapura N; Veena, Jayagopalan; Shankaranarayana Rao, Byrathnahalli S

2017-08-01

Exposure to prolonged stress results in structural and functional alterations in the hippocampus including reduced long-term potentiation (LTP), neurogenesis, spatial learning and working memory impairments, and enhanced anxiety-like behavior. On the other hand, enriched environment (EE) has beneficial effects on hippocampal structure and function, such as improved memory, increased hippocampal neurogenesis, and progressive synaptic plasticity. It is unclear whether exposure to short-term EE for 10 days can overcome restraint stress-induced cognitive deficits and impaired hippocampal plasticity. Consequently, the present study explored the beneficial effects of short-term EE on chronic stress-induced impaired LTP, working memory, and anxiety-like behavior. Male Wistar rats were subjected to chronic restraint stress (6 hr/day) over a period of 21 days, and then they were exposed to EE (6 hr/day) for 10 days. Restraint stress reduced hippocampal CA1-LTP, increased anxiety-like symptoms in elevated plus maze, and impaired working memory in T-maze task. Remarkably, EE facilitated hippocampal LTP, improved working memory performance, and completely overcame the effect of chronic stress on anxiety behavior. In conclusion, exposure to EE can bring out positive effects on synaptic plasticity in the hippocampus and thereby elicit its beneficial effects on cognitive functions. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Acute transient cognitive dysfunction and acute brain injury induced by systemic inflammation occur by dissociable IL-1-dependent mechanisms.

PubMed

Skelly, Donal T; Griffin, Éadaoin W; Murray, Carol L; Harney, Sarah; O'Boyle, Conor; Hennessy, Edel; Dansereau, Marc-Andre; Nazmi, Arshed; Tortorelli, Lucas; Rawlins, J Nicholas; Bannerman, David M; Cunningham, Colm

2018-06-06

Systemic inflammation can impair cognition with relevance to dementia, delirium and post-operative cognitive dysfunction. Episodes of delirium also contribute to rates of long-term cognitive decline, implying that these acute events induce injury. Whether systemic inflammation-induced acute dysfunction and acute brain injury occur by overlapping or discrete mechanisms remains unexplored. Here we show that systemic inflammation, induced by bacterial LPS, produces both working-memory deficits and acute brain injury in the degenerating brain and that these occur by dissociable IL-1-dependent processes. In normal C57BL/6 mice, LPS (100 µg/kg) did not affect working memory but impaired long-term memory consoliodation. However prior hippocampal synaptic loss left mice selectively vulnerable to LPS-induced working memory deficits. Systemically administered IL-1 receptor antagonist (IL-1RA) was protective against, and systemic IL-1β replicated, these working memory deficits. Dexamethasone abolished systemic cytokine synthesis and was protective against working memory deficits, without blocking brain IL-1β synthesis. Direct application of IL-1β to ex vivo hippocampal slices induced non-synaptic depolarisation and irrevesible loss of membrane potential in CA1 neurons from diseased animals and systemic LPS increased apoptosis in the degenerating brain, in an IL-1RI -/- -dependent fashion. The data suggest that LPS induces working memory dysfunction via circulating IL-1β but direct hippocampal action of IL-1β causes neuronal dysfunction and may drive neuronal death. The data suggest that acute systemic inflammation produces both reversible cognitive deficits, resembling delirium, and acute brain injury contributing to long-term cognitive impairment but that these events are mechanistically dissociable. These data have significant implications for management of cognitive dysfunction during acute illness.

Addiction-like Synaptic Impairments in Diet-Induced Obesity.

PubMed

Brown, Robyn Mary; Kupchik, Yonatan Michael; Spencer, Sade; Garcia-Keller, Constanza; Spanswick, David C; Lawrence, Andrew John; Simonds, Stephanie Elise; Schwartz, Danielle Joy; Jordan, Kelsey Ann; Jhou, Thomas Clayton; Kalivas, Peter William

2017-05-01

There is increasing evidence that the pathological overeating underlying some forms of obesity is compulsive in nature and therefore contains elements of an addictive disorder. However, direct physiological evidence linking obesity to synaptic plasticity akin to that occurring in addiction is lacking. We sought to establish whether the propensity to diet-induced obesity (DIO) is associated with addictive-like behavior, as well as synaptic impairments in the nucleus accumbens core considered hallmarks of addiction. Sprague Dawley rats were allowed free access to a palatable diet for 8 weeks then separated by weight gain into DIO-prone and DIO-resistant subgroups. Access to palatable food was then restricted to daily operant self-administration sessions using fixed ratio 1, 3, and 5 and progressive ratio schedules. Subsequently, nucleus accumbens brain slices were prepared, and we tested for changes in the ratio between α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and N-methyl-D-aspartate currents and the ability to exhibit long-term depression. We found that propensity to develop DIO is linked to deficits in the ability to induce long-term depression in the nucleus accumbens, as well as increased potentiation at these synapses as measured by AMPA/N-methyl-D-aspartate currents. Consistent with these impairments, we observed addictive-like behavior in DIO-prone rats, including 1) heightened motivation for palatable food; 2) excessive intake; and 3) increased food seeking when food was unavailable. Our results show overlap between the propensity for DIO and the synaptic changes associated with facets of addictive behavior, supporting partial coincident neurological underpinnings for compulsive overeating and drug addiction. Copyright © 2016 Society of Biological Psychiatry. All rights reserved.

Long-term enhancement of synaptic transmission between antennal lobe and mushroom body in cultured Drosophila brain.

PubMed

Ueno, Kohei; Naganos, Shintaro; Hirano, Yukinori; Horiuchi, Junjiro; Saitoe, Minoru

2013-01-01

In Drosophila, the mushroom body (MB) is a critical brain structure for olfactory associative learning. During aversive conditioning, the MBs are thought to associate odour signals, conveyed by projection neurons (PNs) from the antennal lobe (AL), with shock signals conveyed through ascending fibres of the ventral nerve cord (AFV). Although synaptic transmission between AL and MB might play a crucial role for olfactory associative learning, its physiological properties have not been examined directly. Using a cultured Drosophila brain expressing a Ca(2+) indicator in the MBs, we investigated synaptic transmission and plasticity at the AL-MB synapse. Following stimulation with a glass micro-electrode, AL-induced Ca(2+) responses in the MBs were mediated through Drosophila nicotinic acetylcholine receptors (dnAChRs), while AFV-induced Ca(2+) responses were mediated through Drosophila NMDA receptors (dNRs). AL-MB synaptic transmission was enhanced more than 2 h after the simultaneous 'associative-stimulation' of AL and AFV, and such long-term enhancement (LTE) was specifically formed at the AL-MB synapses but not at the AFV-MB synapses. AL-MB LTE was not induced by intense stimulation of the AL alone, and the LTE decays within 60 min after subsequent repetitive AL stimulation. These phenotypes of associativity, input specificity and persistence of AL-MB LTE are highly reminiscent of olfactory memory. Furthermore, similar to olfactory aversive memory, AL-MB LTE formation required activation of the Drosophila D1 dopamine receptor, DopR, along with dnAChR and dNR during associative stimulations. These physiological and genetic analogies indicate that AL-MB LTE might be a relevant cellular model for olfactory memory.

Long-term enhancement of synaptic transmission between antennal lobe and mushroom body in cultured Drosophila brain

PubMed Central

Ueno, Kohei; Naganos, Shintaro; Hirano, Yukinori; Horiuchi, Junjiro; Saitoe, Minoru

2013-01-01

In Drosophila, the mushroom body (MB) is a critical brain structure for olfactory associative learning. During aversive conditioning, the MBs are thought to associate odour signals, conveyed by projection neurons (PNs) from the antennal lobe (AL), with shock signals conveyed through ascending fibres of the ventral nerve cord (AFV). Although synaptic transmission between AL and MB might play a crucial role for olfactory associative learning, its physiological properties have not been examined directly. Using a cultured Drosophila brain expressing a Ca2+ indicator in the MBs, we investigated synaptic transmission and plasticity at the AL–MB synapse. Following stimulation with a glass micro-electrode, AL-induced Ca2+ responses in the MBs were mediated through Drosophila nicotinic acetylcholine receptors (dnAChRs), while AFV-induced Ca2+ responses were mediated through Drosophila NMDA receptors (dNRs). AL–MB synaptic transmission was enhanced more than 2 h after the simultaneous ‘associative-stimulation’ of AL and AFV, and such long-term enhancement (LTE) was specifically formed at the AL–MB synapses but not at the AFV–MB synapses. AL–MB LTE was not induced by intense stimulation of the AL alone, and the LTE decays within 60 min after subsequent repetitive AL stimulation. These phenotypes of associativity, input specificity and persistence of AL–MB LTE are highly reminiscent of olfactory memory. Furthermore, similar to olfactory aversive memory, AL–MB LTE formation required activation of the Drosophila D1 dopamine receptor, DopR, along with dnAChR and dNR during associative stimulations. These physiological and genetic analogies indicate that AL–MB LTE might be a relevant cellular model for olfactory memory. PMID:23027817

Modulatory role of androgenic and estrogenic neurosteroids in determining the direction of synaptic plasticity in the CA1 hippocampal region of male rats.

PubMed

Pettorossi, Vito Enrico; Di Mauro, Michela; Scarduzio, Mariangela; Panichi, Roberto; Tozzi, Alessandro; Calabresi, Paolo; Grassi, Silvarosa

2013-12-01

Estrogenic and androgenic neurosteroids can rapidly modulate synaptic plasticity in the brain through interaction with membrane receptors for estrogens (ERs) and androgens (ARs). We used electrophysiological recordings in slices of young and adolescent male rats to explore the influence of sex neurosteroids on synaptic plasticity in the CA1 hippocampal region, by blocking ARs or ERs during induction of long-term depression (LTD) and depotentiation (DP) by low-frequency stimulation (LFS) and long-term potentiation (LTP) by high-frequency stimulation (HFS). We found that LTD and DP depend on ARs, while LTP on ERs in both age groups. Accordingly, the AR blocker flutamide affected induction of LTD reverting it into LTP, and prevented DP, while having no effect on HFS-dependent LTP. Conversely, ER blockade with ICI 182,780 (ICI) markedly reduced LTP, but did not influence LTD and DP. However, the receptor blockade did not affect the maintenance of either LTD or LTP. Moreover, we found that similar to LTP and LTD induced in control condition, the LTP unveiled by flutamide during LFS and residual LTP induced by HFS under ICI depended on N-methyl-d aspartate receptor (NMDAR) activation. Furthermore, as the synaptic paired-pulse facilitation (PPF) was not affected by either AR or ER blockade, we suggest that sex neurosteroids act primarily at a postsynaptic level. This study demonstrates for the first time the crucial role of estrogenic and androgenic neurosteroids in determining the sign of hippocampal synaptic plasticity in male rat and the activity-dependent recruitment of androgenic and estrogenic pathways leading to LTD and LTP, respectively.

In vivo activation of Wnt signaling pathway enhances cognitive function of adult mice and reverses cognitive deficits in an Alzheimer's disease model.

PubMed

Vargas, Jessica Y; Fuenzalida, Marco; Inestrosa, Nibaldo C

2014-02-05

The role of the Wnt signaling pathway during synaptic development has been well established. In the adult brain, different components of Wnt signaling are expressed, but little is known about its role in mature synapses. Emerging in vitro studies have implicated Wnt signaling in synaptic plasticity. Furthermore, activation of Wnt signaling has shown to protect against amyloid-β-induced synaptic impairment. The present study provides the first evidence that in vivo activation of Wnt signaling improves episodic memory, increases excitatory synaptic transmission, and enhances long-term potentiation in adult wild-type mice. Moreover, the activation of Wnt signaling also rescues memory loss and improves synaptic dysfunction in APP/PS1-transgenic mice that model the amyloid pathology of Alzheimer's diseases. These findings indicate that Wnt signaling modulates cognitive function in the adult brain and could be a novel promising target for Alzheimer's disease therapy.

Influence of testosterone on synaptic transmission in the rat medial vestibular nuclei: estrogenic and androgenic effects.

PubMed

Grassi, S; Frondaroli, A; Di Mauro, M; Pettorossi, V E

2010-12-15

In brainstem slices of young male rat, we investigated the influence of the neuroactive steroid testosterone (T) on the synaptic responses by analyzing the field potential evoked in the medial vestibular nucleus (MVN) by vestibular afferent stimulation. T induced three distinct and independent long-term synaptic changes: fast long-lasting potentiation (fLP), slow long-lasting potentiation (sLP) and long-lasting depression (LD). The fLP was mediated by 17β-estradiol (E(2)) since it was abolished by blocking the estrogen receptors (ERs) or the enzyme converting T to E(2). Conversely, sLP and LD were mediated by 5α-dihydrotestosterone (DHT) since they were prevented by blocking the androgen receptors (ARs) or the enzyme converting T to DHT. Therefore, the synaptic effects of T were mediated by its androgenic or estrogenic metabolites. The pathways leading to estrogenic and androgenic conversion of T might be co-localized since, the occurrence of fLP under block of androgenic pathway, and that of sLP and LD under estrogenic block, were higher than those observed without blocks. In case of co-localization, the effect on synaptic transmission should depend on the prevailing enzymatic activity. We conclude that circulating and neuronal T can remarkably influence synaptic responses of the vestibular neurons in different and opposite ways, depending on its conversion to estrogenic or androgenic metabolites. Copyright © 2010 IBRO. Published by Elsevier Ltd. All rights reserved.

Hunger States Control the Directions of Synaptic Plasticity via Switching Cell Type-Specific Subunits of NMDA Receptors.

PubMed

Qi, Yong; Yang, Yunlei

2015-09-23

It remains largely unknown whether and how hunger states control activity-dependent synaptic plasticity, such as long-term potentiation (LTP) and long-term depression (LTD). We here report that both LTP and LTD of excitatory synaptic strength within the appetite control circuits residing in hypothalamic arcuate nucleus (ARC) behave in a manner of hunger states dependence and cell type specificity. For instance, we find that tetanic stimulation induces LTP at orexigenic agouti-related protein (AgRP) neurons in ad libitum fed mice, whereas it induces LTD in food-deprived mice. In an opposite direction, the same induction protocol induces LTD at anorexigenic pro-opiomelanocortin (POMC) neurons in fed mice but weak LTP in deprived mice. Mechanistically, we also find that food deprivation increases the expressions of NR2C/NR2D/NR3-containing NMDA receptors (NMDARs) at AgRP neurons that contribute to the inductions of LTD, whereas it decreases their expressions at POMC neurons. Collectively, our data reveal that hunger states control the directions of activity-dependent synaptic plasticity by switching NMDA receptor subpopulations in a cell type-specific manner, providing insights into NMDAR-mediated interactions between energy states and associative memory. Significance statement: Based on the experiments performed in this study, we demonstrate that activity-dependent synaptic plasticity is also under the control of energy states by regulating NMDAR subpopulations in a cell type-specific manner. We thus propose a reversible memory configuration constructed from energy states-dependent cell type-specific bidirectional conversions of LTP and LTD. Together with the distinct functional roles played by NMDAR signaling in the control of food intake and energy states, these findings reveal a new reciprocal interaction between energy states and associative memory, one that might serve as a target for therapeutic treatments of the energy-related memory disorders or vice versa. Copyright © 2015 the authors 0270-6474/15/3513171-12$15.00/0.

Neutralization of Nogo-A Enhances Synaptic Plasticity in the Rodent Motor Cortex and Improves Motor Learning in Vivo

PubMed Central

Weinmann, Oliver; Kellner, Yves; Yu, Xinzhu; Vicente, Raul; Gullo, Miriam; Kasper, Hansjörg; Lussi, Karin; Ristic, Zorica; Luft, Andreas R.; Rioult-Pedotti, Mengia; Zuo, Yi; Zagrebelsky, Marta; Schwab, Martin E.

2014-01-01

The membrane protein Nogo-A is known as an inhibitor of axonal outgrowth and regeneration in the CNS. However, its physiological functions in the normal adult CNS remain incompletely understood. Here, we investigated the role of Nogo-A in cortical synaptic plasticity and motor learning in the uninjured adult rodent motor cortex. Nogo-A and its receptor NgR1 are present at cortical synapses. Acute treatment of slices with function-blocking antibodies (Abs) against Nogo-A or against NgR1 increased long-term potentiation (LTP) induced by stimulation of layer 2/3 horizontal fibers. Furthermore, anti-Nogo-A Ab treatment increased LTP saturation levels, whereas long-term depression remained unchanged, thus leading to an enlarged synaptic modification range. In vivo, intrathecal application of Nogo-A-blocking Abs resulted in a higher dendritic spine density at cortical pyramidal neurons due to an increase in spine formation as revealed by in vivo two-photon microscopy. To investigate whether these changes in synaptic plasticity correlate with motor learning, we trained rats to learn a skilled forelimb-reaching task while receiving anti-Nogo-A Abs. Learning of this cortically controlled precision movement was improved upon anti-Nogo-A Ab treatment. Our results identify Nogo-A as an influential molecular modulator of synaptic plasticity and as a regulator for learning of skilled movements in the motor cortex. PMID:24966370

Ketamine Protects Gamma Oscillations by Inhibiting Hippocampal LTD

PubMed Central

Huang, Lanting; Yang, Xiu-Juan; Huang, Ying; Sun, Eve Y.

2016-01-01

NMDA receptors have been widely reported to be involved in the regulation of synaptic plasticity through effects on long-term potentiation (LTP) and long-term depression (LTD). LTP and LTD have been implicated in learning and memory processes. Besides synaptic plasticity, it is known that the phenomenon of gamma oscillations is critical in cognitive functions. Synaptic plasticity has been widely studied, however it is still not clear, to what degree synaptic plasticity regulates the oscillations of neuronal networks. Two NMDA receptor antagonists, ketamine and memantine, have been shown to regulate LTP and LTD, to promote cognitive functions, and have even been reported to bring therapeutic effects in major depression and Alzheimer’s disease respectively. These compounds allow us to investigate the putative interrelationship between network oscillations and synaptic plasticity and to learn more about the mechanisms of their therapeutic effects. In the present study, we have identified that ketamine and memantine could inhibit LTD, without impairing LTP in the CA1 region of mouse hippocampus, which may underlie the mechanism of these drugs’ therapeutic effects. Our results suggest that NMDA-induced LTD caused a marked loss in the gamma power, and pretreatment with 10 μM ketamine prevented the oscillatory loss via its inhibitory effect on LTD. Our study provides a new understanding of the role of NMDA receptors on hippocampal plasticity and oscillations. PMID:27467732

Forebrain-specific, conditional silencing of Staufen2 alters synaptic plasticity, learning, and memory in rats.

PubMed

Berger, Stefan M; Fernández-Lamo, Iván; Schönig, Kai; Fernández Moya, Sandra M; Ehses, Janina; Schieweck, Rico; Clementi, Stefano; Enkel, Thomas; Grothe, Sascha; von Bohlen Und Halbach, Oliver; Segura, Inmaculada; Delgado-García, José María; Gruart, Agnès; Kiebler, Michael A; Bartsch, Dusan

2017-11-17

Dendritic messenger RNA (mRNA) localization and subsequent local translation in dendrites critically contributes to synaptic plasticity and learning and memory. Little is known, however, about the contribution of RNA-binding proteins (RBPs) to these processes in vivo. To delineate the role of the double-stranded RBP Staufen2 (Stau2), we generate a transgenic rat model, in which Stau2 expression is conditionally silenced by Cre-inducible expression of a microRNA (miRNA) targeting Stau2 mRNA in adult forebrain neurons. Known physiological mRNA targets for Stau2, such as RhoA, Complexin 1, and Rgs4 mRNAs, are found to be dysregulated in brains of Stau2-deficient rats. In vivo electrophysiological recordings reveal synaptic strengthening upon stimulation, showing a shift in the frequency-response function of hippocampal synaptic plasticity to favor long-term potentiation and impair long-term depression in Stau2-deficient rats. These observations are accompanied by deficits in hippocampal spatial working memory, spatial novelty detection, and in tasks investigating associative learning and memory. Together, these experiments reveal a critical contribution of Stau2 to various forms of synaptic plasticity including spatial working memory and cognitive management of new environmental information. These findings might contribute to the development of treatments for conditions associated with learning and memory deficits.

Daily Acclimation Handling Does Not Affect Hippocampal Long-Term Potentiation or Cause Chronic Sleep Deprivation in Mice

PubMed Central

Vecsey, Christopher G.; Wimmer, Mathieu E. J.; Havekes, Robbert; Park, Alan J.; Perron, Isaac J.; Meerlo, Peter; Abel, Ted

2013-01-01

Study Objectives: Gentle handling is commonly used to perform brief sleep deprivation in rodents. It was recently reported that daily acclimation handling, which is often used before behavioral assays, causes alterations in sleep, stress, and levels of N-methyl-D-aspartate receptor subunits prior to the actual period of sleep deprivation. It was therefore suggested that acclimation handling could mediate some of the observed effects of subsequent sleep deprivation. Here, we examine whether acclimation handling, performed as in our sleep deprivation studies, alters sleep/wake behavior, stress, or forms of hippocampal synaptic plasticity that are impaired by sleep deprivation. Design: Adult C57BL/6J mice were either handled daily for 6 days or were left undisturbed in their home cages. On the day after the 6th day of handling, long-term potentiation (LTP) was induced in hippocampal slices with spaced four-train stimulation, which we previously demonstrated to be impaired by brief sleep deprivation. Basal synaptic properties were also assessed. In three other sets of animals, activity monitoring, polysomnography, and stress hormone measurements were performed during the 6 days of handling. Results: Daily gentle handling alone does not alter LTP, rest/activity patterns, or sleep/wake architecture. Handling initially induces a minimal stress response, but by the 6th day, stress hormone levels are unaltered by handling. Conclusion: It is possible to handle mice daily to accustom them to the researcher without causing alterations in sleep, stress, or synaptic plasticity in the hippocampus. Therefore, effects of acclimation handling cannot explain the impairments in signaling mechanisms, synaptic plasticity, and memory that result from brief sleep deprivation. Citation: Vecsey CG; Wimmer MEJ; Havekes R; Park AJ; Perron IJ; Meerlo P; Abel T. Daily acclimation handling does not affect hippocampal long-term potentiation or cause chronic sleep deprivation in mice. SLEEP 2013;36(4):601-607. PMID:23565007

Synaptic plasticity, neural circuits, and the emerging role of altered short-term information processing in schizophrenia

PubMed Central

Crabtree, Gregg W.; Gogos, Joseph A.

2014-01-01

Synaptic plasticity alters the strength of information flow between presynaptic and postsynaptic neurons and thus modifies the likelihood that action potentials in a presynaptic neuron will lead to an action potential in a postsynaptic neuron. As such, synaptic plasticity and pathological changes in synaptic plasticity impact the synaptic computation which controls the information flow through the neural microcircuits responsible for the complex information processing necessary to drive adaptive behaviors. As current theories of neuropsychiatric disease suggest that distinct dysfunctions in neural circuit performance may critically underlie the unique symptoms of these diseases, pathological alterations in synaptic plasticity mechanisms may be fundamental to the disease process. Here we consider mechanisms of both short-term and long-term plasticity of synaptic transmission and their possible roles in information processing by neural microcircuits in both health and disease. As paradigms of neuropsychiatric diseases with strongly implicated risk genes, we discuss the findings in schizophrenia and autism and consider the alterations in synaptic plasticity and network function observed in both human studies and genetic mouse models of these diseases. Together these studies have begun to point toward a likely dominant role of short-term synaptic plasticity alterations in schizophrenia while dysfunction in autism spectrum disorders (ASDs) may be due to a combination of both short-term and long-term synaptic plasticity alterations. PMID:25505409

Long-term plasticity in identified hippocampal GABAergic interneurons in the CA1 area in vivo.

PubMed

Lau, Petrina Yau-Pok; Katona, Linda; Saghy, Peter; Newton, Kathryn; Somogyi, Peter; Lamsa, Karri P

2017-05-01

Long-term plasticity is well documented in synapses between glutamatergic principal cells in the cortex both in vitro and in vivo. Long-term potentiation (LTP) and -depression (LTD) have also been reported in glutamatergic connections to hippocampal GABAergic interneurons expressing parvalbumin (PV+) or nitric oxide synthase (NOS+) in brain slices, but plasticity in these cells has not been tested in vivo. We investigated synaptically-evoked suprathreshold excitation of identified hippocampal neurons in the CA1 area of urethane-anaesthetized rats. Neurons were recorded extracellularly with glass microelectrodes, and labelled with neurobiotin for anatomical analyses. Single-shock electrical stimulation of afferents from the contralateral CA1 elicited postsynaptic action potentials with monosynaptic features showing short delay (9.95 ± 0.41 ms) and small jitter in 13 neurons through the commissural pathway. Theta-burst stimulation (TBS) generated LTP of the synaptically-evoked spike probability in pyramidal cells, and in a bistratified cell and two unidentified fast-spiking interneurons. On the contrary, PV+ basket cells and NOS+ ivy cells exhibited either LTD or LTP. An identified axo-axonic cell failed to show long-term change in its response to stimulation. Discharge of the cells did not explain whether LTP or LTD was generated. For the fast-spiking interneurons, as a group, no correlation was found between plasticity and local field potential oscillations (1-3 or 3-6 Hz components) recorded immediately prior to TBS. The results demonstrate activity-induced long-term plasticity in synaptic excitation of hippocampal PV+ and NOS+ interneurons in vivo. Physiological and pathological activity patterns in vivo may generate similar plasticity in these interneurons.

Dopaminergic tone persistently regulates voltage-gated ion current densities through the D1R-PKA axis, RNA polymerase II transcription, RNAi, mTORC1, and translation

PubMed Central

Krenz, Wulf-Dieter C.; Parker, Anna R.; Rodgers, Edmund W.; Baro, Deborah J.

2014-01-01

Long-term intrinsic and synaptic plasticity must be coordinated to ensure stability and flexibility in neuronal circuits. Coordination might be achieved through shared transduction components. Dopamine (DA) is a well-established participant in many forms of long-term synaptic plasticity. Recent work indicates that DA is also involved in both activity-dependent and -independent forms of long-term intrinsic plasticity. We previously examined DA-enabled long-term intrinsic plasticity in a single identified neuron. The lateral pyloric (LP) neuron is a component of the pyloric network in the crustacean stomatogastric nervous system (STNS). LP expresses type 1 DA receptors (D1Rs). A 1 h bath application of 5 nM DA followed by washout produced a significant increase in the maximal conductance (Gmax) of the LP transient potassium current (IA) that peaked ~4 h after the start of DA application; furthermore, if a change in neuronal activity accompanied the DA application, then a persistent increase in the LP hyperpolarization activated current (Ih) was also observed. Here, we repeated these experiments with pharmacological and peptide inhibitors to determine the cellular processes and signaling proteins involved. We discovered that the persistent, DA-induced activity-independent (IA) and activity-dependent (Ih) changes in ionic conductances depended upon many of the same elements that enable long-term synaptic plasticity, including: the D1R-protein kinase A (PKA) axis, RNA polymerase II transcription, RNA interference (RNAi), and mechanistic target of rapamycin (mTOR)-dependent translation. We interpret the data to mean that increasing the tonic DA concentration enhances expression of a microRNA(s) (miRs), resulting in increased cap-dependent translation of an unidentified protein(s). PMID:24596543

The ubiquitin-proteasome system is necessary for long-term synaptic depression in Aplysia.

PubMed

Fioravante, Diasinou; Liu, Rong-Yu; Byrne, John H

2008-10-08

The neuropeptide Phe-Met-Arg-Phe-NH(2) (FMRFa) can induce transcription-dependent long-term synaptic depression (LTD) in Aplysia sensorimotor synapses. We investigated the role of the ubiquitin-proteasome system and the regulation of one of its components, ubiquitin C-terminal hydrolase (ap-uch), in LTD. LTD was sensitive to presynaptic inhibition of the proteasome and was associated with upregulation of ap-uch mRNA and protein. This upregulation appeared to be mediated by CREB2, which is generally regarded as a transcription repressor. Binding of CREB2 to the promoter region of ap-uch was accompanied by histone hyperacetylation, suggesting that CREB2 cannot only inhibit but also promote gene expression. CREB2 was phosphorylated after FMRFa, and blocking phospho-CREB2 blocked LTD. In addition to changes in the expression of ap-uch, the synaptic vesicle-associated protein synapsin was downregulated in LTD in a proteasome-dependent manner. These results suggest that proteasome-mediated protein degradation is engaged in LTD and that CREB2 may act as a transcription activator under certain conditions.

Prevention of plasticity of endocannabinoid signaling inhibits persistent limbic hyperexcitability caused by developmental seizures.

PubMed

Chen, Kang; Neu, Axel; Howard, Allyson L; Földy, Csaba; Echegoyen, Julio; Hilgenberg, Lutz; Smith, Martin; Mackie, Ken; Soltesz, Ivan

2007-01-03

Depolarization-induced suppression of inhibition (DSI) is an endocannabinoid-mediated short-term plasticity mechanism that couples postsynaptic Ca2+ rises to decreased presynaptic GABA release. Whether the gain of this retrograde synaptic mechanism is subject to long-term modulation by glutamatergic excitatory inputs is not known. Here, we demonstrate that activity-dependent long-term DSI potentiation takes place in hippocampal slices after tetanic stimulation of Schaffer collateral synapses. This activity-dependent, long-term plasticity of endocannabinoid signaling was specific to GABAergic synapses, as it occurred without increases in the depolarization-induced suppression of excitation. Induction of tetanus-induced DSI potentiation in vitro required a complex pathway involving AMPA/kainate and metabotropic glutamate receptor as well as CB1 receptor activation. Because DSI potentiation has been suggested to play a role in persistent limbic hyperexcitability after prolonged seizures in the developing brain, we used these mechanistic insights into activity-dependent DSI potentiation to test whether interference with the induction of DSI potentiation prevents seizure-induced long-term hyperexcitability. The results showed that the in vitro, tetanus-induced DSI potentiation was occluded by previous in vivo fever-induced (febrile) seizures, indicating a common pathway. Accordingly, application of CB1 receptor antagonists during febrile seizures in vivo blocked the seizure-induced persistent DSI potentiation, abolished the seizure-induced upregulation of CB1 receptors, and prevented the emergence of long-term limbic hyperexcitability. These results reveal a new form of activity-dependent, long-term plasticity of endocannabinoid signaling at perisomatic GABAergic synapses, and demonstrate that blocking the induction of this plasticity abolishes the long-term effects of prolonged febrile seizures in the developing brain.

Narp regulates long-term aversive effects of morphine withdrawal.

PubMed

Reti, Irving M; Crombag, Hans S; Takamiya, Kogo; Sutton, Jeffrey M; Guo, Ning; Dinenna, Megan L; Huganir, Richard L; Holland, Peter C; Baraban, Jay M

2008-08-01

Although long-lasting effects of drug withdrawal are thought to play a key role in motivating continued drug use, the mechanisms mediating this type of drug-induced plasticity are unclear. Because Narp is an immediate early gene product that is secreted at synaptic sites and binds to alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, it has been implicated in mediating enduring forms of synaptic plasticity. In previous studies, the authors found that Narp is selectively induced by morphine withdrawal in the extended amygdala, a group of limbic nuclei that mediate aversive behavioral responses. Accordingly, in this study, the authors evaluate whether long-term aversive effects of morphine withdrawal are altered in Narp knockout (KO) mice. The authors found that acute physical signs of morphine withdrawal are unaffected by Narp deletion. However, Narp KO mice acquire and sustain more aversive responses to the environment conditioned with morphine withdrawal than do wild type (WT) controls. Paradoxically, Narp KO mice undergo accelerated extinction of this heightened aversive response. Taken together, these studies suggest that Narp modulates both acquisition and extinction of aversive responses to morphine withdrawal and, therefore, may regulate plasticity processes underlying drug addiction.

Effect of spike-timing-dependent plasticity on stochastic burst synchronization in a scale-free neuronal network.

PubMed

Kim, Sang-Yoon; Lim, Woochang

2018-06-01

We consider an excitatory population of subthreshold Izhikevich neurons which cannot fire spontaneously without noise. As the coupling strength passes a threshold, individual neurons exhibit noise-induced burstings. This neuronal population has adaptive dynamic synaptic strengths governed by the spike-timing-dependent plasticity (STDP). However, STDP was not considered in previous works on stochastic burst synchronization (SBS) between noise-induced burstings of sub-threshold neurons. Here, we study the effect of additive STDP on SBS by varying the noise intensity D in the Barabási-Albert scale-free network (SFN). One of our main findings is a Matthew effect in synaptic plasticity which occurs due to a positive feedback process. Good burst synchronization (with higher bursting measure) gets better via long-term potentiation (LTP) of synaptic strengths, while bad burst synchronization (with lower bursting measure) gets worse via long-term depression (LTD). Consequently, a step-like rapid transition to SBS occurs by changing D , in contrast to a relatively smooth transition in the absence of STDP. We also investigate the effects of network architecture on SBS by varying the symmetric attachment degree [Formula: see text] and the asymmetry parameter [Formula: see text] in the SFN, and Matthew effects are also found to occur by varying [Formula: see text] and [Formula: see text]. Furthermore, emergences of LTP and LTD of synaptic strengths are investigated in details via our own microscopic methods based on both the distributions of time delays between the burst onset times of the pre- and the post-synaptic neurons and the pair-correlations between the pre- and the post-synaptic instantaneous individual burst rates (IIBRs). Finally, a multiplicative STDP case (depending on states) with soft bounds is also investigated in comparison with the additive STDP case (independent of states) with hard bounds. Due to the soft bounds, a Matthew effect with some quantitative differences is also found to occur for the case of multiplicative STDP.

Characterization of postsynaptic calcium signals in the pyramidal neurons of anterior cingulate cortex

PubMed Central

Li, Xu-Hui; Song, Qian; Chen, Tao; Zhuo, Min

2017-01-01

Calcium signaling is critical for synaptic transmission and plasticity. N-methyl-D-aspartic acid (NMDA) receptors play a key role in synaptic potentiation in the anterior cingulate cortex. Most previous studies of calcium signaling focus on hippocampal neurons, little is known about the activity-induced calcium signals in the anterior cingulate cortex. In the present study, we show that NMDA receptor-mediated postsynaptic calcium signals induced by different synaptic stimulation in anterior cingulate cortex pyramidal neurons. Single and multi-action potentials evoked significant suprathreshold Ca2+ increases in somas and spines. Both NMDA receptors and voltage-gated calcium channels contributed to this increase. Postsynaptic Ca2+signals were induced by puff-application of glutamate, and a NMDA receptor antagonist AP5 blocked these signals in both somas and spines. Finally, long-term potentiation inducing protocols triggered postsynaptic Ca2+ influx, and these influx were NMDA receptor dependent. Our results provide the first study of calcium signals in the anterior cingulate cortex and demonstrate that NMDA receptors play important roles in postsynaptic calcium signals in anterior cingulate cortex pyramidal neurons. PMID:28726541

Ablating ErbB4 in PV neurons attenuates synaptic and cognitive deficits in an animal model of Alzheimer's disease.

PubMed

Zhang, Heng; Zhang, Ling; Zhou, Dongming; He, Xiao; Wang, Dongpi; Pan, Hongyu; Zhang, Xiaoqin; Mei, Yufei; Qian, Qi; Zheng, Tingting; Jones, Frank E; Sun, Binggui

2017-10-01

Accumulation of amyloid β (Aβ) induces neuronal, synaptic, and cognitive deficits in patients and animal models of Alzheimer's disease (AD). The underlying mechanisms, however, remain to be fully elucidated. In the present study, we found that Aβ interacted with ErbB4, a member of the receptor tyrosine kinase family and mainly expressed in GABAergic interneurons. Deleting ErbB4 in parvalbumin-expressing neurons (PV neurons) significantly attenuated oligomeric Aβ-induced suppression of long term potentiation (LTP). Furthermore, specific ablation of ErbB4 in PV neurons via Cre/loxP system greatly improved spatial memory and synaptic plasticity in the hippocampus of hAPP-J20 mice. The deposition of Aβ detected by 3D6 and Thioflavin S staining and the proteolytic processing of hAPP analyzed by western blotting were not affected in the hippocampus of hAPP-J20 mice by deleting ErbB4 in PV neurons. Our data suggested that ErbB4 in PV neurons mediated Aβ-induced synaptic and cognitive dysfunctions without affecting Aβ levels. Copyright © 2017 Elsevier Inc. All rights reserved.

Calcium/Calmodulin-dependent Protein Kinase II is a Ubiquitous Molecule in Human Long-term Memory Synaptic Plasticity: A Systematic Review

PubMed Central

Ataei, Negar; Sabzghabaee, Ali Mohammad; Movahedian, Ahmad

2015-01-01

Background: Long-term memory is based on synaptic plasticity, a series of biochemical mechanisms include changes in structure and proteins of brain's neurons. In this article, we systematically reviewed the studies that indicate calcium/calmodulin kinase II (CaMKII) is a ubiquitous molecule among different enzymes involved in human long-term memory and the main downstream signaling pathway of long-term memory. Methods: All of the observational, case–control and review studies were considered and evaluated by the search engines PubMed, Cochrane Central Register of Controlled Trials and ScienceDirect Scopus between 1990 and February 2015. We did not carry out meta-analysis. Results: At the first search, it was fined 1015 articles which included “synaptic plasticity” OR “neuronal plasticity” OR “synaptic density” AND memory AND “molecular mechanism” AND “calcium/calmodulin-dependent protein kinase II” OR CaMKII as the keywords. A total of 335 articles were duplicates in the databases and eliminated. A total of 680 title articles were evaluated. Finally, 40 articles were selected as reference. Conclusions: The studies have shown the most important intracellular signal of long-term memory is calcium-dependent signals. Calcium linked calmodulin can activate CaMKII. After receiving information for learning and memory, CaMKII is activated by Glutamate, the most important neurotransmitter for memory-related plasticity. Glutamate activates CaMKII and it plays some important roles in synaptic plasticity modification and long-term memory. PMID:26445635

Priming of Short-Term Potentiation and Synaptic Tagging/Capture Mechanisms by Ryanodine Receptor Activation in Rat Hippocampal CA1

ERIC Educational Resources Information Center

Sajikumar, Sreedharan; Li, Qin; Abraham, Wickliffe C.; Xiao, Zhi Cheng

2009-01-01

Activity-dependent changes in synaptic strength such as long-term potentiation (LTP) and long-term depression (LTD) are considered to be cellular mechanisms underlying learning and memory. Strengthening of a synapse for a few seconds or minutes is termed short-term potentiation (STP) and is normally unable to take part in the processes of synaptic…

PINK1 heterozygous mutations induce subtle alterations in dopamine-dependent synaptic plasticity

PubMed Central

Madeo, G.; Schirinzi, T.; Martella, G.; Latagliata, E.C.; Puglisi, F.; Shen, J.; Valente, E.M.; Federici, M.; Mercuri, N.B.; Puglisi-Allegra, S.; Bonsi, P.; Pisani, A.

2014-01-01

Background Homozygous or compound heterozygous mutations in the PTEN-induced kinase 1 (PINK1) gene are causative of autosomal recessive, early onset PD. Single heterozygous mutations have been repeatedly detected in a subset of patients as well as in non-affected subjects, and their significance has long been debated. Several neurophysiological studies from non-manifesting PINK1 heterozygotes have shown the existence of neural plasticity abnormalities, indicating the presence of specific endophenotypic traits in the heterozygous state. Methods In the present study, we performed a functional analysis of corticostriatal synaptic plasticity in heterozygous PINK1 knock-out (PINK1+/−) mice by a multidisciplinary approach. Results We found that, despite a normal motor behavior, repetitive activation of cortical inputs to striatal neurons failed to induce long-term potentiation (LTP), whereas long-term depression (LTD) was normal. Although nigral dopaminergic neurons exhibited normal morphological and electrophysiological properties with normal responses to dopamine receptor activation, we measured a significantly lower dopamine release in the striatum of PINK1+/−, compared to control mice, suggesting that a decrease in stimulus-evoked dopamine overflow acts as a major determinant for the LTP deficit. Accordingly, pharmacological agents capable of increasing the availability of dopamine in the synaptic cleft restored a normal LTP in heterozygous mice. Moreover, MAO-B inhibitors rescued a physiological LTP and a normal dopamine release. Conclusions Our results provide novel evidence for striatal plasticity abnormalities even in the heterozygous disease state. These alterations might be considered an endophenotype to this monogenic form of PD, and a valid tool to characterize early disease stage and design possible disease-modifying therapies. PMID:24167038

Kindling-Induced Changes in Plasticity of the Rat Amygdala and Hippocampus

ERIC Educational Resources Information Center

Schubert, Manja; Siegmund, Herbert; Pape, Hans-Christian; Albrecht, Doris

2005-01-01

Temporal lobe epilepsy (TLE) is often accompanied by interictal behavioral abnormalities, such as fear and memory impairment. To identify possible underlying substrates, we analyzed long-term synaptic plasticity in two relevant brain regions, the lateral amygdala (LA) and the CA1 region of the hippocampus, in the kindling model of epilepsy. Wistar…

Pharmacological activation of CB1 receptor modulates long term potentiation by interfering with protein synthesis.

PubMed

Navakkode, Sheeja; Korte, Martin

2014-04-01

Cognitive impairment is one of the most important side effects associated with cannabis drug abuse, as well as the serious issue concerning the therapeutic use of cannabinoids. Cognitive impairments and neuropsychiatric symptoms are caused by early synaptic dysfunctions, such as loss of synaptic connections in different brain structures including the hippocampus, a region that is believed to play an important role in certain forms of learning and memory. We report here that metaplastic priming of synapses with a cannabinoid type 1 receptor (CB1 receptor) agonist, WIN55,212-2 (WIN55), significantly impaired long-term potentiation in the apical dendrites of CA1 pyramidal neurons. Interestingly, the CB1 receptor exerts its effect by altering the balance of protein synthesis machinery towards higher protein production. Therefore the activation of CB1 receptor, prior to strong tetanization, increased the propensity to produce new proteins. In addition, WIN55 priming resulted in the expression of late-LTP in a synaptic input that would have normally expressed early-LTP, thus confirming that WIN55 priming of LTP induces new synthesis of plasticity-related proteins. Furthermore, in addition to the effects on protein translation, WIN55 also induced synaptic deficits due to the ability of CB1 receptors to inhibit the release of acetylcholine, mediated by both muscarinic and nicotinic acetylcholine receptors. Taken together this supports the notion that the modulation of cholinergic activity by CB1 receptor activation is one mechanism that regulates the synthesis of plasticity-related proteins. Copyright © 2014 Elsevier Ltd. All rights reserved.

NMDA receptor-mediated long term modulation of electrically evoked field potentials in the rat medial vestibular nuclei.

PubMed

Capocchi, G; Della Torre, G; Grassi, S; Pettorossi, V E; Zampolini, M

1992-01-01

The effect of high frequency stimulation (HFS) of the primary vestibular afferents on field potentials recorded in the ipsilateral Medial Vestibular Nuclei (MVN) was studied. Our results show that potentiation and depression can be induced in different portions of MVN, which are distinguishable by their anatomical organization. HFS induces potentiation of the monosynaptic component in the ventral portion of the MVN, whereas it provokes depression of the polysynaptic component in the dorsal portion of the same nucleus. The induction of both potentiation and depression was blocked under AP5 perfusion, thus demonstrating that NMDA receptor activation mediates both phenomena. Furthermore, the finding that the field potentials were not modified during perfusion with DL-AP5, as previously reported, supports the hypothesis that NMDA receptors are not involved in the normal synaptic transmission from the primary vestibular afferent fibres, but are only activated following hyperstimulation of this afferent system. Our results suggest that the mechanisms of long term modification of synaptic efficacy observed in MVN may underlie the plasticity phenomena occurring in vestibular nuclei.

Molecular mechanisms of group I metabotropic glutamate receptor mediated LTP and LTD in basolateral amygdala in vitro.

PubMed

Chen, A; Hu, W W; Jiang, X L; Potegal, M; Li, H

2017-02-01

The roles of group I metabotropic glutamate receptors, metabotropic glutamate receptor 1 (mGluR1) and mGluR5, in regulating synaptic plasticity and metaplasticity in the basolateral amygdala (BLA) remain unclear. The present study examined mGluR1- and mGluR5-mediated synaptic plasticity in the BLA and their respective signaling mechanisms. Bath application of the group I mGluR agonist, 3,5-dihydroxyphenylglycine (DHPG) (20 μM), directly suppressed basal fEPSPs (84.5 ± 6.3% of the baseline). The suppressive effect persisted for at least 30 min after washout; it was abolished by the mGluR1 antagonist 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester (CPCCOEt) but was unaffected by the mGluR5 antagonist 2-methyl-6- (phenylethynyl)-pyridine (MPEP). Interestingly, application of DHPG (at both 2 and 20 μM), regardless of the presence of CPCCOEt, could transform single theta burst stimulation (TBS)-induced short-term synaptic potentiation into a long-term potentiation (LTP). Such a facilitating effect could be blocked by the mGluR5 antagonist MPEP. Blockade of phospholipase C (PLC), the downstream enzyme of group I mGluR, with U73122, prevented both mGluR1- and mGluR5-mediated effects on synaptic plasticity. Nevertheless, blockade of protein kinase C (PKC), the downstream enzyme of PLC, with chelerythrine (5 μM) only prevented the transforming effect of DHPG on TBS-induced LTP and did not affect DHPG-induced long-term depression (LTD). These results suggest that mGluR1 activation induced LTD via a PLC-dependent and PKC-independent mechanism, while the priming action of mGluR5 receptor on the BLA LTP is both PLC and PKC dependent. The BLA metaplasticity mediated by mGluR1 and mGluR5 may provide signal switching mechanisms mediating learning and memory with emotional significance.

ALTERED PHOSPHORYLATION OF MAP KINASE AFTER ACUTE EXPOSURE TO PCB153.

EPA Science Inventory

Long-term potentiation (LTP) is a model of synaptic plasticity believed to encompass the physiological substrate of memory. The mitogen-activated protein kinase (ERK1/2) signalling cascade contributes to synaptic plasticity and to long-term memory formation. Learning and LTP st...

Precise Synaptic Efficacy Alignment Suggests Potentiation Dominated Learning.

PubMed

Hartmann, Christoph; Miner, Daniel C; Triesch, Jochen

2015-01-01

Recent evidence suggests that parallel synapses from the same axonal branch onto the same dendritic branch have almost identical strength. It has been proposed that this alignment is only possible through learning rules that integrate activity over long time spans. However, learning mechanisms such as spike-timing-dependent plasticity (STDP) are commonly assumed to be temporally local. Here, we propose that the combination of temporally local STDP and a multiplicative synaptic normalization mechanism is sufficient to explain the alignment of parallel synapses. To address this issue, we introduce three increasingly complex models: First, we model the idealized interaction of STDP and synaptic normalization in a single neuron as a simple stochastic process and derive analytically that the alignment effect can be described by a so-called Kesten process. From this we can derive that synaptic efficacy alignment requires potentiation-dominated learning regimes. We verify these conditions in a single-neuron model with independent spiking activities but more realistic synapses. As expected, we only observe synaptic efficacy alignment for long-term potentiation-biased STDP. Finally, we explore how well the findings transfer to recurrent neural networks where the learning mechanisms interact with the correlated activity of the network. We find that due to the self-reinforcing correlations in recurrent circuits under STDP, alignment occurs for both long-term potentiation- and depression-biased STDP, because the learning will be potentiation dominated in both cases due to the potentiating events induced by correlated activity. This is in line with recent results demonstrating a dominance of potentiation over depression during waking and normalization during sleep. This leads us to predict that individual spine pairs will be more similar after sleep compared to after sleep deprivation. In conclusion, we show that synaptic normalization in conjunction with coordinated potentiation--in this case, from STDP in the presence of correlated pre- and post-synaptic activity--naturally leads to an alignment of parallel synapses.

Caspase-like activity is essential for long-term synaptic plasticity in the terrestrial snail Helix.

PubMed

Bravarenko, N I; Onufriev, M V; Stepanichev, M Yu; Ierusalimsky, V N; Balaban, P M; Gulyaeva, N V

2006-01-01

Although caspase activity in the nervous system of mollusks has not been described before, we suggested that these cysteine proteases might be involved in the phenomena of neuroplasticity in mollusks. We directly measured caspase-3 (DEVDase) activity in the Helix lucorum central nervous system (CNS) using a fluorometrical approach and showed that the caspase-3-like immunoreactivity is present in the central neurons of Helix. Western blots revealed the presence of caspase-3-immunoreactive proteins with a molecular mass of 29 kDa. Staurosporin application, routinely used to induce apoptosis in mammalian neurons through the activating cleavage of caspase-3, did not result in the appearance of a smaller subunit corresponding to the active caspase in the snail. However, it did increase the enzyme activity in the snail CNS. This suggests differences in the regulation of caspase-3 activity in mammals and snails. In the snail CNS, the caspase homolog seems to possess an active center without activating cleavage typical for mammals. In electrophysiological experiments with identified snail neurons, selective blockade of the caspase-3 with the irreversible and cell-permeable inhibitor of caspase-3 N-benzyloxycarbonyl-Asp(OMe)-Glu(OMe)-Val-Asp-(OMe)-fluoro-methylketone prevented development of the long-term stage of synaptic input sensitization, suggesting that caspase is necessary for normal synaptic plasticity in snails. The results of our study give the first direct evidence that the caspase-3-like activity is essential for long-term plasticity in the invertebrate neurons. This activity is presumably involved in removing inhibitory constraints on the storage of long-term memory.

Impaired contextual fear extinction and hippocampal synaptic plasticity in adult rats induced by prenatal morphine exposure.

PubMed

Tan, Ji-Wei; Duan, Ting-Ting; Zhou, Qi-Xin; Ding, Ze-Yang; Jing, Liang; Cao, Jun; Wang, Li-Ping; Mao, Rong-Rong; Xu, Lin

2015-07-01

Prenatal opiate exposure causes a series of neurobehavioral disturbances by affecting brain development. However, the question of whether prenatal opiate exposure increases vulnerability to memory-related neuropsychiatric disorders in adult offspring remains largely unknown. Here, we found that rats prenatally exposed to morphine (PM) showed impaired acquisition but enhanced maintenance of contextual fear memory compared with control animals that were prenatally exposed to saline (PS). The impairment of acquisition was rescued by increasing the intensity of footshocks (1.2 mA rather than 0.8 mA). Meanwhile, we also found that PM rats exhibited impaired extinction of contextual fear, which is associated with enhanced maintenance of fear memory. The impaired extinction lasted for 1 week following extinction training. Furthermore, PM rats exhibited reduced anxiety-like behavior in the elevated plus-maze and light/dark box test without differences in locomotor activity. These alterations in PM rats were mirrored by abnormalities in synaptic plasticity in the Schaffer collateral-CA1 synapses of the hippocampus in vivo. PS rats showed blocked long-term potentiation and enabled long-term depression in CA1 synapses following contextual fear conditioning, while prenatal morphine exposure restricted synaptic plasticity in CA1 synapses. The smaller long-term potentiation in PM rats was not further blocked by contextual fear conditioning, and the long-term depression enabled by contextual fear conditioning was abolished. Taken together, our results provide the first evidence suggesting that prenatal morphine exposure may increase vulnerability to fear memory-related neuropsychiatric disorders in adulthood. © 2014 Society for the Study of Addiction.

Clioquinol and vitamin B12 (cobalamin) synergistically rescue the lead-induced impairments of synaptic plasticity in hippocampal dentate gyrus area of the anesthetized rats in vivo.

PubMed

Chen, W-H; Wang, M; Yu, S-S; Su, L; Zhu, D-M; She, J-Q; Cao, X-J; Ruan, D-Y

2007-07-13

Lead (Pb(2+)) exposure in development induces impairments of synaptic plasticity in the hippocampal dentate gyrus (DG) area of the anesthetized rats in vivo. The common chelating agents have many adverse effects and are incapable of alleviating lead-induced neurotoxicity. Recently, CQ, clioquinol (5-chloro-7-iodo-8-hydroxy-quinoline), which is a transition metal ion chelator and/or ionophore with low affinity for metal ions, has yielded some promising results in animal models and clinical trials related to dysfunctions of metal ions. In addition, CQ-associated side effects are believed to be overcome with vitamin B12 (VB12) supplementation. To determine whether CQ treatment could rescue impairments of synaptic plasticity induced by chronic Pb(2+) exposure, we investigated the input/output functions (I/Os), paired-pulse reactions (PPRs) and long-term potentiation (LTP) of different treatment groups in hippocampal DG area of the anesthetized rat in vivo by recording field potentials and measured hippocampal Pb(2+) concentrations of different treatment groups by PlasmaQuad 3 inductive coupled plasma mass spectroscopy. The results show: CQ alone does not rescue the lead-induced impairments of synaptic plasticity in hippocampal DG area of the anesthetized rats in vivo; VB12 alone partly rescues the lead-induced impairments of LTP; however the co-administration of CQ and VB12 totally rescues these impairments of synaptic plasticity and moreover, the effects of CQ and VB12 co-administration are specific to the lead-exposed animals.

Calcium homeostasis and protein kinase/phosphatase balance participate in nicotine-induced memory improvement in passive avoidance task in mice.

PubMed

Michalak, Agnieszka; Biala, Grazyna

2017-01-15

Long-term potentiation (LTP) and long-term depression (LTD) depend on specific postsynaptic Ca 2+ /calmodulin concentration. LTP results from Ca 2+ influx through the activated NMDA receptors or voltage-gated calcium channels (VGCCs) and is linked with activation of protein kinases including mitogen-activated protein kinase (MAPK). Weaker synaptic stimulation, as a result of low Ca 2+ influx, leads to activation of Ca 2+ /calmodulin-dependent phosphatase (calcineurin - CaN) and triggers LTD. Interestingly, both memory formation and drug addiction share similar neuroplastic changes. Nicotine, which is one of the most common addictive drugs, manifests its memory effects through nicotinic acetylcholine receptors (nAChRs). Because nAChRs may also gate Ca 2+ , it is suggested that calcium signaling pathways are involved in nicotine-induced memory effects. Within the scope of the study was to evaluate the importance of calcium homeostasis and protein kinase/phosphatase balance in nicotine-induced short- and long-term memory effects. To assess memory function in mice passive avoidance test was used. The presented results confirm that acute nicotine (0.1mg/kg) improves short- and long-term memory. Pretreatment with L-type VGCC blockers (amlodipine, nicardipine verapamil) increased nicotine-induced memory improvement in the context of short- and long-term memory. Pretreatment with FK-506 (a potent CaN inhibitor) enhanced short- but not long-term memory effects of nicotine, while SL-327 (a selective MAPK/ERK kinase inhibitor) attenuated both nicotine-induced short- and long-term memory improvement. Acute nicotine enhances both types of memory via L-type VGCC blockade and via ERK1/2 activation. Only short- but not long-term memory enhancement induced by nicotine is dependent on CaN inhibition. Copyright © 2016 Elsevier B.V. All rights reserved.

Estradiol and the Relationship between Dendritic Spines, NR2B Containing NMDA Receptors, and the Magnitude of Long-Term Potentiation at Hippocampal CA3-CA1 Synapses

PubMed Central

Smith, Caroline C.; Vedder, Lindsey C.; McMahon, Lori L.

2009-01-01

Summary When circulating estrogen levels decline as a natural consequence of menopause and aging in women, there is an increased incidence of deficits in working memory. In many cases, these deficits are rescued by estrogen replacement therapy. These clinical data therefore highlight the importance of defining the biological pathways linking estrogen to the cellular substrates of learning and memory. It has been known for nearly two decades that estrogen enhances dendritic spine density on apical dendrites of CA1 pyramidal cells in hippocampus, a brain region required for learning. Interestingly, at synapses between CA3-CA1 pyramidal cells, estrogen has also been shown to enhance synaptic NMDA receptor current and the magnitude of long term potentiation, a cellular correlate of learning and memory. Given that synapse density, NMDAR function, and long term potentiation at CA3-CA1 synapses in hippocampus are associated with normal learning, it is likely that modulation of these parameters by estrogen facilitates the improvement in learning observed in rats, primates and humans following estrogen replacement. To facilitate the design of clinical strategies to potentially prevent or reverse the age-related decline in learning and memory during menopause, the relationship between the estrogen-induced morphological and functional changes in hippocampus must be defined and the role these changes play in facilitating learning must be elucidated. The aim of this report is to provide a summary of the proposed mechanisms by which this hormone increases synaptic function and in doing so, it briefly addresses potential mechanisms contributing to the estrogen-induced increase in synaptic morphology and plasticity, as well as important future directions. PMID:19596521

Enhanced Long-Term and Impaired Short-Term Spatial Memory in GluA1 AMPA Receptor Subunit Knockout Mice: Evidence for a Dual-Process Memory Model

ERIC Educational Resources Information Center

Sanderson, David J.; Good, Mark A.; Skelton, Kathryn; Sprengel, Rolf; Seeburg, Peter H.; Rawlins, J. Nicholas P.; Bannerman, David M.

2009-01-01

The GluA1 AMPA receptor subunit is a key mediator of hippocampal synaptic plasticity and is especially important for a rapidly-induced, short-lasting form of potentiation. GluA1 gene deletion impairs hippocampus-dependent, spatial working memory, but spares hippocampus-dependent spatial reference memory. These findings may reflect the necessity of…

Induced neural stem cells achieve long-term survival and functional integration in the adult mouse brain.

PubMed

Hemmer, Kathrin; Zhang, Mingyue; van Wüllen, Thea; Sakalem, Marna; Tapia, Natalia; Baumuratov, Aidos; Kaltschmidt, Christian; Kaltschmidt, Barbara; Schöler, Hans R; Zhang, Weiqi; Schwamborn, Jens C

2014-09-09

Differentiated cells can be converted directly into multipotent neural stem cells (i.e., induced neural stem cells [iNSCs]). iNSCs offer an attractive alternative to induced pluripotent stem cell (iPSC) technology with regard to regenerative therapies. Here, we show an in vivo long-term analysis of transplanted iNSCs in the adult mouse brain. iNSCs showed sound in vivo long-term survival rates without graft overgrowths. The cells displayed a neural multilineage potential with a clear bias toward astrocytes and a permanent downregulation of progenitor and cell-cycle markers, indicating that iNSCs are not predisposed to tumor formation. Furthermore, the formation of synaptic connections as well as neuronal and glial electrophysiological properties demonstrated that differentiated iNSCs migrated, functionally integrated, and interacted with the existing neuronal circuitry. We conclude that iNSC long-term transplantation is a safe procedure; moreover, it might represent an interesting tool for future personalized regenerative applications. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

A model of activity-dependent changes in dendritic spine density and spine structure.

PubMed

Crook, S M; Dur-E-Ahmad, M; Baer, S M

2007-10-01

Recent evidence indicates that the morphology and density of dendritic spines are regulated during synaptic plasticity. See, for instance, a review by Hayashi and Majewska [9]. In this work, we extend previous modeling studies [27] by combining a model for activity-dependent spine density with one for calcium-mediated spine stem restructuring. The model is based on the standard dimensionless cable equation, which represents the change in the membrane potential in a passive dendrite. Additional equations characterize the change in spine density along the dendrite, the current balance equation for an individual spine head, the change in calcium concentration in the spine head, and the dynamics of spine stem resistance. We use computational studies to investigate the changes in spine density and structure for differing synaptic inputs and demonstrate the effects of these changes on the input-output properties of the dendritic branch. Moderate amounts of high-frequency synaptic activation to dendritic spines result in an increase in spine stem resistance that is correlated with spine stem elongation. In addition, the spine density increases both inside and outside the input region. The model is formulated so that this long-term potentiation-inducing stimulus eventually leads to structural stability. In contrast, a prolonged low-frequency stimulation paradigm that would typically induce long-term depression results in a decrease in stem resistance (correlated with stem shortening) and an eventual decrease in spine density.

A Place at the Table: LTD as a Mediator of Memory Genesis.

PubMed

Connor, Steven A; Wang, Yu Tian

2016-08-01

Resolving how our brains encode information requires an understanding of the cellular processes taking place during memory formation. Since the 1970s, considerable effort has focused on determining the properties and mechanisms underlying long-term potentiation (LTP) at glutamatergic synapses and how these processes influence initiation of new memories. However, accumulating evidence suggests that long-term depression (LTD) of synaptic strength, particularly at glutamatergic synapses, is a bona fide learning and memory mechanism in the mammalian brain. The known range of mechanisms capable of inducing LTD has been extended to those including NMDAR-independent forms, neuromodulator-dependent LTD, synaptic depression following stress, and non-synaptically induced forms. The examples of LTD observed at the hippocampal CA1 synapse to date demonstrate features consistent with LTP, including homo- and heterosynaptic expression, extended duration beyond induction (several hours to weeks), and association with encoding of distinct types of memories. Canonical mechanisms through which synapses undergo LTD include activation of phosphatases, initiation of protein synthesis, and dynamic regulation of presynaptic glutamate release and/or postsynaptic glutamate receptor endocytosis. Here, we will discuss the pre- and postsynaptic changes underlying LTD, recent advances in the identification and characterization of novel mechanisms underlying LTD, and how engagement of these processes constitutes a cellular analog for the genesis of specific types of memories. © The Author(s) 2015.

Effects of perinatal asphyxia on rat striatal cytoskeleton.

PubMed

Saraceno, G E; Ayala, M V; Badorrey, M S; Holubiec, M; Romero, J I; Galeano, P; Barreto, G; Giraldez-Alvárez, L D; Kölliker-Fres, R; Coirini, H; Capani, F

2012-01-01

Perinatal asphyxia (PA) is a medical condition associated with a high short-term morbimortality and different long-term neurological diseases. In previous works, we have shown that neuronal and synaptic changes in rat striatum lead to ubi-protein accumulation in post-synaptic density (PSD) after six months of sub-severe PA. However, very little is known about the synaptic and related structural modifications induced by PA in young rats. In the present work, we studied neuronal cytoskeleton modifications in striatum induced by subsevere PA in 30-day-old rats. We observed a significant decrease in the number of neurons, in particular calbindin immunoreactive neurons after PA. In addition, it was also observed that actin cytoskeleton was highly modified in the PSD as well as an increment of F-actin staining by Phalloidin-alexa(488) in the striatum of PA rats. Using correlative fluorescence-electron microscopy photooxidation, we confirmed and extended confocal observations. F-actin staining augmentation was mostly related with an increment in the number of mushroom-shaped spines. Consistent with microscopic data, Western blot analysis revealed a β-actin increment in PSD in PA rats. On the other hand, MAP-2 immunostaining was decreased after PA, being NF-200 expression unmodified. Although neuronal death was observed, signs of generalized neurodegeneration were absent. Taken together these results showed early post-synaptic F-actin cytoskeleton changes induced by PA with slightly modifications in the other components of the neuronal cytoskeleton, suggesting that F-actin accumulation in the dendritic spines could be involved in the neuronal loss induced by PA. Copyright © 2011 Wiley Periodicals, Inc.

Influence of sex and estrous cycle on synaptic responses of the medial vestibular nuclei in rats: role of circulating 17β-estradiol.

PubMed

Grassi, Silvarosa; Frondaroli, Adele; Scarduzio, Mariangela; Dieni, Cristina V; Brecchia, Gabriele; Boiti, Cristiano; Pettorossi, Vito E

2012-02-10

We investigated the possible influence of sex and estrous cycle on the synaptic responses of neurons in the medial vestibular nucleus (MVN) and their long-term modifications. In brain stem slices of male and female rats during proestrus (PE) and diestrus (DE), we evaluated the field potential evoked in the MVN by vestibular afferent stimulation. Here we find that in PE females the field potential had a lower threshold and higher amplitude than in DE females and in males and also that the stimulus-response curve was shifted to the left. Such difference is related to the level and cyclic fluctuation of circulating 17β-estradiol (E(2)). This is supported by the exogenous administration of E(2) in DE females and males, with low levels of circulating E(2) that enhanced the field potential amplitude to values close to those of PE females. Sex and estrous cycle also influence the MVN synaptic plasticity. This has been shown by investigating the effect of testosterone (T) on the induction of long-term effects, since T is the precursor for the neural synthesis of E(2) (estrogenic pathway), which is involved in the induction of fast long-term potentiation (LTP), or of 5α-dihydrotestosterone (DHT, androgenic pathway) which mediates slow LTP and long-term depression (LTD). We found that T mostly induced LTD in PE females and no effect in DE females, while it only provoked fast LTP in males. We suggest that high level of circulating E(2) may interfere with the conversion of T, by inhibiting the neural estrogenic pathway and facilitating the androgenic one. On the whole these results demonstrate an influence of circulating E(2) on vestibular synaptic transmission and plasticity that in some cases may contribute to the sex and menstrual cycle dependence of symptoms in human vestibular pathology. Copyright © 2011 Elsevier Inc. All rights reserved.

Fast Learning with Weak Synaptic Plasticity.

PubMed

Yger, Pierre; Stimberg, Marcel; Brette, Romain

2015-09-30

New sensory stimuli can be learned with a single or a few presentations. Similarly, the responses of cortical neurons to a stimulus have been shown to increase reliably after just a few repetitions. Long-term memory is thought to be mediated by synaptic plasticity, but in vitro experiments in cortical cells typically show very small changes in synaptic strength after a pair of presynaptic and postsynaptic spikes. Thus, it is traditionally thought that fast learning requires stronger synaptic changes, possibly because of neuromodulation. Here we show theoretically that weak synaptic plasticity can, in fact, support fast learning, because of the large number of synapses N onto a cortical neuron. In the fluctuation-driven regime characteristic of cortical neurons in vivo, the size of membrane potential fluctuations grows only as √N, whereas a single output spike leads to potentiation of a number of synapses proportional to N. Therefore, the relative effect of a single spike on synaptic potentiation grows as √N. This leverage effect requires precise spike timing. Thus, the large number of synapses onto cortical neurons allows fast learning with very small synaptic changes. Significance statement: Long-term memory is thought to rely on the strengthening of coactive synapses. This physiological mechanism is generally considered to be very gradual, and yet new sensory stimuli can be learned with just a few presentations. Here we show theoretically that this apparent paradox can be solved when there is a tight balance between excitatory and inhibitory input. In this case, small synaptic modifications applied to the many synapses onto a given neuron disrupt that balance and produce a large effect even for modifications induced by a single stimulus. This effect makes fast learning possible with small synaptic changes and reconciles physiological and behavioral observations. Copyright © 2015 the authors 0270-6474/15/3513351-12$15.00/0.

Forebrain glutamatergic neurons mediate leptin action on depression-like behaviors and synaptic depression

PubMed Central

Guo, M; Lu, Y; Garza, J C; Li, Y; Chua, S C; Zhang, W; Lu, B; Lu, X-Y

2012-01-01

The glutamatergic system has been implicated in the pathophysiology of depression and the mechanism of action of antidepressants. Leptin, an adipocyte-derived hormone, has antidepressant-like properties. However, the functional role of leptin receptor (Lepr) signaling in glutamatergic neurons remains to be elucidated. In this study, we generated conditional knockout mice in which the long form of Lepr was ablated selectively in glutamatergic neurons located in the forebrain structures, including the hippocampus and prefrontal cortex (Lepr cKO). Lepr cKO mice exhibit normal growth and body weight. Behavioral characterization of Lepr cKO mice reveals depression-like behavioral deficits, including anhedonia, behavioral despair, enhanced learned helplessness and social withdrawal, with no evident signs of anxiety. In addition, loss of Lepr in forebrain glutamatergic neurons facilitates N-methyl--aspartate (NMDA)-induced hippocampal long-term synaptic depression (LTD), whereas conventional LTD or long-term potentiation (LTP) was not affected. The facilitated LTD induction requires activation of the NMDA receptor GluN2B (NR2B) subunit as it was completely blocked by a selective GluN2B antagonist. Moreover, Lepr cKO mice are highly sensitive to the antidepressant-like behavioral effects of the GluN2B antagonist but resistant to leptin. These results support important roles for Lepr signaling in glutamatergic neurons in regulating depression-related behaviors and modulating excitatory synaptic strength, suggesting a possible association between synaptic depression and behavioral manifestation of behavioral depression. PMID:22408745

Use-dependent plasticity in clock neurons regulates sleep need in Drosophila.

PubMed

Donlea, Jeffrey M; Ramanan, Narendrakumar; Shaw, Paul J

2009-04-03

Sleep is important for memory consolidation and is responsive to waking experience. Clock circuitry is uniquely positioned to coordinate interactions between processes underlying memory and sleep need. Flies increase sleep both after exposure to an enriched social environment and after protocols that induce long-term memory. We found that flies mutant for rutabaga, period, and blistered were deficient for experience-dependent increases in sleep. Rescue of each of these genes within the ventral lateral neurons (LNVs) restores increased sleep after social enrichment. Social experiences that induce increased sleep were associated with an increase in the number of synaptic terminals in the LNV projections into the medulla. The number of synaptic terminals was reduced during sleep and this decline was prevented by sleep deprivation.

Brain signaling and behavioral responses induced by exposure to (56)Fe-particle radiation

NASA Technical Reports Server (NTRS)

Denisova, N. A.; Shukitt-Hale, B.; Rabin, B. M.; Joseph, J. A.

2002-01-01

Previous experiments have demonstrated that exposure to 56Fe-particle irradiation (1.5 Gy, 1 GeV) produced aging-like accelerations in neuronal and behavioral deficits. Astronauts on long-term space flights will be exposed to similar heavy-particle radiations that might have similar deleterious effects on neuronal signaling and cognitive behavior. Therefore, the present study evaluated whether radiation-induced spatial learning and memory behavioral deficits are associated with region-specific brain signaling deficits by measuring signaling molecules previously found to be essential for behavior [pre-synaptic vesicle proteins, synaptobrevin and synaptophysin, and protein kinases, calcium-dependent PRKCs (also known as PKCs) and PRKA (PRKA RIIbeta)]. The results demonstrated a significant radiation-induced increase in reference memory errors. The increases in reference memory errors were significantly negatively correlated with striatal synaptobrevin and frontal cortical synaptophysin expression. Both synaptophysin and synaptobrevin are synaptic vesicle proteins that are important in cognition. Striatal PRKA, a memory signaling molecule, was also significantly negatively correlated with reference memory errors. Overall, our findings suggest that radiation-induced pre-synaptic facilitation may contribute to some previously reported radiation-induced decrease in striatal dopamine release and for the disruption of the central dopaminergic system integrity and dopamine-mediated behavior.

Brain signaling and behavioral responses induced by exposure to (56)Fe-particle radiation.

PubMed

Denisova, N A; Shukitt-Hale, B; Rabin, B M; Joseph, J A

2002-12-01

Previous experiments have demonstrated that exposure to 56Fe-particle irradiation (1.5 Gy, 1 GeV) produced aging-like accelerations in neuronal and behavioral deficits. Astronauts on long-term space flights will be exposed to similar heavy-particle radiations that might have similar deleterious effects on neuronal signaling and cognitive behavior. Therefore, the present study evaluated whether radiation-induced spatial learning and memory behavioral deficits are associated with region-specific brain signaling deficits by measuring signaling molecules previously found to be essential for behavior [pre-synaptic vesicle proteins, synaptobrevin and synaptophysin, and protein kinases, calcium-dependent PRKCs (also known as PKCs) and PRKA (PRKA RIIbeta)]. The results demonstrated a significant radiation-induced increase in reference memory errors. The increases in reference memory errors were significantly negatively correlated with striatal synaptobrevin and frontal cortical synaptophysin expression. Both synaptophysin and synaptobrevin are synaptic vesicle proteins that are important in cognition. Striatal PRKA, a memory signaling molecule, was also significantly negatively correlated with reference memory errors. Overall, our findings suggest that radiation-induced pre-synaptic facilitation may contribute to some previously reported radiation-induced decrease in striatal dopamine release and for the disruption of the central dopaminergic system integrity and dopamine-mediated behavior.

Andrographolide reduces cognitive impairment in young and mature AβPPswe/PS-1 mice.

PubMed

Serrano, Felipe G; Tapia-Rojas, Cheril; Carvajal, Francisco J; Hancke, Juan; Cerpa, Waldo; Inestrosa, Nibaldo C

2014-12-18

Alzheimer's disease (AD) is a neurodegenerative disorder in which the amyloid-β (Aβ) oligomers are a key factor in synaptic impairment and in spatial memory decline associated with neuronal dysfunction. This impairment includes synaptic failure associated with the loss of synaptic proteins that contribute to AD progression. Interestingly, the use of natural compounds is an emergent conceptual strategy in the search for drugs with therapeutic potentials for treating neurodegenerative disorders. In the present study, we report that andrographolide (ANDRO), which is a labdane diterpene extracted from Andrographis paniculata, increases slope of field excitatory postsynaptic potentials (fEPSP) in the CA1 region of hippocampal slices and inhibits long-term depression (LTD), protecting the long-term potentiation (LTP) against the damage induced by Aβ oligomers in vitro, most likely by inhibiting glycogen synthase kinase-3β (GSK-3β). Additionally, ANDRO prevents changes in neuropathology in two different age groups (7- and 12-month-old mice) of an AβPPswe/PS-1 Alzheimer's model. ANDRO reduces the Aβ levels, changing the ontogeny of amyloid plaques in hippocampi and cortices in 7-month-old mice, and reduces tau phosphorylation around the Aβ oligomeric species in both age groups. Additionally, we observed that ANDRO recovers spatial memory functions that correlate with protecting synaptic plasticity and synaptic proteins in two different age groups. Our results suggest that ANDRO could be used in a potential preventive therapy during AD progression.

Progesterone Regulation of Synaptic Transmission and Plasticity in Rodent Hippocampus

ERIC Educational Resources Information Center

Foy, Michael R.; Akopian, Garnik; Thompson, Richard F.

2008-01-01

Ovarian hormones influence memory formation by eliciting changes in neural activity. The effects of various concentrations of progesterone (P4) on synaptic transmission and plasticity associated with long-term potentiation (LTP) and long-term depression (LTD) were studied using in vitro hippocampal slices. Extracellular studies show that the…

Mechanisms of potentiation of mossy fiber EPSCs in the cerebellar nuclei by coincident synaptic excitation and inhibition

PubMed Central

Pugh, Jason R.; Raman, Indira M.

2008-01-01

Neurons of the cerebellar nuclei receive synaptic excitation from cerebellar mossy fibers. Unlike in many principal neurons, coincident presynaptic activity and postsynaptic depolarization do not generate long-term potentiation at these synapses. Instead, EPSCs are potentiated by high-frequency trains of presynaptic activity applied with postsynaptic hyperpolarization, in patterns resembling the mossy fiber-mediated excitation and Purkinje cell-mediated inhibition predicted to occur during delay eyelid conditioning. Here, we have used electrophysiology and Ca imaging to test how synaptic excitation and inhibition interact to generate long-lasting synaptic plasticity in nuclear cells in cerebellar slices. We find that the extent of plasticity varies with the relative timing of synaptic excitation and hyperpolarization. Potentiation is most effective when synaptic stimuli precede the post-inhibitory rebound by ~400 ms, whereas with longer intervals, or with a reverse sequence, EPSCs tend to depress. When basal intracellular Ca is raised by spontaneous firing or reduced by voltage-clamping at subthreshold potentials, potentiation is induced as long as the synaptic-rebound temporal sequence is maintained, suggesting that plasticity does not require Ca levels to exceed a threshold or attain a specific concentration. Although rebound and spike-dependent Ca influx are global, potentiation is synapse-specific, and is disrupted by inhibitors of calcineurin or CaMKII, but not PKC. When IPSPs replace the hyperpolarizing step in the induction protocol, potentiation proceeds normally. These results lead us to propose that synaptic and inhibitory/rebound stimuli initiate separate processes, with local NMDA-receptor-mediated Ca influx “priming” synapses, and Ca changes from the inhibition and rebound “triggering” potentiation at recently activated synapses. PMID:18923031

High-Frequency Stimulation-Induced Synaptic Potentiation in Dorsal and Ventral CA1 Hippocampal Synapses: The Involvement of NMDA Receptors, mGluR5, and (L-Type) Voltage-Gated Calcium Channels

ERIC Educational Resources Information Center

Papatheodoropoulos, Costas; Kouvaros, Stylianos

2016-01-01

The ability of the ventral hippocampus (VH) for long-lasting long-term potentiation (LTP) and the mechanisms underlying its lower ability for shortlasting LTP compared with the dorsal hippocampus (DH) are unknown. Using recordings of field excitatory postsynaptic potentials (EPSPs) from the CA1 field of adult rat hippocampal slices, we found that…

Acute food deprivation enhances fear extinction but inhibits long-term depression in the lateral amygdala via ghrelin signaling.

PubMed

Huang, Chiung-Chun; Chou, Dylan; Yeh, Che-Ming; Hsu, Kuei-Sen

2016-02-01

Fear memory-encoding thalamic input synapses to the lateral amygdala (T-LA) exhibit dynamic efficacy changes that are tightly correlated with fear memory strength. Previous studies have shown that auditory fear conditioning involves strengthening of synaptic strength, and conversely, fear extinction training leads to T-LA synaptic weakening and occlusion of long-term depression (LTD) induction. These findings suggest that the mechanisms governing LTD at T-LA synapses may determine the behavioral outcomes of extinction training. Here, we explored this hypothesis by implementing food deprivation (FD) stress in mice to determine its effects on fear extinction and LTD induction at T-LA synapses. We found that FD increased plasma acylated ghrelin levels and enhanced fear extinction and its retention. Augmentation of fear extinction by FD was blocked by pretreatment with growth hormone secretagogue receptor type-1a antagonist D-Lys(3)-GHRP-6, suggesting an involvement of ghrelin signaling. Confirming previous findings, two distinct forms of LTD coexist at thalamic inputs to LA pyramidal neurons that can be induced by low-frequency stimulation (LFS) or paired-pulse LFS (PP-LFS) paired with postsynaptic depolarization, respectively. Unexpectedly, we found that FD impaired the induction of PP-LFS- and group I metabotropic glutamate receptor agonist (S)-3,5-dihydroxyphenylglycine (DHPG)-induced LTD, but not LFS-induced LTD. Ghrelin mimicked the effects of FD to impair the induction of PP-LFS- and DHPG-induced LTD at T-LA synapses, which were blocked by co-application of D-Lys(3)-GHRP-6. The sensitivity of synaptic transmission to 1-naphthyl acetyl spermine was not altered by either FD or ghrelin treatment. These results highlight distinct features of fear extinction and LTD at T-LA synapses. Copyright © 2015 Elsevier Ltd. All rights reserved.

Synaptic plasticity functions in an organic electrochemical transistor

NASA Astrophysics Data System (ADS)

Gkoupidenis, Paschalis; Schaefer, Nathan; Strakosas, Xenofon; Fairfield, Jessamyn A.; Malliaras, George G.

2015-12-01

Synaptic plasticity functions play a crucial role in the transmission of neural signals in the brain. Short-term plasticity is required for the transmission, encoding, and filtering of the neural signal, whereas long-term plasticity establishes more permanent changes in neural microcircuitry and thus underlies memory and learning. The realization of bioinspired circuits that can actually mimic signal processing in the brain demands the reproduction of both short- and long-term aspects of synaptic plasticity in a single device. Here, we demonstrate the implementation of neuromorphic functions similar to biological memory, such as short- to long-term memory transition, in non-volatile organic electrochemical transistors (OECTs). Depending on the training of the OECT, the device displays either short- or long-term plasticity, therefore, exhibiting non von Neumann characteristics with merged processing and storing functionalities. These results are a first step towards the implementation of organic-based neuromorphic circuits.

Left-right dissociation of hippocampal memory processes in mice.

PubMed

Shipton, Olivia A; El-Gaby, Mohamady; Apergis-Schoute, John; Deisseroth, Karl; Bannerman, David M; Paulsen, Ole; Kohl, Michael M

2014-10-21

Left-right asymmetries have likely evolved to make optimal use of bilaterian nervous systems; however, little is known about the synaptic and circuit mechanisms that support divergence of function between equivalent structures in each hemisphere. Here we examined whether lateralized hippocampal memory processing is present in mice, where hemispheric asymmetry at the CA3-CA1 pyramidal neuron synapse has recently been demonstrated, with different spine morphology, glutamate receptor content, and synaptic plasticity, depending on whether afferents originate in the left or right CA3. To address this question, we used optogenetics to acutely silence CA3 pyramidal neurons in either the left or right dorsal hippocampus while mice performed hippocampus-dependent memory tasks. We found that unilateral silencing of either the left or right CA3 was sufficient to impair short-term memory. However, a striking asymmetry emerged in long-term memory, wherein only left CA3 silencing impaired performance on an associative spatial long-term memory task, whereas right CA3 silencing had no effect. To explore whether synaptic properties intrinsic to the hippocampus might contribute to this left-right behavioral asymmetry, we investigated the expression of hippocampal long-term potentiation. Following the induction of long-term potentiation by high-frequency electrical stimulation, synapses between CA3 and CA1 pyramidal neurons were strengthened only when presynaptic input originated in the left CA3, confirming an asymmetry in synaptic properties. The dissociation of hippocampal long-term memory function between hemispheres suggests that memory is routed via distinct left-right pathways within the mouse hippocampus, and provides a promising approach to help elucidate the synaptic basis of long-term memory.

Synaptic Transmission Optimization Predicts Expression Loci of Long-Term Plasticity.

PubMed

Costa, Rui Ponte; Padamsey, Zahid; D'Amour, James A; Emptage, Nigel J; Froemke, Robert C; Vogels, Tim P

2017-09-27

Long-term modifications of neuronal connections are critical for reliable memory storage in the brain. However, their locus of expression-pre- or postsynaptic-is highly variable. Here we introduce a theoretical framework in which long-term plasticity performs an optimization of the postsynaptic response statistics toward a given mean with minimal variance. Consequently, the state of the synapse at the time of plasticity induction determines the ratio of pre- and postsynaptic modifications. Our theory explains the experimentally observed expression loci of the hippocampal and neocortical synaptic potentiation studies we examined. Moreover, the theory predicts presynaptic expression of long-term depression, consistent with experimental observations. At inhibitory synapses, the theory suggests a statistically efficient excitatory-inhibitory balance in which changes in inhibitory postsynaptic response statistics specifically target the mean excitation. Our results provide a unifying theory for understanding the expression mechanisms and functions of long-term synaptic transmission plasticity. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Endogenous neurotrophin-3 regulates short-term plasticity at lateral perforant path-granule cell synapses.

PubMed

Kokaia, M; Asztely, F; Olofsdotter, K; Sindreu, C B; Kullmann, D M; Lindvall, O

1998-11-01

In the adult brain, neurotrophin-3 (NT-3) is mainly localized in dentate granule cells, and its expression is decreased by various stimuli, e.g., seizure activity. We have examined the role of endogenous NT-3 for excitatory synaptic transmission at lateral perforant path-dentate granule cell synapses using hippocampal slices from NT-3 knock-out (+/-) and wild-type (+/+) mice. Paired-pulse facilitation (PPF) and also short-term synaptic plasticity induced by a brief, high-frequency train of afferent stimulation were reduced, but the expression of long-term potentiation was not affected in the NT-3+/- mice. Incubation of the slices with recombinant NT-3 reversed the deficit in PPF through a mechanism requiring de novo protein synthesis, implying that the impaired short-term plasticity does not result from a developmental alteration. No changes of overall presynaptic release probability, measured by the progressive block of NMDA receptor-mediated synaptic currents by MK-801, or desensitization of AMPA receptors were detected. Because NT-3 expression is reduced after focal seizures, impaired short-term facilitation may represent a protective response that limits the propagation of epileptiform activity from the entorhinal cortex to the hippocampus.

Synaptic dynamics contribute to long-term single neuron response fluctuations.

PubMed

Reinartz, Sebastian; Biro, Istvan; Gal, Asaf; Giugliano, Michele; Marom, Shimon

2014-01-01

Firing rate variability at the single neuron level is characterized by long-memory processes and complex statistics over a wide range of time scales (from milliseconds up to several hours). Here, we focus on the contribution of non-stationary efficacy of the ensemble of synapses-activated in response to a given stimulus-on single neuron response variability. We present and validate a method tailored for controlled and specific long-term activation of a single cortical neuron in vitro via synaptic or antidromic stimulation, enabling a clear separation between two determinants of neuronal response variability: membrane excitability dynamics vs. synaptic dynamics. Applying this method we show that, within the range of physiological activation frequencies, the synaptic ensemble of a given neuron is a key contributor to the neuronal response variability, long-memory processes and complex statistics observed over extended time scales. Synaptic transmission dynamics impact on response variability in stimulation rates that are substantially lower compared to stimulation rates that drive excitability resources to fluctuate. Implications to network embedded neurons are discussed.

Conversion of Short-Term Potentiation to Long-Term Potentiation in Mouse CA1 by Coactivation of [beta]-Adrenergic and Muscarinic Receptors

ERIC Educational Resources Information Center

Connor, Steven A.; Maity, Sabyasachi; Roy, Birbickram; Ali, Declan W.; Nguyen, Peter V.

2012-01-01

Encoding new information requires dynamic changes in synaptic strength. The brain can boost synaptic plasticity through the secretion of neuromodulatory substances, including acetylcholine and noradrenaline. Considerable effort has focused on elucidating how neuromodulatory substances alter synaptic properties. However, determination of the…

Attenuated response to methamphetamine sensitization and deficits in motor learning and memory after selective deletion of β-catenin in dopamine neurons.

PubMed

Diaz-Ruiz, Oscar; Zhang, Yajun; Shan, Lufei; Malik, Nasir; Hoffman, Alexander F; Ladenheim, Bruce; Cadet, Jean Lud; Lupica, Carl R; Tagliaferro, Adriana; Brusco, Alicia; Bäckman, Cristina M

2012-07-20

In the present study, we analyzed mice with a targeted deletion of β-catenin in DA neurons (DA-βcat KO mice) to address the functional significance of this molecule in the shaping of synaptic responses associated with motor learning and following exposure to drugs of abuse. Relative to controls, DA-βcat KO mice showed significant deficits in their ability to form long-term memories and displayed reduced expression of methamphetamine-induced behavioral sensitization after subsequent challenge doses with this drug, suggesting that motor learning and drug-induced learning plasticity are altered in these mice. Morphological analyses showed no changes in the number or distribution of tyrosine hydroxylase-labeled neurons in the ventral midbrain. While electrochemical measurements in the striatum determined no changes in acute DA release and uptake, a small but significant decrease in DA release was detected in mutant animals after prolonged repetitive stimulation, suggesting a possible deficit in the DA neurotransmitter vesicle reserve pool. However, electron microscopy analyses did not reveal significant differences in the content of synaptic vesicles per terminal, and striatal DA levels were unchanged in DA-βcat KO animals. In contrast, striatal mRNA levels for several markers known to regulate synaptic plasticity and DA neurotransmission were altered in DA-βcat KO mice. This study demonstrates that ablation of β-catenin in DA neurons leads to alterations of motor and reward-associated memories and to adaptations of the DA neurotransmitter system and suggests that β-catenin signaling in DA neurons is required to facilitate the synaptic remodeling underlying the consolidation of long-term memories.

Daily acclimation handling does not affect hippocampal long-term potentiation or cause chronic sleep deprivation in mice.

PubMed

Vecsey, Christopher G; Wimmer, Mathieu E J; Havekes, Robbert; Park, Alan J; Perron, Isaac J; Meerlo, Peter; Abel, Ted

2013-04-01

Gentle handling is commonly used to perform brief sleep deprivation in rodents. It was recently reported that daily acclimation handling, which is often used before behavioral assays, causes alterations in sleep, stress, and levels of N-methyl-D-aspartate receptor subunits prior to the actual period of sleep deprivation. It was therefore suggested that acclimation handling could mediate some of the observed effects of subsequent sleep deprivation. Here, we examine whether acclimation handling, performed as in our sleep deprivation studies, alters sleep/wake behavior, stress, or forms of hippocampal synaptic plasticity that are impaired by sleep deprivation. Adult C57BL/6J mice were either handled daily for 6 days or were left undisturbed in their home cages. On the day after the 6(th) day of handling, long-term potentiation (LTP) was induced in hippocampal slices with spaced four-train stimulation, which we previously demonstrated to be impaired by brief sleep deprivation. Basal synaptic properties were also assessed. In three other sets of animals, activity monitoring, polysomnography, and stress hormone measurements were performed during the 6 days of handling. Daily gentle handling alone does not alter LTP, rest/activity patterns, or sleep/wake architecture. Handling initially induces a minimal stress response, but by the 6(th) day, stress hormone levels are unaltered by handling. It is possible to handle mice daily to accustom them to the researcher without causing alterations in sleep, stress, or synaptic plasticity in the hippocampus. Therefore, effects of acclimation handling cannot explain the impairments in signaling mechanisms, synaptic plasticity, and memory that result from brief sleep deprivation.

An essential role for UBE2A/HR6A in learning and memory and mGLUR-dependent long-term depression.

PubMed

Bruinsma, Caroline F; Savelberg, Sanne M C; Kool, Martijn J; Jolfaei, Mehrnoush Aghadavoud; Van Woerden, Geeske M; Baarends, Willy M; Elgersma, Ype

2016-01-01

UBE2A deficiency syndrome (also known as X-linked intellectual disability type Nascimento) is an intellectual disability syndrome characterized by prominent dysmorphic features, impaired speech and often epilepsy. The syndrome is caused by Xq24 deletions encompassing the UBE2A (HR6A) gene or by intragenic UBE2A mutations. UBE2A encodes an E2 ubiquitin-conjugating enzyme involved in DNA repair and female fertility. A recent study in Drosophila showed that dUBE2A binds to the E3 ligase Parkin, which is required for mitochondrial function and responsible for juvenile Parkinson's disease. In addition, these studies showed impairments in synaptic transmission in dUBE2A mutant flies. However, a causal role of UBE2A in of cognitive deficits has not yet been established. Here, we show that Ube2a knockout mice have a major deficit in spatial learning tasks, whereas other tested phenotypes, including epilepsy and motor coordination, were normal. Results from electrophysiological measurements in the hippocampus showed no deficits in synaptic transmission nor in the ability to induce long-term synaptic potentiation. However, a small but significant deficit was observed in mGLUR-dependent long-term depression, a pathway previously implied in several other mouse models for neurodevelopmental disorders. Our results indicate a causal role of UBE2A in learning and mGLUR-dependent long-term depression, and further indicate that the Ube2a knockout mouse is a good model to study the molecular mechanisms underlying UBE2A deficiency syndrome. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

MPTP-induced changes in hippocampal synaptic plasticity and memory are prevented by memantine through the BDNF-TrkB pathway

PubMed Central

Zhu, Guoqi; Li, Junyao; He, Ling; Wang, Xuncui; Hong, Xiaoqi

2015-01-01

Background and Purpose Mild cognitive deficit in early Parkinson's disease (PD) has been widely studied. Here we have examined the effects of memantine in preventing memory deficit in experimental PD models and elucidated some of the underlying mechanisms. Experimental Approaches I.p. injection of 1-methyl-4- phenyl-1,2,3,6-tetrahydro pyridine (MPTP) in C57BL/6 mice was used to produce models of PD. We used behavioural tasks to test memory. In vitro, we used slices of hippocampus, with electrophysiological, Western blotting, real time PCR, elisa and immunochemical techniques. Key Results Following MPTP injection, long-term memory was impaired and these changes were prevented by pre-treatment with memantine. In hippocampal slices from MPTP treated mice, long-term potentiation (LTP) –induced by θ burst stimulation (10 bursts, 4 pulses) was decreased, while long-term depression (LTD) induced by low-frequency stimulation (1 Hz, 900 pulses) was enhanced, compared with control values. A single dose of memantine (i.p., 10 mg·kg−1) reversed the decreased LTP and the increased LTD in this PD model. Activity-dependent changes in tyrosine kinase receptor B (TrkB), ERK and brain-derived neurotrophic factor (BDNF) expression were decreased in slices from mice after MPTP treatment. These effects were reversed by pretreatment with memantine. Incubation of slices in vitro with 1-methyl-4-phenylpyridinium (MPP+) decreased depolarization-induced expression of BDNF. This effect was prevented by pretreatment of slices with memantine or with calpain inhibitor III, suggesting the involvement of an overactivated calcium signalling pathway. Conclusions and Implications Memantine should be useful in preventing loss of memory and hippocampal synaptic plasticity in PD models. PMID:25560396

Staufen 2 regulates mGluR long-term depression and Map1b mRNA distribution in hippocampal neurons.

PubMed

Lebeau, Geneviève; Miller, Linda C; Tartas, Maylis; McAdam, Robyn; Laplante, Isabel; Badeaux, Frédérique; DesGroseillers, Luc; Sossin, Wayne S; Lacaille, Jean-Claude

2011-01-01

The two members of the Staufen family of RNA-binding proteins, Stau1 and Stau2, are present in distinct ribonucleoprotein complexes and associate with different mRNAs. Stau1 is required for protein synthesis-dependent long-term potentiation (L-LTP) in hippocampal pyramidal cells. However, the role of Stau2 in synaptic plasticity remains unexplored. We found that unlike Stau1, Stau2 is not required for L-LTP. In contrast, Stau2, but not Stau1, is necessary for DHPG-induced protein synthesis-dependent long-term depression (mGluR-LTD). While Stau2 is involved in early development of spines, its down-regulation does not alter spine morphology or spontaneous miniature synaptic activity in older cultures where LTD occurs. In addition, Stau2, but not Stau1, knockdown reduces the dendritic localization of Map1b mRNA, a specific transcript involved in mGluR-LTD. Moreover, mGluR stimulation with DHPG induces Map1b, but not Map2, mRNA dissociation from mRNA granules containing Stau2 and the ribosomal protein P0. This dissociation was not observed in cells in which Stau2 was depleted. Finally, Stau2 knockdown reduces basal Map1b protein expression in dendrites and prevents DHPG-induced increases in dendritic Map1b protein level. We suggest a role for Stau2 in the generation and regulation of Map1b mRNA containing granules that are required for mGluR-LTD.

SorCS2 is required for BDNF-dependent plasticity in the hippocampus.

PubMed

Glerup, S; Bolcho, U; Mølgaard, S; Bøggild, S; Vaegter, C B; Smith, A H; Nieto-Gonzalez, J L; Ovesen, P L; Pedersen, L F; Fjorback, A N; Kjolby, M; Login, H; Holm, M M; Andersen, O M; Nyengaard, J R; Willnow, T E; Jensen, K; Nykjaer, A

2016-12-01

SorCS2 is a member of the Vps10p-domain receptor gene family receptors with critical roles in the control of neuronal viability and function. Several genetic studies have suggested SORCS2 to confer risk of bipolar disorder, schizophrenia and attention deficit-hyperactivity disorder. Here we report that hippocampal N-methyl-d-aspartate receptor-dependent synaptic plasticity is eliminated in SorCS2-deficient mice. This defect was traced to the ability of SorCS2 to form complexes with the neurotrophin receptor p75 NTR , required for pro-brain-derived neurotrophic factor (BDNF) to induce long-term depression, and with the BDNF receptor tyrosine kinase TrkB to elicit long-term potentiation. Although the interaction with p75 NTR was static, SorCS2 bound to TrkB in an activity-dependent manner to facilitate its translocation to postsynaptic densities for synaptic tagging and maintenance of synaptic potentiation. Neurons lacking SorCS2 failed to respond to BDNF by TrkB autophosphorylation, and activation of downstream signaling cascades, impacting neurite outgrowth and spine formation. Accordingly, Sorcs2 -/- mice displayed impaired formation of long-term memory, increased risk taking and stimulus seeking behavior, enhanced susceptibility to stress and impaired prepulse inhibition. Our results identify SorCS2 as an indispensable coreceptor for p75 NTR and TrkB in hippocampal neurons and suggest SORCS2 as the link between proBDNF/BDNF signaling and mental disorders.

Synaptic correlates of increased cognitive vulnerability with aging: peripheral immune challenge and aging interact to disrupt theta-burst late-phase long-term potentiation in hippocampal area CA1.

PubMed

Chapman, Timothy R; Barrientos, Ruth M; Ahrendsen, Jared T; Maier, Steven F; Patterson, Susan L

2010-06-02

Variability in cognitive functioning increases markedly with age, as does cognitive vulnerability to physiological and psychological challenges. Exploring the basis of this vulnerability may provide important insights into the mechanisms underlying aging-associated cognitive decline. As we have previously reported, the cognitive abilities of aging (24-month-old) F344 x BN rats are generally good, but are more vulnerable to the consequences of a peripheral immune challenge (an intraperitoneal injection of live Escherichia coli) than those of their younger (3-month-old) counterparts. Four days after the injection, the aging, but not the young rats show profound memory deficits, specific to the consolidation of hippocampus-dependent memory processes. Here, we have extended these observations, using hippocampal slices to examine for the first time the combined effects of aging and a recent infection on several forms of synaptic plasticity. We have found that the specific deficit in long-lasting memory observed in the aged animals after infection is mirrored by a specific deficit in a form of long-lasting synaptic plasticity. The late-phase long-term potentiation induced in area CA1 using theta-burst stimulation is particularly compromised by the combined effects of aging and infection-a deficit that can be ameliorated by intra-cisterna magna administration of the naturally occurring antiinflammatory cytokine IL-1Ra (interleukin-1 receptor antagonist). These data support the idea that the combination of aging and a negative life event such as an infection might produce selective, early-stage failures of synaptic plasticity in the hippocampus, with corresponding selective deficits in memory.

Bidirectional synaptic plasticity in the cerebellum-like mammalian dorsal cochlear nucleus

NASA Astrophysics Data System (ADS)

Fujino, Kiyohiro; Oertel, Donata

2003-01-01

The dorsal cochlear nucleus integrates acoustic with multimodal sensory inputs from widespread areas of the brain. Multimodal inputs are brought to spiny dendrites of fusiform and cartwheel cells in the molecular layer by parallel fibers through synapses that are subject to long-term potentiation and long-term depression. Acoustic cues are brought to smooth dendrites of fusiform cells in the deep layer by auditory nerve fibers through synapses that do not show plasticity. Plasticity requires Ca2+-induced Ca2+ release; its sensitivity to antagonists of N-methyl-D-aspartate and metabotropic glutamate receptors differs in fusiform and cartwheel cells.

N-Acetylcysteine reverses cocaine-induced metaplasticity.

PubMed

Moussawi, Khaled; Pacchioni, Alejandra; Moran, Megan; Olive, M Foster; Gass, Justin T; Lavin, Antonieta; Kalivas, Peter W

2009-02-01

Cocaine addiction is characterized by an impaired ability to develop adaptive behaviors that can compete with cocaine seeking, implying a deficit in the ability to induce plasticity in cortico-accumbens circuitry crucial for regulating motivated behavior. We found that rats withdrawn from cocaine self-administration had a marked in vivo deficit in the ability to develop long-term potentiation (LTP) and long-term depression (LTD) in the nucleus accumbens core subregion after stimulation of the prefrontal cortex. N-acetylcysteine (NAC) treatment prevents relapse in animal models and craving in humans by activating cystine-glutamate exchange and thereby stimulating extrasynaptic metabotropic glutamate receptors (mGluR). NAC treatment of rats restored the ability to induce LTP and LTD by indirectly stimulating mGluR2/3 and mGluR5, respectively. Our findings show that cocaine self-administration induces metaplasticity that inhibits further induction of synaptic plasticity, and this impairment can be reversed by NAC, a drug that also prevents relapse.

Long-term depression of inhibitory synaptic transmission induced by spike-timing dependent plasticity requires coactivation of endocannabinoid and muscarinic receptors.

PubMed

Ahumada, Juan; Fernández de Sevilla, David; Couve, Alejandro; Buño, Washington; Fuenzalida, Marco

2013-12-01

The precise timing of pre-postsynaptic activity is vital for the induction of long-term potentiation (LTP) or depression (LTD) at many central synapses. We show in synapses of rat CA1 pyramidal neurons in vitro that spike timing dependent plasticity (STDP) protocols that induce LTP at glutamatergic synapses can evoke LTD of inhibitory postsynaptic currents or STDP-iLTD. The STDP-iLTD requires a postsynaptic Ca(2+) increase, a release of endocannabinoids (eCBs), the activation of type-1 endocananabinoid receptors and presynaptic muscarinic receptors that mediate a decreased probability of GABA release. In contrast, the STDP-iLTD is independent of the activation of nicotinic receptors, GABAB Rs and G protein-coupled postsynaptic receptors at pyramidal neurons. We determine that the downregulation of presynaptic Cyclic adenosine monophosphate/protein Kinase A pathways is essential for the induction of STDP-iLTD. These results suggest a novel mechanism by which the activation of cholinergic neurons and retrograde signaling by eCBs can modulate the efficacy of GABAergic synaptic transmission in ways that may contribute to information processing and storage in the hippocampus. Copyright © 2013 Wiley Periodicals, Inc.

Long-term exposure to high glucose induces changes in the content and distribution of some exocytotic proteins in cultured hippocampal neurons.

PubMed

Gaspar, J M; Castilho, Á; Baptista, F I; Liberal, J; Ambrósio, A F

2010-12-29

A few studies have reported the existence of depletion of synaptic vesicles, and changes in neurotransmitter release and in the content of exocytotic proteins in the hippocampus of diabetic rats. Recently, we found that diabetes alters the levels of synaptic proteins in hippocampal nerve terminals. Hyperglycemia is considered the main trigger of diabetic complications, although other factors, such as low insulin levels, also contribute to diabetes-induced changes. Thus, the aim of this work was to evaluate whether long-term elevated glucose per se, which mimics prolonged hyperglycemia, induces significant changes in the content and localization of synaptic proteins involved in exocytosis in hippocampal neurons. Hippocampal cell cultures were cultured for 14 days and were exposed to high glucose (50 mM) or mannitol (osmotic control; 25 mM plus 25 mM glucose), for 7 days. Cell viability and nuclear morphology were evaluated by MTT and Hoechst assays, respectively. The protein levels of vesicle-associated membrane protein-2 (VAMP-2), synaptosomal-associated protein-25 (SNAP-25), syntaxin-1, synapsin-1, synaptophysin, synaptotagmin-1, rabphilin 3a, and also of vesicular glutamate and GABA transporters (VGluT-1 and VGAT), were evaluated by immunoblotting, and its localization was analyzed by immunocytochemistry. The majority of the proteins were not affected. However, elevated glucose decreased the content of SNAP-25 and increased the content of synaptotagmin-1 and VGluT-1. Moreover, there was an accumulation of syntaxin-1, synaptotagmin-1 and VGluT-1 in the cell body of some hippocampal neurons exposed to high glucose. No changes were detected in mannitol-treated cells. In conclusion, elevated glucose per se did not induce significant changes in the content of the majority of the synaptic proteins studied in hippocampal cultures, with the exception of SNAP-25, synaptotagmin-1 and VGluT-1. However, there was an accumulation of some proteins in cell bodies of hippocampal neurons exposed to elevated glucose, suggesting that the trafficking of these proteins to the synapse may be compromised. Moreover, these results also suggest that other factors, in addition to hyperglycemia, certainly contribute to alterations detected in synaptic proteins in diabetic animals. Copyright © 2010 IBRO. Published by Elsevier Ltd. All rights reserved.

The protein kinase Mζ network as a bistable switch to store neuronal memory.

PubMed

Ogasawara, Hideaki; Kawato, Mitsuo

2010-12-31

Protein kinase Mζ (PKMζ), the brain-specific, atypical protein kinase C isoform, plays a key role in long-term maintenance of memory. This molecule is essential for long-term potentiation of the neuron and various modalities of learning such as spatial memory and fear conditioning. It is unknown, however, how PKMζ stores information for long periods of time despite molecular turnover. We hypothesized that PKMζ forms a bistable switch because it appears to constitute a positive feedback loop (PKMζ induces its local synthesis) part of which is ultrasensitive (PKMζ stimulates its synthesis through dual pathways). To examine this hypothesis, we modeled the biochemical network of PKMζ with realistic kinetic parameters. Bifurcation analyses of the model showed that the system maintains either the up state or the down state according to previous inputs. Furthermore, the model was able to reproduce a variety of previous experimental results regarding synaptic plasticity and learning, which suggested that it captures the essential mechanism for neuronal memory. We proposed in vitro and in vivo experiments that would critically examine the validity of the model and illuminate the pivotal role of PKMζ in synaptic plasticity and learning. This study revealed bistability of the PKMζ network and supported its pivotal role in long-term storage of memory.

Calcitonin gene-related peptide erases the fear memory and facilitates long-term potentiation in the central nucleus of the amygdala in rats.

PubMed

Wu, Xin; Zhang, Jie-Ting; Liu, Jue; Yang, Si; Chen, Tao; Chen, Jian-Guo; Wang, Fang

2015-11-01

Calcitonin gene-related peptide (CGRP) is a 37 amino acid neuropeptide, which plays a critical role in the central nervous system. CGRP binds to G protein-coupled receptors, including CGRP1, which couples positively to adenylyl cyclase (AC) and protein kinase A (PKA) activation. CGRP and CGRP1 receptors are enriched in central nucleus of the amygdala (CeA), the main part of the amygdala, which regulates conditioned fear memories. Here, we reported the importance of CGRP and CGRP1 receptor for synaptic plasticity in the CeA and the extinction of fear memory in rats. Our electrophysiological and behavioral in vitro and in vivo results showed exogenous application of CGRP induced an immediate and lasting long-term potentiation in the basolateral nucleus of amygdala-CeA pathway, but not in the lateral nucleus of amygdala-CeA pathway, while bilateral intra-CeA infusion CGRP (0, 5, 13 and 21 μM/side) dose dependently enhanced fear memory extinction. The effects were blocked by CGRP1 receptor antagonist (CGRP8-37 ), N-methyl-d-aspartate receptors antagonist MK801 and PKA inhibitor H89. These results demonstrate that CGRP can lead to long-term potentiation of basolateral nucleus of amygdala-CeA pathway through a PKA-dependent postsynaptic mechanism that involved N-methyl-d-aspartate receptors and enhance the extinction of fear memory in rats. Together, the results strongly support a pivotal role of CGRP in the synaptic plasticity of CeA and extinction of fear memory. Calcitonin gene-related peptide (CGRP) plays an essential role in synaptic plasticity in the amygdala and fear memory. We found that CGRP-induced chemical long-term potentiation (LTP) in a dose-dependent way in the BLA-CeA (basolateral and central nucleus of amygdala, respectively) pathway and enhanced fear memory extinction in rats through a protein kinase A (PKA)-dependent postsynaptic mechanism that involved NMDA receptors. These results support a pivotal role of CGRP in amygdala. © 2015 International Society for Neurochemistry.

[Involvement of aquaporin-4 in synaptic plasticity, learning and memory].

PubMed

Wu, Xin; Gao, Jian-Feng

2017-06-25

Aquaporin-4 (AQP-4) is the predominant water channel in the central nervous system (CNS) and primarily expressed in astrocytes. Astrocytes have been generally believed to play important roles in regulating synaptic plasticity and information processing. However, the role of AQP-4 in regulating synaptic plasticity, learning and memory, cognitive function is only beginning to be investigated. It is well known that synaptic plasticity is the prime candidate for mediating of learning and memory. Long term potentiation (LTP) and long term depression (LTD) are two forms of synaptic plasticity, and they share some but not all the properties and mechanisms. Hippocampus is a part of limbic system that is particularly important in regulation of learning and memory. This article is to review some research progresses of the function of AQP-4 in synaptic plasticity, learning and memory, and propose the possible role of AQP-4 as a new target in the treatment of cognitive dysfunction.

Enriched environment ameliorates depression-induced cognitive deficits and restores abnormal hippocampal synaptic plasticity.

PubMed

Mahati, K; Bhagya, V; Christofer, T; Sneha, A; Shankaranarayana Rao, B S

2016-10-01

Severe depression compromises structural and functional integrity of the brain and results in impaired learning and memory, maladaptive synaptic plasticity as well as degenerative changes in the hippocampus and amygdala. The precise mechanisms underlying cognitive dysfunctions in depression remain largely unknown. On the other hand, enriched environment (EE) offers beneficial effects on cognitive functions, synaptic plasticity in the hippocampus. However, the effect of EE on endogenous depression associated cognitive dysfunction has not been explored. Accordingly, we have attempted to address this issue by investigating behavioural, structural and synaptic plasticity mechanisms in an animal model of endogenous depression after exposure to enriched environment. Our results demonstrate that depression is associated with impaired spatial learning and enhanced anxiety-like behaviour which is correlated with hypotrophy of the dentate gyrus and amygdalar hypertrophy. We also observed a gross reduction in the hippocampal long-term potentiation (LTP). We report a complete behavioural recovery with reduced indices of anhedonia and behavioural despair, reduced anxiety-like behaviour and improved spatial learning along with a complete restoration of dentate gyrus and amygdalar volumes in depressive rats subjected to EE. Enrichment also facilitated CA3-Schaffer collateral LTP. Our study convincingly proves that depression-induces learning deficits and impairs hippocampal synaptic plasticity. It also highlights the role of environmental stimuli in restoring depression-induced cognitive deficits which might prove vital in outlining more effective strategies to treat major depressive disorders. Copyright © 2016 Elsevier Inc. All rights reserved.

Tunicamycin impairs olfactory learning and synaptic plasticity in the olfactory bulb.

PubMed

Tong, Jia; Okutani, Fumino; Murata, Yoshihiro; Taniguchi, Mutsuo; Namba, Toshiharu; Wang, Yu-Jie; Kaba, Hideto

2017-03-06

Tunicamycin (TM) induces endoplasmic reticulum (ER) stress and inhibits N-glycosylation in cells. ER stress is associated with neuronal death in neurodegenerative disorders, such as Parkinson's disease and Alzheimer's disease, and most patients complain of the impairment of olfactory recognition. Here we examined the effects of TM on aversive olfactory learning and the underlying synaptic plasticity in the main olfactory bulb (MOB). Behavioral experiments demonstrated that the intrabulbar infusion of TM disabled aversive olfactory learning without affecting short-term memory. Histological analyses revealed that TM infusion upregulated C/EBP homologous protein (CHOP), a marker of ER stress, in the mitral and granule cell layers of MOB. Electrophysiological data indicated that TM inhibited tetanus-induced long-term potentiation (LTP) at the dendrodendritic excitatory synapse from mitral to granule cells. A low dose of TM (250nM) abolished the late phase of LTP, and a high dose (1μM) inhibited the early and late phases of LTP. Further, high-dose, but not low-dose, TM reduced the paired-pulse facilitation ratio, suggesting that the inhibitory effects of TM on LTP are partially mediated through the presynaptic machinery. Thus, our results support the hypothesis that TM-induced ER stress impairs olfactory learning by inhibiting synaptic plasticity via presynaptic and postsynaptic mechanisms in MOB. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

Transcription Factors in Long-Term Memory and Synaptic Plasticity

PubMed Central

Alberini, Cristina M.

2013-01-01

Transcription is a molecular requisite for long-term synaptic plasticity and long-term memory formation. Thus, in the last several years, one main interest of molecular neuroscience has been the identification of families of transcription factors that are involved in both of these processes. Transcription is a highly regulated process that involves the combined interaction and function of chromatin and many other proteins, some of which are essential for the basal process of transcription, while others control the selective activation or repression of specific genes. These regulated interactions ultimately allow a sophisticated response to multiple environmental conditions, as well as control of spatial and temporal differences in gene expression. Evidence based on correlative changes in expression, genetic mutations, and targeted molecular inhibition of gene expression have shed light on the function of transcription in both synaptic plasticity and memory formation. This review provides a brief overview of experimental work showing that several families of transcription factors, including CREB, C/EBP, Egr, AP-1, and Rel have essential functions in both processes. The results of this work suggest that patterns of transcription regulation represent the molecular signatures of long-term synaptic changes and memory formation. PMID:19126756

Dual Influence of Endocannabinoids on Long-Term Potentiation of Synaptic Transmission

PubMed Central

Silva-Cruz, Armando; Carlström, Mattias; Ribeiro, Joaquim A.; Sebastião, Ana M.

2017-01-01

Cannabinoid receptor 1 (CB1R) is widely distributed in the central nervous system, in excitatory and inhibitory neurons, and in astrocytes. CB1R agonists impair cognition and prevent long-term potentiation (LTP) of synaptic transmission, but the influence of endogenously formed cannabinoids (eCBs) on hippocampal LTP remains ambiguous. Based on the knowledge that eCBs are released upon high frequency neuronal firing, we hypothesized that the influence of eCBs upon LTP could change according to the paradigm of LTP induction. We thus tested the influence of eCBs on hippocampal LTP using two θ-burst protocols that induce either a weak or a strong LTP. LTP induced by a weak-θ-burst protocol is facilitated while preventing the endogenous activation of CB1Rs. In contrast, the same procedures lead to inhibition of LTP induced by the strong-θ-burst protocol, suggestive of a facilitatory action of eCBs upon strong LTP. Accordingly, an inhibitor of the metabolism of the predominant eCB in the hippocampus, 2-arachidonoyl-glycerol (2-AG), facilitates strong LTP. The facilitatory action of endogenous CB1R activation does not require the activity of inhibitory A1 adenosine receptors, is not affected by inhibition of astrocytic metabolism, but involves inhibitory GABAergic transmission. The continuous activation of CB1Rs via exogenous cannabinoids, or by drugs known to prevent metabolism of the non-prevalent hippocampal eCB, anandamide, inhibited LTP. We conclude that endogenous activation of CB1Rs by physiologically formed eCBs exerts a fine-tune homeostatic control of LTP in the hippocampus, acting as a high-pass filter, therefore likely reducing the signal-to-noise ratio of synaptic strengthening. PMID:29311928

RNG105/caprin1, an RNA granule protein for dendritic mRNA localization, is essential for long-term memory formation.

PubMed

Nakayama, Kei; Ohashi, Rie; Shinoda, Yo; Yamazaki, Maya; Abe, Manabu; Fujikawa, Akihiro; Shigenobu, Shuji; Futatsugi, Akira; Noda, Masaharu; Mikoshiba, Katsuhiko; Furuichi, Teiichi; Sakimura, Kenji; Shiina, Nobuyuki

2017-11-21

Local regulation of synaptic efficacy is thought to be important for proper networking of neurons and memory formation. Dysregulation of global translation influences long-term memory in mice, but the relevance of the regulation specific for local translation by RNA granules remains elusive. Here, we demonstrate roles of RNG105/caprin1 in long-term memory formation. RNG105 deletion in mice impaired synaptic strength and structural plasticity in hippocampal neurons. Furthermore, RNG105-deficient mice displayed unprecedentedly severe defects in long-term memory formation in spatial and contextual learning tasks. Genome-wide profiling of mRNA distribution in the hippocampus revealed an underlying mechanism: RNG105 deficiency impaired the asymmetric somato-dendritic localization of mRNAs. Particularly, RNG105 deficiency reduced the dendritic localization of mRNAs encoding regulators of AMPAR surface expression, which was consistent with attenuated homeostatic AMPAR scaling in dendrites and reduced synaptic strength. Thus, RNG105 has an essential role, as a key regulator of dendritic mRNA localization, in long-term memory formation.

Childhood and adolescent obesity and long-term cognitive consequences during aging.

PubMed

Wang, Jun; Freire, Daniel; Knable, Lindsay; Zhao, Wei; Gong, Bing; Mazzola, Paolo; Ho, Lap; Levine, Samara; Pasinetti, Giulio M

2015-04-01

The prevalence of childhood/adolescent obesity and insulin resistance has reached an epidemic level. Obesity's immediate clinical impacts have been extensively studied; however, current clinical evidence underscores the long-term implications. The current study explored the impacts of brief childhood/adolescent obesity and insulin resistance on cognitive function in later life. To mimic childhood/adolescent obesity and insulin resistance, we exposed 9-week-old C57BL/6J mice to a high-fat diet for 15 weeks, after which the mice exhibited diet-induced obesity and insulin resistance. We then put these mice back on a normal low-fat diet, after which the mice exhibited normal body weight and glucose tolerance. However, a spatial memory test in the forms of the Morris water maze (MWM) and contextual fear conditioning at 85 weeks of age showed that these mice had severe deficits in learning and long-term memory consolidation. Mechanistic investigations identified increased expression of histone deacetylases 5, accompanied by reduced expression of brain-derived neurotrophic factor, in the brains 61 weeks after the mice had been off the high-fat diet. Electrophysiology studies showed that hippocampal slices isolated from these mice are more susceptible to synaptic impairments compared with slices isolated from the control mice. We demonstrated that a 15-week occurrence of obesity and insulin resistance during childhood/adolescence induces irreversible epigenetic modifications in the brain that persist following restoration of normal metabolic homeostasis, leading to brain synaptic dysfunction during aging. Our study provides experimental evidence that limited early-life exposure to obesity and insulin resistance may have long-term deleterious consequences in the brain, contributing to the onset/progression of cognitive dysfunction during aging. © 2014 Wiley Periodicals, Inc.

Aluminium chloride impairs long-term memory and downregulates cAMP-PKA-CREB signalling in rats.

PubMed

Zhang, Lifeng; Jin, Cuihong; Lu, Xiaobo; Yang, Jinghua; Wu, Shengwen; Liu, Qiufang; Chen, Rong; Bai, Chunyu; Zhang, Di; Zheng, Linlin; Du, Yanqiu; Cai, Yuan

2014-09-02

Epidemiological investigations have indicated that aluminium (Al) is an important environmental neurotoxicant that may be involved in the aetiology of the cognitive dysfunction associated with neurodegenerative diseases. Additionally, exposure to Al is known to cause neurobehavioural abnormalities in animals. Previous studies demonstrated that Al impaired early-phase long-term potentiation (E-LTP) in vivo and in vitro. Our previous research revealed that Al could impair long-term memory via the impairment of late-phase long-term potentiation (L-LTP) in vivo. However, the exact mechanism by which Al impairs long-term memory has been poorly studied thus far. This study was designed not only to observe the effects of subchronic Al treatment on long-term memory and hippocampal ultrastructure but also to explore a possible underlying mechanism (involving the cAMP-PKA-CREB signalling pathway) in the hippocampus of rats.. Pregnant Wistar rats were assigned to four groups. Neonatal rats were exposed to Al by parental lactation for 3 weeks and then fed with distilled water containing 0, 0.2%, 0.4% or 0.6% Al chloride (AlCl3) for 3 postnatal months. The levels of Al in the blood and hippocampus were quantified by atomic absorption spectrophotometry. The shuttle-box test was performed to detect long-term memory. The hippocampus was collected for ultrastructure observation, and the level of cAMP-PKA-CREB signalling was examined. The results showed that the Al concentrations in the blood and hippocampus of Al-treated rats were higher than those of the control rats. Al may impair the long-term memory of rats. Hippocampal cAMP, cPKA, pCREB, BDNF and c-jun expression decreased significantly, and the neuronal and synaptic ultrastructure exhibited pathological changes after Al treatment. These results indicated that Al may induce long-term memory damage in rats by inhibiting cAMP-PKA-CREB signalling and altering the synaptic and neuronal ultrastructure in the hippocampus. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Modulation of CaV2.1 channels by neuronal calcium sensor-1 induces short-term synaptic facilitation.

PubMed

Yan, Jin; Leal, Karina; Magupalli, Venkat G; Nanou, Evanthia; Martinez, Gilbert Q; Scheuer, Todd; Catterall, William A

2014-11-01

Facilitation and inactivation of P/Q-type Ca2+ currents mediated by Ca2+/calmodulin binding to Ca(V)2.1 channels contribute to facilitation and rapid depression of synaptic transmission, respectively. Other calcium sensor proteins displace calmodulin from its binding site and differentially modulate P/Q-type Ca2 + currents, resulting in diverse patterns of short-term synaptic plasticity. Neuronal calcium sensor-1 (NCS-1, frequenin) has been shown to enhance synaptic facilitation, but the underlying mechanism is unclear. We report here that NCS-1 directly interacts with IQ-like motif and calmodulin-binding domain in the C-terminal domain of Ca(V)2.1 channel. NCS-1 reduces Ca2 +-dependent inactivation of P/Q-type Ca2+ current through interaction with the IQ-like motif and calmodulin-binding domain without affecting peak current or activation kinetics. Expression of NCS-1 in presynaptic superior cervical ganglion neurons has no effect on synaptic transmission, eliminating effects of this calcium sensor protein on endogenous N-type Ca2+ currents and the endogenous neurotransmitter release machinery. However, in superior cervical ganglion neurons expressing wild-type Ca(V)2.1 channels, co-expression of NCS-1 induces facilitation of synaptic transmission in response to paired pulses and trains of depolarizing stimuli, and this effect is lost in Ca(V)2.1 channels with mutations in the IQ-like motif and calmodulin-binding domain. These results reveal that NCS-1 directly modulates Ca(V)2.1 channels to induce short-term synaptic facilitation and further demonstrate that CaS proteins are crucial in fine-tuning short-term synaptic plasticity.

Enhanced long-term and impaired short-term spatial memory in GluA1 AMPA receptor subunit knockout mice: evidence for a dual-process memory model.

PubMed

Sanderson, David J; Good, Mark A; Skelton, Kathryn; Sprengel, Rolf; Seeburg, Peter H; Rawlins, J Nicholas P; Bannerman, David M

2009-06-01

The GluA1 AMPA receptor subunit is a key mediator of hippocampal synaptic plasticity and is especially important for a rapidly-induced, short-lasting form of potentiation. GluA1 gene deletion impairs hippocampus-dependent, spatial working memory, but spares hippocampus-dependent spatial reference memory. These findings may reflect the necessity of GluA1-dependent synaptic plasticity for short-term memory of recently visited places, but not for the ability to form long-term associations between a particular spatial location and an outcome. This hypothesis is in concordance with the theory that short-term and long-term memory depend on dissociable psychological processes. In this study we tested GluA1-/- mice on both short-term and long-term spatial memory using a simple novelty preference task. Mice were given a series of repeated exposures to a particular spatial location (the arm of a Y-maze) before their preference for a novel spatial location (the unvisited arm of the maze) over the familiar spatial location was assessed. GluA1-/- mice were impaired if the interval between the trials was short (1 min), but showed enhanced spatial memory if the interval between the trials was long (24 h). This enhancement was caused by the interval between the exposure trials rather than the interval prior to the test, thus demonstrating enhanced learning and not simply enhanced performance or expression of memory. This seemingly paradoxical enhancement of hippocampus-dependent spatial learning may be caused by GluA1 gene deletion reducing the detrimental effects of short-term memory on subsequent long-term learning. Thus, these results support a dual-process model of memory in which short-term and long-term memory are separate and sometimes competitive processes.

Influence of visual experience on developmental shift from long-term depression to long-term potentiation in the rat medial vestibular nuclei.

PubMed

Grassi, Silvarosa; Dieni, Cristina; Frondaroli, Adele; Pettorossi, Vito Enrico

2004-11-01

The influence of visual experience deprivation on changes in synaptic plasticity during postnatal development was studied in the ventral part of the rat medial vestibular nuclei (vMVN). We analysed the differences in the occurrence, expressed as a percentage, of long-term depression (LTD) and long-term potentiation (LTP) induced by high frequency stimulation (HFS) of the primary vestibular afferents in rats reared in the light (LR) and those in the dark (DR). In LR rats, HFS only induced LTD in the early stages of development, but the occurrence of LTD progressively decreased to zero before their eyes opened, while that of LTP enhanced from zero to about 50%. Once the rats' eyes had opened, LTD was no longer inducible while LTP occurrence gradually reached the normal adult value (70%). In DR rats, a similar shift from LTD to LTP was observed before their eyes opened, showing only a slightly slower LTD decay and LTP growth, and the LTD annulment was delayed by 1 day. By contrast, the time courses of LTD and LTP development in DR and LR rats showed remarkable differences following eye opening. In fact, LTD occurrence increased to about 50% in a short period of time and remained high until the adult stage. In addition, the occurrence of LTP slowly decreased to less than 20%. The effect of light-deprivation was reversible, since the exposure of DR rats to light, 5 days after eye opening, caused a sudden disappearance of LTD and a partial recover of LTP occurrence. In addition, we observed that a week of light deprivation in LR adult rats did not affect the normal adult LTP occurrence. These results provide evidence that in a critical period of development visual input plays a crucial role in shaping synaptic plasticity of the vMVN, and suggest that the visual guided shift from LTD to LTP during development may be necessary to refine and consolidate vestibular circuitry.

Ephrin-B2 prevents N-methyl-D-aspartate receptor antibody effects on memory and neuroplasticity.

PubMed

Planagumà, Jesús; Haselmann, Holger; Mannara, Francesco; Petit-Pedrol, Mar; Grünewald, Benedikt; Aguilar, Esther; Röpke, Luise; Martín-García, Elena; Titulaer, Maarten J; Jercog, Pablo; Graus, Francesc; Maldonado, Rafael; Geis, Christian; Dalmau, Josep

2016-09-01

To demonstrate that ephrin-B2 (the ligand of EphB2 receptor) antagonizes the pathogenic effects of patients' N-methyl-D-aspartate receptor (NMDAR) antibodies on memory and synaptic plasticity. One hundred twenty-two C57BL/6J mice infused with cerebrospinal fluid (CSF) from patients with anti-NMDAR encephalitis or controls, with or without ephrin-B2, were investigated. CSF was infused through ventricular catheters connected to subcutaneous osmotic pumps over 14 days. Memory, behavioral tasks, locomotor activity, presence of human antibodies specifically bound to hippocampal NMDAR, and antibody effects on the density of cell-surface and synaptic NMDAR and EphB2 were examined at different time points using reported techniques. Short- and long-term synaptic plasticity were determined in acute brain sections; the Schaffer collateral pathway was stimulated and the field excitatory postsynaptic potentials were recorded in the CA1 region of the hippocampus. Mice infused with patients' CSF, but not control CSF, developed progressive memory deficit and depressive-like behavior along with deposits of NMDAR antibodies in the hippocampus. These findings were associated with a decrease of the density of cell-surface and synaptic NMDAR and EphB2, and marked impairment of long-term synaptic plasticity without altering short-term plasticity. Administration of ephrin-B2 prevented the pathogenic effects of the antibodies in all the investigated paradigms assessing memory, depressive-like behavior, density of cell-surface and synaptic NMDAR and EphB2, and long-term synaptic plasticity. Administration of ephrin-B2 prevents the pathogenic effects of anti-NMDAR encephalitis antibodies on memory and behavior, levels of cell-surface NMDAR, and synaptic plasticity. These findings reveal a strategy beyond immunotherapy to antagonize patients' antibody effects. Ann Neurol 2016;80:388-400. © 2016 American Neurological Association.

The restless engram: consolidations never end.

PubMed

Dudai, Yadin

2012-01-01

Memory consolidation is the hypothetical process in which an item in memory is transformed into a long-term form. It is commonly addressed at two complementary levels of description and analysis: the cellular/synaptic level (synaptic consolidation) and the brain systems level (systems consolidation). This article focuses on selected recent advances in consolidation research, including the reconsolidation of long-term memory items, the brain mechanisms of transformation of the content and of cue-dependency of memory items over time, as well as the role of rest and sleep in consolidating and shaping memories. Taken together, the picture that emerges is of dynamic engrams that are formed, modified, and remodified over time at the systems level by using synaptic consolidation mechanisms as subroutines. This implies that, contrary to interpretations that have dominated neuroscience for a while, but similar to long-standing cognitive concepts, consolidation of at least some items in long-term memory may never really come to an end.

Persistent ERK Activation Maintains Learning-Induced Long-Lasting Modulation of Synaptic Connectivity

ERIC Educational Resources Information Center

Cohen-Matsliah, Sivan Ida; Seroussi, Yaron; Rosenblum, Kobi; Barkai, Edi

2008-01-01

Pyramidal neurons in the piriform cortex from olfactory-discrimination (OD) trained rats undergo synaptic modifications that last for days after learning. A particularly intriguing modification is reduced paired-pulse facilitation (PPF) in the synapses interconnecting these cells; a phenomenon thought to reflect enhanced synaptic release. The…

Expression of the Immediate-Early Gene-Encoded Protein Egr-1 ("zif268") during in Vitro Classical Conditioning

ERIC Educational Resources Information Center

Mokin, Maxim; Keifer, Joyce

2005-01-01

Expression of the immediate-early genes (IEGs) has been shown to be induced by activity-dependent synaptic plasticity or behavioral training and is thought to play an important role in long-term memory. In the present study, we examined the induction and expression of the IEG-encoded protein Egr-1 during an in vitro neural correlate of eyeblink…

The AMPA receptor-associated protein Shisa7 regulates hippocampal synaptic function and contextual memory

PubMed Central

Zamri, Azra Elia; Stroeder, Jasper; Rao-Ruiz, Priyanka; Lodder, Johannes C; van der Loo, Rolinka J

2017-01-01

Glutamatergic synapses rely on AMPA receptors (AMPARs) for fast synaptic transmission and plasticity. AMPAR auxiliary proteins regulate receptor trafficking, and modulate receptor mobility and its biophysical properties. The AMPAR auxiliary protein Shisa7 (CKAMP59) has been shown to interact with AMPARs in artificial expression systems, but it is unknown whether Shisa7 has a functional role in glutamatergic synapses. We show that Shisa7 physically interacts with synaptic AMPARs in mouse hippocampus. Shisa7 gene deletion resulted in faster AMPAR currents in CA1 synapses, without affecting its synaptic expression. Shisa7 KO mice showed reduced initiation and maintenance of long-term potentiation of glutamatergic synapses. In line with this, Shisa7 KO mice showed a specific deficit in contextual fear memory, both short-term and long-term after conditioning, whereas auditory fear memory and anxiety-related behavior were normal. Thus, Shisa7 is a bona-fide AMPAR modulatory protein affecting channel kinetics of AMPARs, necessary for synaptic hippocampal plasticity, and memory recall. PMID:29199957

The E3 Ligase APC/C-Cdh1 Is Required for Associative Fear Memory and Long-Term Potentiation in the Amygdala of Adult Mice

ERIC Educational Resources Information Center

Pick, Joseph E.; Malumbres, Marcos; Klann, Eric

2013-01-01

The anaphase promoting complex/cyclosome (APC/C) is an E3 ligase regulated by Cdh1. Beyond its role in controlling cell cycle progression, APC/C-Cdh1 has been detected in neurons and plays a role in long-lasting synaptic plasticity and long-term memory. Herein, we further examined the role of Cdh1 in synaptic plasticity and memory by generating…

Drug-Induced Alterations of Endocannabinoid-Mediated Plasticity in Brain Reward Regions.

PubMed

Zlebnik, Natalie E; Cheer, Joseph F

2016-10-05

The endocannabinoid (eCB) system has emerged as one of the most important mediators of physiological and pathological reward-related synaptic plasticity. eCBs are retrograde messengers that provide feedback inhibition, resulting in the suppression of neurotransmitter release at both excitatory and inhibitory synapses, and they serve a critical role in the spatiotemporal regulation of both short- and long-term synaptic plasticity that supports adaptive learning of reward-motivated behaviors. However, mechanisms of eCB-mediated synaptic plasticity in reward areas of the brain are impaired following exposure to drugs of abuse. Because of this, it is theorized that maladaptive eCB signaling may contribute to the development and maintenance of addiction-related behavior. Here we review various forms of eCB-mediated synaptic plasticity present in regions of the brain involved in reward and reinforcement and explore the potential physiological relevance of maladaptive eCB signaling to addiction vulnerability. Copyright © 2016 the authors 0270-6474/16/3610230-09$15.00/0.

MicroRNA-132 regulates recognition memory and synaptic plasticity in the perirhinal cortex

PubMed Central

Scott, Helen L; Tamagnini, Francesco; Narduzzo, Katherine E; Howarth, Joanna L; Lee, Youn-Bok; Wong, Liang-Fong; Brown, Malcolm W; Warburton, Elizabeth C; Bashir, Zafar I; Uney, James B

2012-01-01

Evidence suggests that the acquisition of recognition memory depends upon CREB-dependent long-lasting changes in synaptic plasticity in the perirhinal cortex. The CREB-responsive microRNA miR-132 has been shown to regulate synaptic transmission and we set out to investigate a role for this microRNA in recognition memory and its underlying plasticity mechanisms. To this end we mediated the specific overexpression of miR-132 selectively in the rat perirhinal cortex and demonstrated impairment in short-term recognition memory. This functional deficit was associated with a reduction in both long-term depression and long-term potentiation. These results confirm that microRNAs are key coordinators of the intracellular pathways that mediate experience-dependent changes in the brain. In addition, these results demonstrate a role for miR-132 in the neuronal mechanisms underlying the formation of short-term recognition memory. PMID:22845676

Sensory-evoked LTP driven by dendritic plateau potentials in vivo.

PubMed

Gambino, Frédéric; Pagès, Stéphane; Kehayas, Vassilis; Baptista, Daniela; Tatti, Roberta; Carleton, Alan; Holtmaat, Anthony

2014-11-06

Long-term synaptic potentiation (LTP) is thought to be a key process in cortical synaptic network plasticity and memory formation. Hebbian forms of LTP depend on strong postsynaptic depolarization, which in many models is generated by action potentials that propagate back from the soma into dendrites. However, local dendritic depolarization has been shown to mediate these forms of LTP as well. As pyramidal cells in supragranular layers of the somatosensory cortex spike infrequently, it is unclear which of the two mechanisms prevails for those cells in vivo. Using whole-cell recordings in the mouse somatosensory cortex in vivo, we demonstrate that rhythmic sensory whisker stimulation efficiently induces synaptic LTP in layer 2/3 (L2/3) pyramidal cells in the absence of somatic spikes. The induction of LTP depended on the occurrence of NMDAR (N-methyl-d-aspartate receptor)-mediated long-lasting depolarizations, which bear similarities to dendritic plateau potentials. In addition, we show that whisker stimuli recruit synaptic networks that originate from the posteromedial complex of the thalamus (POm). Photostimulation of channelrhodopsin-2 expressing POm neurons generated NMDAR-mediated plateau potentials, whereas the inhibition of POm activity during rhythmic whisker stimulation suppressed the generation of those potentials and prevented whisker-evoked LTP. Taken together, our data provide evidence for sensory-driven synaptic LTP in vivo, in the absence of somatic spiking. Instead, LTP is mediated by plateau potentials that are generated through the cooperative activity of lemniscal and paralemniscal synaptic circuitry.

Neural Protein Synthesis during Aging: Effects on Plasticity and Memory

PubMed Central

Schimanski, Lesley A.; Barnes, Carol A.

2010-01-01

During aging, many experience a decline in cognitive function that includes memory loss. The encoding of long-term memories depends on new protein synthesis, and this is also reduced during aging. Thus, it is possible that changes in the regulation of protein synthesis contribute to the memory impairments observed in older animals. Several lines of evidence support this hypothesis. For instance, protein synthesis is required for a longer period following learning to establish long-term memory in aged rodents. Also, under some conditions, synaptic activity or pharmacological activation can induce de novo protein synthesis and lasting changes in synaptic transmission in aged, but not young, rodents; the opposite results can be observed in other conditions. These changes in plasticity likely play a role in manifesting the altered place field properties observed in awake and behaving aged rats. The collective evidence suggests a link between memory loss and the regulation of protein synthesis in senescence. In fact, pharmaceuticals that target the signaling pathways required for induction of protein synthesis have improved memory, synaptic plasticity, and place cell properties in aged animals. We suggest that a better understanding of the mechanisms that lead to different protein expression patterns in the neural circuits that change as a function of age will enable the development of more effective therapeutic treatments for memory loss. PMID:20802800

The M-current inhibitor XE991 decreases the stimulation threshold for long-term synaptic plasticity in healthy mice and in models of cognitive disease.

PubMed

Fontán-Lozano, Angela; Suárez-Pereira, Irene; Delgado-García, José María; Carrión, Angel Manuel

2011-01-01

Aging, mental retardation, number of psychiatric and neurological disorders are all associated with learning and memory impairments. As the underlying causes of such conditions are very heterogeneous, manipulations that can enhance learning and memory in mice under different circumstances might be able to overcome the cognitive deficits in patients. The M-current regulates neuronal excitability and action potential firing, suggesting that its inhibition may increase cognitive capacities. We demonstrate that XE991, a specific M-current blocker, enhances learning and memory in healthy mice. This effect may be achieved by altering basal hippocampal synaptic activity and by diminishing the stimulation threshold for long-term changes in synaptic efficacy and learning-related gene expression. We also show that training sessions regulate the M-current by transiently decreasing the levels of KCNQ/Kv7.3 protein, a pivotal subunit for the M-current. Furthermore, we found that XE991 can revert the cognitive impairment associated with acetylcholine depletion and the neurodegeneration induced by kainic acid. Together, these results show that inhibition of the M-current as a general strategy may be useful to enhance cognitive capacities in healthy and aging individuals, as well as in those with neurodegenerative diseases. Copyright © 2010 Wiley-Liss, Inc.

Sleep, Plasticity and Memory from Molecules to Whole-Brain Networks

PubMed Central

Abel, Ted; Havekes, Robbert; Saletin, Jared M.; Walker, Matthew P.

2014-01-01

Despite the ubiquity of sleep across phylogeny, its function remains elusive. In this review, we consider one compelling candidate: brain plasticity associated with memory processing. Focusing largely on hippocampus-dependent memory in rodents and humans, we describe molecular, cellular, network, whole-brain and behavioral evidence establishing a role for sleep both in preparation for initial memory encoding, and in the subsequent offline consolidation ofmemory. Sleep and sleep deprivation bidirectionally alter molecular signaling pathways that regulate synaptic strength and control plasticity-related gene transcription and protein translation. At the cellular level, sleep deprivation impairs cellular excitability necessary for inducing synaptic potentiation and accelerates the decay of long-lasting forms of synaptic plasticity. In contrast, NREM and REM sleep enhance previously induced synaptic potentiation, although synaptic de-potentiation during sleep has also been observed. Beyond single cell dynamics, large-scale cell ensembles express coordinated replay of prior learning-related firing patterns during subsequent sleep. This occurs in the hippocampus, in the cortex, and between the hippocampus and cortex, commonly in association with specific NREM sleep oscillations. At the whole-brain level, somewhat analogous learning-associated hippocampal (re)activation during NREM sleep has been reported in humans. Moreover, the same cortical NREM oscillations associated with replay in rodents also promote human hippocampal memory consolidation, and this process can be manipulated using exogenous reactivation cues during sleep. Mirroring molecular findings in rodents, specific NREM sleep oscillations before encoding refresh human hippocampal learning capacity, while deprivation of sleep conversely impairs subsequent hippocampal activity and associated encoding. Together, these cross-descriptive level findings demonstrate that the unique neurobiology of sleep exert powerful effects on molecular, cellular and network mechanism of plasticity that govern both initial learning and subsequent long-term memory consolidation. PMID:24028961

Extracellular signal-regulated protein kinases 1 and 2 activation by addictive drugs: a signal toward pathological adaptation.

PubMed

Pascoli, Vincent; Cahill, Emma; Bellivier, Frank; Caboche, Jocelyne; Vanhoutte, Peter

2014-12-15

Addiction is a chronic and relapsing psychiatric disorder that is thought to occur in vulnerable individuals. Synaptic plasticity evoked by drugs of abuse in the so-called neuronal circuits of reward has been proposed to underlie behavioral adaptations that characterize addiction. By increasing dopamine in the striatum, addictive drugs alter the balance of dopamine and glutamate signals converging onto striatal medium-sized spiny neurons (MSNs) and activate intracellular events involved in long-term behavioral alterations. Our laboratory contributed to the identification of salient molecular changes induced by administration of addictive drugs to rodents. We pioneered the observation that a common feature of addictive drugs is to activate, by a double tyrosine/threonine phosphorylation, the extracellular signal-regulated kinases 1 and 2 (ERK1/2) in the striatum, which control a plethora of substrates, some of them being critically involved in cocaine-mediated molecular and behavioral adaptations. Herein, we review how the interplay between dopamine and glutamate signaling controls cocaine-induced ERK1/2 activation in MSNs. We emphasize the key role of N-methyl-D-aspartate receptor potentiation by D1 receptor to trigger ERK1/2 activation and its subsequent nuclear translocation where it modulates both epigenetic and genetic processes engaged by cocaine. We discuss how cocaine-induced long-term synaptic and structural plasticity of MSNs, as well as behavioral adaptations, are influenced by ERK1/2-controlled targets. We conclude that a better knowledge of molecular mechanisms underlying ERK1/2 activation by drugs of abuse and/or its role in long-term neuronal plasticity in the striatum may provide a new route for therapeutic treatment in addiction. Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Plasticity of Hippocampal Excitatory-Inhibitory Balance: Missing the Synaptic Control in the Epileptic Brain.

PubMed

Bonansco, Christian; Fuenzalida, Marco

2016-01-01

Synaptic plasticity is the capacity generated by experience to modify the neural function and, thereby, adapt our behaviour. Long-term plasticity of glutamatergic and GABAergic transmission occurs in a concerted manner, finely adjusting the excitatory-inhibitory (E/I) balance. Imbalances of E/I function are related to several neurological diseases including epilepsy. Several evidences have demonstrated that astrocytes are able to control the synaptic plasticity, with astrocytes being active partners in synaptic physiology and E/I balance. Here, we revise molecular evidences showing the epileptic stage as an abnormal form of long-term brain plasticity and propose the possible participation of astrocytes to the abnormal increase of glutamatergic and decrease of GABAergic neurotransmission in epileptic networks.

Plasticity of Hippocampal Excitatory-Inhibitory Balance: Missing the Synaptic Control in the Epileptic Brain

PubMed Central

Bonansco, Christian; Fuenzalida, Marco

2016-01-01

Synaptic plasticity is the capacity generated by experience to modify the neural function and, thereby, adapt our behaviour. Long-term plasticity of glutamatergic and GABAergic transmission occurs in a concerted manner, finely adjusting the excitatory-inhibitory (E/I) balance. Imbalances of E/I function are related to several neurological diseases including epilepsy. Several evidences have demonstrated that astrocytes are able to control the synaptic plasticity, with astrocytes being active partners in synaptic physiology and E/I balance. Here, we revise molecular evidences showing the epileptic stage as an abnormal form of long-term brain plasticity and propose the possible participation of astrocytes to the abnormal increase of glutamatergic and decrease of GABAergic neurotransmission in epileptic networks. PMID:27006834

Calcium sensor regulation of the CaV2.1 Ca2+ channel contributes to short-term synaptic plasticity in hippocampal neurons.

PubMed

Nanou, Evanthia; Sullivan, Jane M; Scheuer, Todd; Catterall, William A

2016-01-26

Short-term synaptic plasticity is induced by calcium (Ca(2+)) accumulating in presynaptic nerve terminals during repetitive action potentials. Regulation of voltage-gated CaV2.1 Ca(2+) channels by Ca(2+) sensor proteins induces facilitation of Ca(2+) currents and synaptic facilitation in cultured neurons expressing exogenous CaV2.1 channels. However, it is unknown whether this mechanism contributes to facilitation in native synapses. We introduced the IM-AA mutation into the IQ-like motif (IM) of the Ca(2+) sensor binding site. This mutation does not alter voltage dependence or kinetics of CaV2.1 currents, or frequency or amplitude of spontaneous miniature excitatory postsynaptic currents (mEPSCs); however, synaptic facilitation is completely blocked in excitatory glutamatergic synapses in hippocampal autaptic cultures. In acutely prepared hippocampal slices, frequency and amplitude of mEPSCs and amplitudes of evoked EPSCs are unaltered. In contrast, short-term synaptic facilitation in response to paired stimuli is reduced by ∼ 50%. In the presence of EGTA-AM to prevent global increases in free Ca(2+), the IM-AA mutation completely blocks short-term synaptic facilitation, indicating that synaptic facilitation by brief, local increases in Ca(2+) is dependent upon regulation of CaV2.1 channels by Ca(2+) sensor proteins. In response to trains of action potentials, synaptic facilitation is reduced in IM-AA synapses in initial stimuli, consistent with results of paired-pulse experiments; however, synaptic depression is also delayed, resulting in sustained increases in amplitudes of later EPSCs during trains of 10 stimuli at 10-20 Hz. Evidently, regulation of CaV2.1 channels by CaS proteins is required for normal short-term plasticity and normal encoding of information in native hippocampal synapses.

Synaptic long-term potentiation realized in Pavlov's dog model based on a NiOx-based memristor

NASA Astrophysics Data System (ADS)

Hu, S. G.; Liu, Y.; Liu, Z.; Chen, T. P.; Yu, Q.; Deng, L. J.; Yin, Y.; Hosaka, Sumio

2014-12-01

Synaptic Long-Term Potentiation (LTP), which is a long-lasting enhancement in signal transmission between neurons, is widely considered as the major cellular mechanism during learning and memorization. In this work, a NiOx-based memristor is found to be able to emulate the synaptic LTP. Electrical conductance of the memristor is increased by electrical pulse stimulation and then spontaneously decays towards its initial state, which resembles the synaptic LTP. The lasting time of the LTP in the memristor can be estimated with the relaxation equation, which well describes the conductance decay behavior. The LTP effect of the memristor has a dependence on the stimulation parameters, including pulse height, width, interval, and number of pulses. An artificial network consisting of three neurons and two synapses is constructed to demonstrate the associative learning and LTP behavior in extinction of association in Pavlov's dog experiment.

Calcium sensor regulation of the CaV2.1 Ca2+ channel contributes to long-term potentiation and spatial learning.

PubMed

Nanou, Evanthia; Scheuer, Todd; Catterall, William A

2016-11-15

Many forms of short-term synaptic plasticity rely on regulation of presynaptic voltage-gated Ca 2+ type 2.1 (Ca V 2.1) channels. However, the contribution of regulation of Ca V 2.1 channels to other forms of neuroplasticity and to learning and memory are not known. Here we have studied mice with a mutation (IM-AA) that disrupts regulation of Ca V 2.1 channels by calmodulin and related calcium sensor proteins. Surprisingly, we find that long-term potentiation (LTP) of synaptic transmission at the Schaffer collateral-CA1 synapse in the hippocampus is substantially weakened, even though this form of synaptic plasticity is thought to be primarily generated postsynaptically. LTP in response to θ-burst stimulation and to 100-Hz tetanic stimulation is much reduced. However, a normal level of LTP can be generated by repetitive 100-Hz stimulation or by depolarization of the postsynaptic cell to prevent block of NMDA-specific glutamate receptors by Mg 2+ The ratio of postsynaptic responses of NMDA-specific glutamate receptors to those of AMPA-specific glutamate receptors is decreased, but the postsynaptic current from activation of NMDA-specific glutamate receptors is progressively increased during trains of stimuli and exceeds WT by the end of 1-s trains. Strikingly, these impairments in long-term synaptic plasticity and the previously documented impairments in short-term synaptic plasticity in IM-AA mice are associated with pronounced deficits in spatial learning and memory in context-dependent fear conditioning and in the Barnes circular maze. Thus, regulation of Ca V 2.1 channels by calcium sensor proteins is required for normal short-term synaptic plasticity, LTP, and spatial learning and memory in mice.

Aß Facilitates LTD at Schaffer Collateral Synapses Preferentially in the Left Hippocampus.

PubMed

O'Riordan, Kenneth J; Hu, Neng-Wei; Rowan, Michael J

2018-02-20

Promotion of long-term depression (LTD) mechanisms by synaptotoxic soluble oligomers of amyloid-β (Aß) has been proposed to underlie synaptic dysfunction in Alzheimer's disease (AD). Previously, LTD was induced by relatively non-specific electrical stimulation. Exploiting optogenetics, we studied LTD using a more physiologically diffuse spatial pattern of selective pathway activation in the rat hippocampus in vivo. This relatively sparse synaptic LTD requires both the ion channel function and GluN2B subunit of the NMDA receptor but, in contrast to electrically induced LTD, is not facilitated by boosting endogenous muscarinic acetylcholine or metabotropic glutamate 5 receptor activation. Although in the absence of Aß, there is no evidence of hippocampal LTD asymmetry, in the presence of Aß, the induction of LTD is preferentially enhanced in the left hippocampus in an mGluR5-dependent manner. This circuit-selective disruption of synaptic plasticity by Aß provides a route to understanding the development of aberrant brain lateralization in AD. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Δ9-THC-caused synaptic and memory impairments are mediated through COX-2 signaling

PubMed Central

Yang, Hongwei; Tang, Ya-ping; Sun, Hao; Song, Yunping; Chen, Chu

2013-01-01

SUMMARY Marijuana has been used for thousands of years as a treatment for medical conditions. However, untoward side effects limit its medical value. Here we show that synaptic and cognitive impairments following repeated exposure to Δ9-tetrahydrocannabinol (Δ9-THC) are associated with the induction of cyclooxygenase-2 (COX-2), an inducible enzyme that converts arachidonic acid to prostanoids, in the brain. COX-2 induction by Δ9-THC is mediated via CB1 receptor-coupled G-protein βγ subunits. Pharmacological or genetic inhibition of COX-2 blocks down-regulation and internalization of glutamate receptor subunits and alterations of the dendritic spine density of hippocampal neurons induced by repeated Δ9-THC exposures. Ablation of COX-2 also eliminates Δ9-THC-impaired hippocampal long-term synaptic plasticity, spatial, and fear memories. Importantly, the beneficial effects of decreasing β-amyloid plaques and neurodegeneration by Δ9-THC in Alzheimer’s disease animals are retained in the presence of COX-2 inhibition. These results suggest that the applicability of medical marijuana would be broadened by concurrent inhibition of COX-2. PMID:24267894

Learning modifies subsequent induction of long-term potentiation-like and long-term depression-like plasticity in human motor cortex.

PubMed

Ziemann, Ulf; Ilić, Tihomir V; Iliać, Tihomir V; Pauli, Christian; Meintzschel, Frank; Ruge, Diane

2004-02-18

Learning may alter rapidly the output organization of adult motor cortex. It is a long-held hypothesis that modification of synaptic strength along cortical horizontal connections through long-term potentiation (LTP) and long-term depression (LTD) forms one important mechanism for learning-induced cortical plasticity. Strong evidence in favor of this hypothesis was provided for rat primary motor cortex (M1) by showing that motor learning reduced subsequent LTP but increased LTD. Whether a similar relationship exists in humans is unknown. Here, we induced LTP-like and LTD-like plasticity in the intact human M1 by an established paired associative stimulation (PAS) protocol. PAS consisted of 200 pairs of electrical stimulation of the right median nerve, followed by focal transcranial magnetic stimulation of the hand area of the left M1 at an interval equaling the individual N20 latency of the median nerve somatosensory-evoked cortical potential (PAS(N20)) or N20-5 msec (PAS(N20-5)). PAS(N20) induced reproducibly a LTP-like long-lasting (>30 min) increase in motor-evoked potentials from the left M1 to a thumb abductor muscle of the right hand, whereas PAS(N20-5) induced a LTD-like decrease. Repeated fastest possible thumb abduction movements resulted in learning, defined by an increase in maximum peak acceleration of the practiced movements, and prevented subsequent PAS(N20)-induced LTP-like plasticity but enhanced subsequent PAS(N20-5)-induced LTD-like plasticity. The same number of repeated slow thumb abduction movements did not result in learning and had no effects on PAS-induced plasticity. Findings support the view that learning in human M1 occurs through LTP-like mechanisms.

The Longevity of Hippocampus-Dependent Memory Is Orchestrated by the Locus Coeruleus-Noradrenergic System

PubMed Central

2017-01-01

The locus coeruleus is connected to the dorsal hippocampus via strong fiber projections. It becomes activated after arousal and novelty, whereupon noradrenaline is released in the hippocampus. Noradrenaline from the locus coeruleus is involved in modulating the encoding, consolidation, retrieval, and reversal of hippocampus-based memory. Memory storage can be modified by the activation of the locus coeruleus and subsequent facilitation of hippocampal long-term plasticity in the forms of long-term depression and long-term potentiation. Recent evidence indicates that noradrenaline and dopamine are coreleased in the hippocampus from locus coeruleus terminals, thus fostering neuromodulation of long-term synaptic plasticity and memory. Noradrenaline is an inductor of epigenetic modifications regulating transcriptional control of synaptic long-term plasticity to gate the endurance of memory storage. In conclusion, locus coeruleus activation primes the persistence of hippocampus-based long-term memory. PMID:28695015

Neurophysiological modification of CA1 pyramidal neurons in a transgenic mouse expressing a truncated form of disrupted-in-schizophrenia 1

PubMed Central

Booth, Clair A; Brown, Jonathan T; Randall, Andrew D

2014-01-01

A t(1;11) balanced chromosomal translocation transects the Disc1 gene in a large Scottish family and produces genome-wide linkage to schizophrenia and recurrent major depressive disorder. This study describes our in vitro investigations into neurophysiological function in hippocampal area CA1 of a transgenic mouse (DISC1tr) that expresses a truncated version of DISC1 designed to reproduce aspects of the genetic situation in the Scottish t(1;11) pedigree. We employed both patch-clamp and extracellular recording methods in vitro to compare intrinsic properties and synaptic function and plasticity between DISC1tr animals and wild-type littermates. Patch-clamp analysis of CA1 pyramidal neurons (CA1-PNs) revealed no genotype dependence in multiple subthreshold parameters, including resting potential, input resistance, hyperpolarization-activated ‘sag’ and resonance properties. Suprathreshold stimuli revealed no alteration to action potential (AP) waveform, although the initial rate of AP production was higher in DISC1tr mice. No difference was observed in afterhyperpolarizing potentials following trains of 5–25 APs at 50 Hz. Patch-clamp analysis of synaptic responses in the Schaffer collateral commissural (SC) pathway indicated no genotype-dependence of paired pulse facilitation, excitatory postsynaptic potential summation or AMPA/NMDA ratio. Extracellular recordings also revealed an absence of changes to SC synaptic responses and indicated input–output and short-term plasticity were also unaltered in the temporoammonic (TA) input. However, in DISC1tr mice theta burst-induced long-term potentiation was enhanced in the SC pathway but completely lost in the TA pathway. These data demonstrate that expressing a truncated form of DISC1 affects intrinsic properties of CA1-PNs and produces pathway-specific effects on long-term synaptic plasticity. PMID:24712988

Long-term potentiation expands information content of hippocampal dentate gyrus synapses.

PubMed

Bromer, Cailey; Bartol, Thomas M; Bowden, Jared B; Hubbard, Dusten D; Hanka, Dakota C; Gonzalez, Paola V; Kuwajima, Masaaki; Mendenhall, John M; Parker, Patrick H; Abraham, Wickliffe C; Sejnowski, Terrence J; Harris, Kristen M

2018-03-06

An approach combining signal detection theory and precise 3D reconstructions from serial section electron microscopy (3DEM) was used to investigate synaptic plasticity and information storage capacity at medial perforant path synapses in adult hippocampal dentate gyrus in vivo. Induction of long-term potentiation (LTP) markedly increased the frequencies of both small and large spines measured 30 minutes later. This bidirectional expansion resulted in heterosynaptic counterbalancing of total synaptic area per unit length of granule cell dendrite. Control hemispheres exhibited 6.5 distinct spine sizes for 2.7 bits of storage capacity while LTP resulted in 12.9 distinct spine sizes (3.7 bits). In contrast, control hippocampal CA1 synapses exhibited 4.7 bits with much greater synaptic precision than either control or potentiated dentate gyrus synapses. Thus, synaptic plasticity altered total capacity, yet hippocampal subregions differed dramatically in their synaptic information storage capacity, reflecting their diverse functions and activation histories.

Synaptic Basis for Whisker Deprivation-Induced Synaptic Depression in Rat Somatosensory Cortex

PubMed Central

Bender, Kevin J.; Allen, Cara B.; Bender, Vanessa A.; Feldman, Daniel E.

2011-01-01

Whisker deprivation weakens excitatory layer 4 (L4) inputs to L2/3 pyramidal cells in rat primary somatosensory (S1) cortex, which is likely to contribute to whisker map plasticity. This weakening has been proposed to represent long-term depression (LTD) induced by sensory deprivation in vivo. Here, we studied the synaptic expression mechanisms for deprivation-induced weakening of L4-L2/3 inputs and assessed its similarity to LTD, which is known to be expressed presynaptically at L4-L2/3 synapses. Whisker deprivation increased the paired pulse ratio at L4-L2/3 synapses and slowed the use-dependent block of NMDA receptor currents by MK-801 [(5S,10R)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate], indicating that deprivation reduced transmitter release probability at these synapses. In contrast, deprivation did not alter either miniature EPSC amplitude in L2/3 neurons or the amplitude of quantal L4-L2/3 synaptic responses measured in strontium, indicating that postsynaptic responsiveness was unchanged. In young postnatal day 12 (P12) rats, at least 4 d of deprivation were required to significantly weaken L4-L2/3 synapses. Similar weakening occurred when deprivation began at older ages (P20), when synapses are mostly mature, indicating that weakening is unlikely to represent a failure of synaptic maturation but instead represents a reduction in the strength of existing synapses. Thus, whisker deprivation weakens L4-L2/3 synapses by decreasing presynaptic function, similar to known LTD mechanisms at this synapse. PMID:16624936

The Chemokine MIP-1α/CCL3 impairs mouse hippocampal synaptic transmission, plasticity and memory.

PubMed

Marciniak, Elodie; Faivre, Emilie; Dutar, Patrick; Alves Pires, Claire; Demeyer, Dominique; Caillierez, Raphaëlle; Laloux, Charlotte; Buée, Luc; Blum, David; Humez, Sandrine

2015-10-29

Chemokines are signaling molecules playing an important role in immune regulations. They are also thought to regulate brain development, neurogenesis and neuroendocrine functions. While chemokine upsurge has been associated with conditions characterized with cognitive impairments, their ability to modulate synaptic plasticity remains ill-defined. In the present study, we specifically evaluated the effects of MIP1-α/CCL3 towards hippocampal synaptic transmission, plasticity and spatial memory. We found that CCL3 (50 ng/ml) significantly reduced basal synaptic transmission at the Schaffer collateral-CA1 synapse without affecting NMDAR-mediated field potentials. This effect was ascribed to post-synaptic regulations, as CCL3 did not impact paired-pulse facilitation. While CCL3 did not modulate long-term depression (LTD), it significantly impaired long-term potentiation (LTP), an effect abolished by Maraviroc, a CCR5 specific antagonist. In addition, sub-chronic intracerebroventricular (icv) injections of CCL3 also impair LTP. In accordance with these electrophysiological findings, we demonstrated that the icv injection of CCL3 in mouse significantly impaired spatial memory abilities and long-term memory measured using the two-step Y-maze and passive avoidance tasks. These effects of CCL3 on memory were inhibited by Maraviroc. Altogether, these data suggest that the chemokine CCL3 is an hippocampal neuromodulator able to regulate synaptic plasticity mechanisms involved in learning and memory functions.

Hypoxia-Induced neonatal seizures diminish silent synapses and long-term potentiation in hippocampal CA1 neurons

PubMed Central

Zhou, Chengwen; Bell, Jocelyn J. Lippman; Sun, Hongyu; Jensen, Frances E.

2012-01-01

Neonatal seizures can lead to epilepsy and long-term cognitive deficits in adulthood. Using a rodent model of the most common form of human neonatal seizures, hypoxia-induced seizures (HS), we aimed to determine whether these seizures modify long-term potentiation (LTP) and “silent” N-methyl-D-aspartate receptor (NMDAR)-only synapses in hippocampal CA1. At 48-72 hours (hrs) post-HS, electrophysiology and immunofluorescent confocal microscopy revealed a significant decrease in the incidence of silent synapses, and an increase in amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) at the synapses. Coincident with this decrease in silent synapses, there was an attenuation of LTP elicited by either tetanic stimulation of Schaffer collaterals or a pairing protocol, and persistent attenuation of LTP in slices removed in later adulthood after P10 HS. Furthermore, post-seizure treatment in vivo with the AMPAR antagonist 2,3-dihydroxy-6-nitro-7-sulfonyl-benzo[f]quinoxaline (NBQX) protected against the HS-induced depletion of silent synapses and preserved LTP. Thus, this study demonstrates a novel mechanism by which early-life seizures could impair synaptic plasticity, suggesting a potential target for therapeutic strategies to prevent long-term cognitive deficits. PMID:22171027

Short-Term Plasticity and Long-Term Potentiation in Magnetic Tunnel Junctions: Towards Volatile Synapses

NASA Astrophysics Data System (ADS)

Sengupta, Abhronil; Roy, Kaushik

2016-02-01

Synaptic memory is considered to be the main element responsible for learning and cognition in humans. Although traditionally nonvolatile long-term plasticity changes are implemented in nanoelectronic synapses for neuromorphic applications, recent studies in neuroscience reveal that biological synapses undergo metastable volatile strengthening followed by a long-term strengthening provided that the frequency of the input stimulus is sufficiently high. Such "memory strengthening" and "memory decay" functionalities can potentially lead to adaptive neuromorphic architectures. In this paper, we demonstrate the close resemblance of the magnetization dynamics of a magnetic tunnel junction (MTJ) to short-term plasticity and long-term potentiation observed in biological synapses. We illustrate that, in addition to the magnitude and duration of the input stimulus, the frequency of the stimulus plays a critical role in determining long-term potentiation of the MTJ. Such MTJ synaptic memory arrays can be utilized to create compact, ultrafast, and low-power intelligent neural systems.

Alpha-Linolenic Acid Confers Neuroprotection and Improves Behavioral Deficits After Soman Exposure: Involvement of Neurogenesis Through an mTOR-Mediated Pathway

DTIC Science & Technology

2015-01-15

chemical warfare agent that irreversibly inhibits acetylcholinesterase in the periphery and central nervous system. Soman induces status epilepticus ...of signs and symptoms including status epilepticus and death. The neuropathology leads to severe cognitive performance, including long-term cognitive... status epilepticus and excessive synaptic accumulation of acetylcholine affects other organ systems beside the brain causing hypersecretions

Reversible optical switching memristors with tunable STDP synaptic plasticity: a route to hierarchical control in artificial intelligent systems.

PubMed

Jaafar, Ayoub H; Gray, Robert J; Verrelli, Emanuele; O'Neill, Mary; Kelly, Stephen M; Kemp, Neil T

2017-11-09

Optical control of memristors opens the route to new applications in optoelectronic switching and neuromorphic computing. Motivated by the need for reversible and latched optical switching we report on the development of a memristor with electronic properties tunable and switchable by wavelength and polarization specific light. The device consists of an optically active azobenzene polymer, poly(disperse red 1 acrylate), overlaying a forest of vertically aligned ZnO nanorods. Illumination induces trans-cis isomerization of the azobenzene molecules, which expands or contracts the polymer layer and alters the resistance of the off/on states, their ratio and retention time. The reversible optical effect enables dynamic control of a memristor's learning properties including control of synaptic potentiation and depression, optical switching between short-term and long-term memory and optical modulation of the synaptic efficacy via spike timing dependent plasticity. The work opens the route to the dynamic patterning of memristor networks both spatially and temporally by light, thus allowing the development of new optically reconfigurable neural networks and adaptive electronic circuits.

Formation and stability of synaptic receptor domains.

PubMed

Haselwandter, Christoph A; Calamai, Martino; Kardar, Mehran; Triller, Antoine; da Silveira, Rava Azeredo

2011-06-10

Neurotransmitter receptor molecules, concentrated in postsynaptic domains along with scaffold and a number of other molecules, are key regulators of signal transmission across synapses. Combining experiment and theory, we develop a quantitative description of synaptic receptor domains in terms of a reaction-diffusion model. We show that interactions between only receptors and scaffolds, together with the rapid diffusion of receptors on the cell membrane, are sufficient for the formation and stable characteristic size of synaptic receptor domains. Our work reconciles long-term stability of synaptic receptor domains with rapid turnover and diffusion of individual receptors, and suggests novel mechanisms for a form of short-term, postsynaptic plasticity.

Protection against β-amyloid-induced synaptic and memory impairments via altering β-amyloid assembly by bis(heptyl)-cognitin

PubMed Central

Chang, Lan; Cui, Wei; Yang, Yong; Xu, Shujun; Zhou, Wenhua; Fu, Hongjun; Hu, Shengquan; Mak, Shinghung; Hu, Juwei; Wang, Qin; Pui-Yan Ma, Victor; Chung-lit Choi, Tony; Dik-lung Ma, Edmond; Tao, Liang; Pang, Yuanping; Rowan, Michael J.; Anwyl, Roger; Han, Yifan; Wang, Qinwen

2015-01-01

β-amyloid (Aβ) oligomers have been closely implicated in the pathogenesis of Alzheimer’s disease (AD). We found, for the first time, that bis(heptyl)-cognitin, a novel dimeric acetylcholinesterase (AChE) inhibitor derived from tacrine, prevented Aβ oligomers-induced inhibition of long-term potentiation (LTP) at concentrations that did not interfere with normal LTP. Bis(heptyl)-cognitin also prevented Aβ oligomers-induced synaptotoxicity in primary hippocampal neurons. In contrast, tacrine and donepezil, typical AChE inhibitors, could not prevent synaptic impairments in these models, indicating that the modification of Aβ oligomers toxicity by bis(heptyl)-cognitin might be attributed to a mechanism other than AChE inhibition. Studies by using dot blotting, immunoblotting, circular dichroism spectroscopy, and transmission electron microscopy have shown that bis(heptyl)-cognitin altered Aβ assembly via directly inhibiting Aβ oligomers formation and reducing the amount of preformed Aβ oligomers. Molecular docking analysis further suggested that bis(heptyl)-cognitin presumably interacted with the hydrophobic pockets of Aβ, which confers stabilizing powers and assembly alteration effects on Aβ. Most importantly, bis(heptyl)-cognitin significantly reduced cognitive impairments induced by intra-hippocampal infusion of Aβ oligomers in mice. These results clearly demonstrated how dimeric agents prevent Aβ oligomers-induced synaptic and memory impairments, and offered a strong support for the beneficial therapeutic effects of bis(heptyl)-cognitin in the treatment of AD. PMID:26194093

Translational control by eIF2α phosphorylation regulates vulnerability to the synaptic and behavioral effects of cocaine

PubMed Central

Huang, Wei; Placzek, Andon N; Viana Di Prisco, Gonzalo; Khatiwada, Sanjeev; Sidrauski, Carmela; Krnjević, Krešimir; Walter, Peter; Dani, John A; Costa-Mattioli, Mauro

2016-01-01

Adolescents are especially prone to drug addiction, but the underlying biological basis of their increased vulnerability remains unknown. We reveal that translational control by phosphorylation of the translation initiation factor eIF2α (p-eIF2α) accounts for adolescent hypersensitivity to cocaine. In adolescent (but not adult) mice, a low dose of cocaine reduced p-eIF2α in the ventral tegmental area (VTA), potentiated synaptic inputs to VTA dopaminergic neurons, and induced drug-reinforced behavior. Like adolescents, adult mice with reduced p-eIF2α-mediated translational control were more susceptible to cocaine-induced synaptic potentiation and behavior. Conversely, like adults, adolescent mice with increased p-eIF2α became more resistant to cocaine's effects. Accordingly, metabotropic glutamate receptor-mediated long-term depression (mGluR-LTD)—whose disruption is postulated to increase vulnerability to drug addiction—was impaired in both adolescent mice and adult mice with reduced p-eIF2α mediated translation. Thus, during addiction, cocaine hijacks translational control by p-eIF2α, initiating synaptic potentiation and addiction-related behaviors. These insights may hold promise for new treatments for addiction. DOI: http://dx.doi.org/10.7554/eLife.12052.001 PMID:26928234

Leptin: a potential anxiolytic by facilitation of fear extinction.

PubMed

Wang, Wei; Liu, Song-Lin; Li, Kuan; Chen, Yu; Jiang, Bo; Li, Yan-Kun; Xiao, Jun-Li; Yang, Si; Chen, Tao; Chen, Jian-Guo; Li, Jia-Geng; Wang, Fang

2015-05-01

Anxiety disorders are characterized by a deficient extinction of fear memory. Evidence is growing that leptin influences numerous neuronal functions. The aims of this study were to investigate the effects and the mechanism of leptin on fear extinction. Leptin (1 mg/kg, i.p) was applied to evaluate the anxiolytic effect in rat behavioral tests. Field potentials recording were used to investigate the changes in synaptic transmission in the thalamic-lateral amygadala (LA) pathway of rat. We found that leptin produced strong anxiolytic effects under basal condition and after acute stress. Systemic administration and intra-LA infusions of leptin facilitated extinction of conditioned fear responses. The antagonist of NMDA receptor, MK-801, blocked the effect of leptin on fear extinction completely. Furthermore, these effects of leptin on fear extinction were accompanied by a reversal of conditioning-induced synaptic potentiation in the LA. Leptin facilitated NMDA receptor-mediated synaptic transmission, and reversed amygdala long-term potentiation (LTP) in a dose-dependent manner in vitro, and this LTP depotentiation effect was mediated by NMDA receptor and MAPK signaling pathway. These results identify a key role of leptin in dampening fear conditioning-induced synaptic potentiation in the LA through NMDA receptor and indicate a new strategy for treating anxiety disorders. © 2015 John Wiley & Sons Ltd.

Calmodulin Activation by Calcium Transients in the Postsynaptic Density of Dendritic Spines

PubMed Central

Keller, Daniel X.; Franks, Kevin M.; Bartol, Thomas M.; Sejnowski, Terrence J.

2008-01-01

The entry of calcium into dendritic spines can trigger a sequence of biochemical reactions that begins with the activation of calmodulin (CaM) and ends with long-term changes to synaptic strengths. The degree of activation of CaM can depend on highly local elevations in the concentration of calcium and the duration of transient increases in calcium concentration. Accurate measurement of these local changes in calcium is difficult because the spaces are so small and the numbers of molecules are so low. We have therefore developed a Monte Carlo model of intracellular calcium dynamics within the spine that included calcium binding proteins, calcium transporters and ion channels activated by voltage and glutamate binding. The model reproduced optical recordings using calcium indicator dyes and showed that without the dye the free intracellular calcium concentration transient was much higher than predicted from the fluorescent signal. Excitatory postsynaptic potentials induced large, long-lasting calcium gradients across the postsynaptic density, which activated CaM. When glutamate was released at the synapse 10 ms before an action potential occurred, simulating activity patterns that strengthen hippocampal synapses, the calcium gradient and activation of CaM in the postsynaptic density were much greater than when the order was reversed, a condition that decreases synaptic strengths, suggesting a possible mechanism underlying the induction of long-term changes in synaptic strength. The spatial and temporal mechanisms for selectivity in CaM activation demonstrated here could be used in other signaling pathways. PMID:18446197

Timing-dependent LTP and LTD in mouse primary visual cortex following different visual deprivation models

PubMed Central

Chen, Xia; Fu, Junhong; Cheng, Wenbo; Song, Desheng; Qu, Xiaolei; Yang, Zhuo; Zhao, Kanxing

2017-01-01

Visual deprivation during the critical period induces long-lasting changes in cortical circuitry by adaptively modifying neuro-transmission and synaptic connectivity at synapses. Spike timing-dependent plasticity (STDP) is considered a strong candidate for experience-dependent changes. However, the visual deprivation forms that affect timing-dependent long-term potentiation(LTP) and long-term depression(LTD) remain unclear. Here, we demonstrated the temporal window changes of tLTP and tLTD, elicited by coincidental pre- and post-synaptic firing, following different modes of 6-day visual deprivation. Markedly broader temporal windows were found in robust tLTP and tLTD in the V1M of the deprived visual cortex in mice after 6-day MD and DE. The underlying mechanism for the changes seen with visual deprivation in juvenile mice using 6 days of dark exposure or monocular lid suture involves an increased fraction of NR2b-containing NMDAR and the consequent prolongation of NMDAR-mediated response duration. Moreover, a decrease in NR2A protein expression at the synapse is attributable to the reduction of the NR2A/2B ratio in the deprived cortex. PMID:28520739

Impaired synaptic clustering of postsynaptic density proteins and altered signal transmission in hippocampal neurons, and disrupted learning behavior in PDZ1 and PDZ2 ligand binding-deficient PSD-95 knockin mice

PubMed Central

2012-01-01

Background Postsynaptic density (PSD)-95-like membrane-associated guanylate kinases (PSD-MAGUKs) are scaffold proteins in PSDs that cluster signaling molecules near NMDA receptors. PSD-MAGUKs share a common domain structure, including three PDZ (PDZ1/2/3) domains in their N-terminus. While multiple domains enable the PSD-MAGUKs to bind various ligands, the contribution of each PDZ domain to synaptic organization and function is not fully understood. Here, we focused on the PDZ1/2 domains of PSD-95 that bind NMDA-type receptors, and studied the specific roles of the ligand binding of these domains in the assembly of PSD proteins, synaptic properties of hippocampal neurons, and behavior, using ligand binding-deficient PSD-95 cDNA knockin (KI) mice. Results The KI mice showed decreased accumulation of mutant PSD-95, PSD-93 and AMPA receptor subunits in the PSD fraction of the hippocampus. In the hippocampal CA1 region of young KI mice, basal synaptic efficacy was reduced and long-term potentiation (LTP) was enhanced with intact long-term depression. In adult KI mice, there was no significant change in the magnitude of LTP in CA1, but robustly enhanced LTP was induced at the medial perforant path-dentate gyrus synapses, suggesting that PSD-95 has an age- and subregion-dependent role. In a battery of behavioral tests, KI mice showed markedly abnormal anxiety-like behavior, impaired spatial reference and working memory, and impaired remote memory and pattern separation in fear conditioning test. Conclusions These findings reveal that PSD-95 including its ligand binding of the PDZ1/2 domains controls the synaptic clustering of PSD-MAGUKs and AMPA receptors, which may have an essential role in regulating hippocampal synaptic transmission, plasticity, and hippocampus-dependent behavior. PMID:23268962

Impaired synaptic clustering of postsynaptic density proteins and altered signal transmission in hippocampal neurons, and disrupted learning behavior in PDZ1 and PDZ2 ligand binding-deficient PSD-95 knockin mice.

PubMed

Nagura, Hitoshi; Ishikawa, Yasuyuki; Kobayashi, Katsunori; Takao, Keizo; Tanaka, Tomo; Nishikawa, Kouki; Tamura, Hideki; Shiosaka, Sadao; Suzuki, Hidenori; Miyakawa, Tsuyoshi; Fujiyoshi, Yoshinori; Doi, Tomoko

2012-12-26

Postsynaptic density (PSD)-95-like membrane-associated guanylate kinases (PSD-MAGUKs) are scaffold proteins in PSDs that cluster signaling molecules near NMDA receptors. PSD-MAGUKs share a common domain structure, including three PDZ (PDZ1/2/3) domains in their N-terminus. While multiple domains enable the PSD-MAGUKs to bind various ligands, the contribution of each PDZ domain to synaptic organization and function is not fully understood. Here, we focused on the PDZ1/2 domains of PSD-95 that bind NMDA-type receptors, and studied the specific roles of the ligand binding of these domains in the assembly of PSD proteins, synaptic properties of hippocampal neurons, and behavior, using ligand binding-deficient PSD-95 cDNA knockin (KI) mice. The KI mice showed decreased accumulation of mutant PSD-95, PSD-93 and AMPA receptor subunits in the PSD fraction of the hippocampus. In the hippocampal CA1 region of young KI mice, basal synaptic efficacy was reduced and long-term potentiation (LTP) was enhanced with intact long-term depression. In adult KI mice, there was no significant change in the magnitude of LTP in CA1, but robustly enhanced LTP was induced at the medial perforant path-dentate gyrus synapses, suggesting that PSD-95 has an age- and subregion-dependent role. In a battery of behavioral tests, KI mice showed markedly abnormal anxiety-like behavior, impaired spatial reference and working memory, and impaired remote memory and pattern separation in fear conditioning test. These findings reveal that PSD-95 including its ligand binding of the PDZ1/2 domains controls the synaptic clustering of PSD-MAGUKs and AMPA receptors, which may have an essential role in regulating hippocampal synaptic transmission, plasticity, and hippocampus-dependent behavior.

Administration of the TrkB receptor agonist 7,8-dihydroxyflavone prevents traumatic stress-induced spatial memory deficits and changes in synaptic plasticity.

PubMed

Sanz-García, Ancor; Knafo, Shira; Pereda-Pérez, Inmaculada; Esteban, José A; Venero, César; Armario, Antonio

2016-09-01

Post-traumatic stress disorder (PTSD) occurs after exposure to traumatic situations and it is characterized by cognitive deficits that include impaired explicit memory. The neurobiological bases of such PTSD-associated memory alterations are yet to be elucidated and no satisfactory treatment for them exists. To address this issue, we first studied whether a single exposure of young adult rats (60 days) to immobilization on boards (IMO), a putative model of PTSD, produces long-term behavioral effects (2-8 days) similar to those found in PTSD patients. Subsequently, we investigated whether the administration of the TrkB agonist 7,8-dihydroxyflavone (DHF) 8 h after stress (therapeutic window) ameliorated the PTSD-like effect of IMO and the associated changes in synaptic plasticity. A single IMO exposure induced a spatial memory impairment similar to that found in other animal models of PTSD or in PTSD patients. IMO also increased spine density and long-term potentiation (LTP) in the CA3-CA1 pathway. Significantly, DHF reverted both spatial memory impairment and the increase in LTP, while it produced no effect in the controls. These data provide novel insights into the possible neurobiological substrate for explicit memory impairment in PTSD patients, supporting the idea that the activation of the BDNF/TrkB pathway fulfils a protective role after severe stress. Administration of DHF in the aftermath of a traumatic experience might be relevant to prevent its long-term consequences. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Interplay between Short- and Long-Term Plasticity in Cell-Assembly Formation

PubMed Central

Hiratani, Naoki; Fukai, Tomoki

2014-01-01

Various hippocampal and neocortical synapses of mammalian brain show both short-term plasticity and long-term plasticity, which are considered to underlie learning and memory by the brain. According to Hebb’s postulate, synaptic plasticity encodes memory traces of past experiences into cell assemblies in cortical circuits. However, it remains unclear how the various forms of long-term and short-term synaptic plasticity cooperatively create and reorganize such cell assemblies. Here, we investigate the mechanism in which the three forms of synaptic plasticity known in cortical circuits, i.e., spike-timing-dependent plasticity (STDP), short-term depression (STD) and homeostatic plasticity, cooperatively generate, retain and reorganize cell assemblies in a recurrent neuronal network model. We show that multiple cell assemblies generated by external stimuli can survive noisy spontaneous network activity for an adequate range of the strength of STD. Furthermore, our model predicts that a symmetric temporal window of STDP, such as observed in dopaminergic modulations on hippocampal neurons, is crucial for the retention and integration of multiple cell assemblies. These results may have implications for the understanding of cortical memory processes. PMID:25007209

DREAM (Downstream Regulatory Element Antagonist Modulator) contributes to synaptic depression and contextual fear memory

PubMed Central

2010-01-01

The downstream regulatory element antagonist modulator (DREAM), a multifunctional Ca2+-binding protein, binds specifically to DNA and several nucleoproteins regulating gene expression and with proteins outside the nucleus to regulate membrane excitability or calcium homeostasis. DREAM is highly expressed in the central nervous system including the hippocampus and cortex; however, the roles of DREAM in hippocampal synaptic transmission and plasticity have not been investigated. Taking advantage of transgenic mice overexpressing a Ca2+-insensitive DREAM mutant (TgDREAM), we used integrative methods including electrophysiology, biochemistry, immunostaining, and behavior tests to study the function of DREAM in synaptic transmission, long-term plasticity and fear memory in hippocampal CA1 region. We found that NMDA receptor but not AMPA receptor-mediated current was decreased in TgDREAM mice. Moreover, synaptic plasticity, such as long-term depression (LTD) but not long-term potentiation (LTP), was impaired in TgDREAM mice. Biochemical experiments found that DREAM interacts with PSD-95 and may inhibit NMDA receptor function through this interaction. Contextual fear memory was significantly impaired in TgDREAM mice. By contrast, sensory responses to noxious stimuli were not affected. Our results demonstrate that DREAM plays a novel role in postsynaptic modulation of the NMDA receptor, and contributes to synaptic plasticity and behavioral memory. PMID:20205763

Satb2 determines miRNA expression and long-term memory in the adult central nervous system.

PubMed

Jaitner, Clemens; Reddy, Chethan; Abentung, Andreas; Whittle, Nigel; Rieder, Dietmar; Delekate, Andrea; Korte, Martin; Jain, Gaurav; Fischer, Andre; Sananbenesi, Farahnaz; Cera, Isabella; Singewald, Nicolas; Dechant, Georg; Apostolova, Galina

2016-11-29

SATB2 is a risk locus for schizophrenia and encodes a DNA-binding protein that regulates higher-order chromatin configuration. In the adult brain Satb2 is almost exclusively expressed in pyramidal neurons of two brain regions important for memory formation, the cerebral cortex and the CA1-hippocampal field. Here we show that Satb2 is required for key hippocampal functions since deletion of Satb2 from the adult mouse forebrain prevents the stabilization of synaptic long-term potentiation and markedly impairs long-term fear and object discrimination memory. At the molecular level, we find that synaptic activity and BDNF up-regulate Satb2, which itself binds to the promoters of coding and non-coding genes. Satb2 controls the hippocampal levels of a large cohort of miRNAs, many of which are implicated in synaptic plasticity and memory formation. Together, our findings demonstrate that Satb2 is critically involved in long-term plasticity processes in the adult forebrain that underlie the consolidation and stabilization of context-linked memory.

Burst-induced anti-Hebbian depression acts through short-term synaptic dynamics to cancel redundant sensory signals.

PubMed

Harvey-Girard, Erik; Lewis, John; Maler, Leonard

2010-04-28

Weakly electric fish can enhance the detection and localization of important signals such as those of prey in part by cancellation of redundant spatially diffuse electric signals due to, e.g., their tail bending. The cancellation mechanism is based on descending input, conveyed by parallel fibers emanating from cerebellar granule cells, that produces a negative image of the global low-frequency signals in pyramidal cells within the first-order electrosensory region, the electrosensory lateral line lobe (ELL). Here we demonstrate that the parallel fiber synaptic input to ELL pyramidal cell undergoes long-term depression (LTD) whenever both parallel fiber afferents and their target cells are stimulated to produce paired burst discharges. Paired large bursts (4-4) induce robust LTD over pre-post delays of up to +/-50 ms, whereas smaller bursts (2-2) induce weaker LTD. Single spikes (either presynaptic or postsynaptic) paired with bursts did not induce LTD. Tetanic presynaptic stimulation was also ineffective in inducing LTD. Thus, we have demonstrated a form of anti-Hebbian LTD that depends on the temporal correlation of burst discharge. We then demonstrated that the burst-induced LTD is postsynaptic and requires the NR2B subunit of the NMDA receptor, elevation of postsynaptic Ca(2+), and activation of CaMKIIbeta. A model incorporating local inhibitory circuitry and previously identified short-term presynaptic potentiation of the parallel fiber synapses further suggests that the combination of burst-induced LTD, presynaptic potentiation, and local inhibition may be sufficient to explain the generation of the negative image and cancellation of redundant sensory input by ELL pyramidal cells.

A computational simulation of long-term synaptic potentiation inducing protocol processes with model of CA3 hippocampal microcircuit.

PubMed

Świetlik, D; Białowąs, J; Kusiak, A; Cichońska, D

2018-01-01

An experimental study of computational model of the CA3 region presents cog-nitive and behavioural functions the hippocampus. The main property of the CA3 region is plastic recurrent connectivity, where the connections allow it to behave as an auto-associative memory. The computer simulations showed that CA3 model performs efficient long-term synaptic potentiation (LTP) induction and high rate of sub-millisecond coincidence detection. Average frequency of the CA3 pyramidal cells model was substantially higher in simulations with LTP induction protocol than without the LTP. The entropy of pyramidal cells with LTP seemed to be significantly higher than without LTP induction protocol (p = 0.0001). There was depression of entropy, which was caused by an increase of forgetting coefficient in pyramidal cells simulations without LTP (R = -0.88, p = 0.0008), whereas such correlation did not appear in LTP simulation (p = 0.4458). Our model of CA3 hippocampal formation microcircuit biologically inspired lets you understand neurophysiologic data. (Folia Morphol 2018; 77, 2: 210-220).

Mechanisms for localising calcineurin and CaMKII in dendritic spines.

PubMed

Penny, Christopher J; Gold, Matthew G

2018-05-27

Calcineurin and calmodulin-dependent protein kinase II (CaMKII) are both highly abundant in neurons, and both are activated by calmodulin at similar Ca 2+ concentrations in the test tube. However, they fulfill opposite functions in dendritic spines, with CaMKII activity driving long-term synaptic potentiation following large influxes of Ca 2+ through NMDA-type glutamate receptors (NMDARs), and calcineurin responding to smaller influxes of Ca 2+ through the same receptors to induce long-term depression. In this review, we explore the notion that precise dynamic localisation of the two enzymes at different sites within dendritic spines is fundamental to this behavior. We describe the structural basis of calcineurin and CaMKII localisation by their interaction with proteins including AKAP79, densin-180, α-actinin, and NMDARs. We then consider how interactions with these proteins likely position calcineurin and CaMKII at different distances from Ca 2+ microdomains emanating from the mouths of NMDARs in order to drive the divergent responses. We also highlight shortcomings in our current understanding of synaptic localisation of these two important signalling enzymes. Copyright © 2017. Published by Elsevier Inc.

JIP1-Mediated JNK Activation Negatively Regulates Synaptic Plasticity and Spatial Memory.

PubMed

Morel, Caroline; Sherrin, Tessi; Kennedy, Norman J; Forest, Kelly H; Avcioglu Barutcu, Seda; Robles, Michael; Carpenter-Hyland, Ezekiel; Alfulaij, Naghum; Standen, Claire L; Nichols, Robert A; Benveniste, Morris; Davis, Roger J; Todorovic, Cedomir

2018-04-11

The c-Jun N-terminal kinase (JNK) signal transduction pathway is implicated in learning and memory. Here, we examined the role of JNK activation mediated by the JNK-interacting protein 1 (JIP1) scaffold protein. We compared male wild-type mice with a mouse model harboring a point mutation in the Jip1 gene that selectively blocks JIP1-mediated JNK activation. These male mutant mice exhibited increased NMDAR currents, increased NMDAR-mediated gene expression, and a lower threshold for induction of hippocampal long-term potentiation. The JIP1 mutant mice also displayed improved hippocampus-dependent spatial memory and enhanced associative fear conditioning. These results were confirmed using a second JIP1 mutant mouse model that suppresses JNK activity. Together, these observations establish that JIP1-mediated JNK activation contributes to the regulation of hippocampus-dependent, NMDAR-mediated synaptic plasticity and learning. SIGNIFICANCE STATEMENT The results of this study demonstrate that c-Jun N-terminal kinase (JNK) activation induced by the JNK-interacting protein 1 (JIP1) scaffold protein negatively regulates the threshold for induction of long-term synaptic plasticity through the NMDA-type glutamate receptor. This change in plasticity threshold influences learning. Indeed, mice with defects in JIP1-mediated JNK activation display enhanced memory in hippocampus-dependent tasks, such as contextual fear conditioning and Morris water maze, indicating that JIP1-JNK constrains spatial memory. This study identifies JIP1-mediated JNK activation as a novel molecular pathway that negatively regulates NMDAR-dependent synaptic plasticity and memory. Copyright © 2018 the authors 0270-6474/18/383708-21$15.00/0.

Nitrogen dioxide (NO(2)) pollution as a potential risk factor for developing vascular dementia and its synaptic mechanisms.

PubMed

Li, Hongyan; Xin, Xiaoyun

2013-06-01

Recent epidemiological literatures reported that NO(2) is a potential risk factor of ischemic stroke in polluted area. Meanwhile, our previous in vivo study found that NO(2) could delay the recovery of nerve function after stroke, implying a possible risk of vascular dementia (VaD) with NO(2) inhalation, which is often a common cognitive complication resulting from stroke. However, the effect and detailed mechanisms have not been fully elucidated. In the present study, synaptic mechanisms, the foundation of neuronal function and viability, were investigated in both model rats of ischemic stroke and healthy rats after NO(2) exposure. Transmission electron microscope (TEM) observation showed that 5 mg m(-3) NO(2) exposure not only exacerbated the ultrastructural impairment of synapses in stroke model rats, but also induced neuronal damage in healthy rats. Meantime, we found that the expression of synaptophysin (SYP) and postsynaptic density protein 95 (PSD-95), two structural markers of synapses in ischemic stroke model were inhibited by NO(2) inhalation; and so it was with the key proteins mediating long-term potentiation (LTP), the major form of synaptic plasticity. On the contrary, NO(2) inhalation induced the expression of nearly all these proteins in healthy rats in a concentration-dependent manner. Our results implied that NO(2) exposure could increase the risk of VaD through inducing excitotoxicity in healthy rats but weakening synaptic plasticity directly in stroke model rats. Copyright © 2013 Elsevier Ltd. All rights reserved.

Decreased synaptic plasticity in the medial prefrontal cortex underlies short-term memory deficits in 6-OHDA-lesioned rats.

PubMed

Matheus, Filipe C; Rial, Daniel; Real, Joana I; Lemos, Cristina; Ben, Juliana; Guaita, Gisele O; Pita, Inês R; Sequeira, Ana C; Pereira, Frederico C; Walz, Roger; Takahashi, Reinaldo N; Bertoglio, Leandro J; Da Cunha, Cláudio; Cunha, Rodrigo A; Prediger, Rui D

2016-03-15

Parkinson's disease (PD) is characterized by motor dysfunction associated with dopaminergic degeneration in the dorsolateral striatum (DLS). However, motor symptoms in PD are often preceded by short-term memory deficits, which have been argued to involve deregulation of medial prefrontal cortex (mPFC). We now used a 6-hydroxydopamine (6-OHDA) rat PD model to explore if alterations of synaptic plasticity in DLS and mPFC underlie short-term memory impairments in PD prodrome. The bilateral injection of 6-OHDA (20μg/hemisphere) in the DLS caused a marked loss of dopaminergic neurons in the substantia nigra (>80%) and decreased monoamine levels in the striatum and PFC, accompanied by motor deficits evaluated after 21 days in the open field and accelerated rotarod. A lower dose of 6-OHDA (10μg/hemisphere) only induced a partial degeneration (about 60%) of dopaminergic neurons in the substantia nigra with no gross motor impairments, thus mimicking an early premotor stage of PD. Notably, 6-OHDA (10μg)-lesioned rats displayed decreased monoamine levels in the PFC as well as short-term memory deficits evaluated in the novel object discrimination and in the modified Y-maze tasks; this was accompanied by a selective decrease in the amplitude of long-term potentiation in the mPFC, but not in DLS, without changes of synaptic transmission in either brain regions. These results indicate that the short-term memory dysfunction predating the motor alterations in the 6-OHDA model of PD is associated with selective changes of information processing in PFC circuits, typified by persistent changes of synaptic plasticity. Copyright © 2015 Elsevier B.V. All rights reserved.

Iron Mediates N-Methyl-d-aspartate Receptor-dependent Stimulation of Calcium-induced Pathways and Hippocampal Synaptic Plasticity*

PubMed Central

Muñoz, Pablo; Humeres, Alexis; Elgueta, Claudio; Kirkwood, Alfredo; Hidalgo, Cecilia; Núñez, Marco T.

2011-01-01

Iron deficiency hinders hippocampus-dependent learning processes and impairs cognitive performance, but current knowledge on the molecular mechanisms underlying the unique role of iron in neuronal function is sparse. Here, we investigated the participation of iron on calcium signal generation and ERK1/2 stimulation induced by the glutamate agonist N-methyl-d-aspartate (NMDA), and the effects of iron addition/chelation on hippocampal basal synaptic transmission and long-term potentiation (LTP). Addition of NMDA to primary hippocampal cultures elicited persistent calcium signals that required functional NMDA receptors and were independent of calcium influx through L-type calcium channels or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors; NMDA also promoted ERK1/2 phosphorylation and nuclear translocation. Iron chelation with desferrioxamine or inhibition of ryanodine receptor (RyR)-mediated calcium release with ryanodine-reduced calcium signal duration and prevented NMDA-induced ERK1/2 activation. Iron addition to hippocampal neurons readily increased the intracellular labile iron pool and stimulated reactive oxygen species production; the antioxidant N-acetylcysteine or the hydroxyl radical trapper MCI-186 prevented these responses. Iron addition to primary hippocampal cultures kept in calcium-free medium elicited calcium signals and stimulated ERK1/2 phosphorylation; RyR inhibition abolished these effects. Iron chelation decreased basal synaptic transmission in hippocampal slices, inhibited iron-induced synaptic stimulation, and impaired sustained LTP in hippocampal CA1 neurons induced by strong stimulation. In contrast, iron addition facilitated sustained LTP induction after suboptimal tetanic stimulation. Together, these results suggest that hippocampal neurons require iron to generate RyR-mediated calcium signals after NMDA receptor stimulation, which in turn promotes ERK1/2 activation, an essential step of sustained LTP. PMID:21296883

Deleting Both PHLPP1 and CANP1 Rescues Impairments in Long-Term Potentiation and Learning in Both Single Knockout Mice

ERIC Educational Resources Information Center

Liu, Yan; Sun, Jiandong; Wang, Yubin; Lopez, Dulce; Tran, Jennifer; Bi, Xiaoning; Baudry, Michel

2016-01-01

Calpain-1 (CANP1) has been shown to play a critical role in synaptic plasticity and learning and memory, as its deletion in mice results in impairment in theta-burst stimulation (TBS)-induced LTP and various forms of learning and memory. Likewise, PHLPP1 (aka SCOP) has also been found to participate in learning and memory, as PHLPP1 overexpression…

Network, cellular, and molecular mechanisms underlying long-term memory formation.

PubMed

Carasatorre, Mariana; Ramírez-Amaya, Víctor

2013-01-01

The neural network stores information through activity-dependent synaptic plasticity that occurs in populations of neurons. Persistent forms of synaptic plasticity may account for long-term memory storage, and the most salient forms are the changes in the structure of synapses. The theory proposes that encoding should use a sparse code and evidence suggests that this can be achieved through offline reactivation or by sparse initial recruitment of the network units. This idea implies that in some cases the neurons that underwent structural synaptic plasticity might be a subpopulation of those originally recruited; However, it is not yet clear whether all the neurons recruited during acquisition are the ones that underwent persistent forms of synaptic plasticity and responsible for memory retrieval. To determine which neural units underlie long-term memory storage, we need to characterize which are the persistent forms of synaptic plasticity occurring in these neural ensembles and the best hints so far are the molecular signals underlying structural modifications of the synapses. Structural synaptic plasticity can be achieved by the activity of various signal transduction pathways, including the NMDA-CaMKII and ACh-MAPK. These pathways converge with the Rho family of GTPases and the consequent ERK 1/2 activation, which regulates multiple cellular functions such as protein translation, protein trafficking, and gene transcription. The most detailed explanation may come from models that allow us to determine the contribution of each piece of this fascinating puzzle that is the neuron and the neural network.

Acute Increases in Protein O-GlcNAcylation Dampen Epileptiform Activity in Hippocampus

PubMed Central

Wang, Kai; Pati, Sandipan; Olsen, Michelle L.; Chatham, John C.

2017-01-01

O-GlcNAcylation is a ubiquitous and dynamic post-translational modification involving the O-linkage of β-N-acetylglucosamine to serine/threonine residues of membrane, cytosolic, and nuclear proteins. This modification is similar to phosphorylation and regarded as a key regulator of cell survival and homeostasis. Previous studies have shown that phosphorylation of serine residues on synaptic proteins is a major regulator of synaptic strength and long-term plasticity, suggesting that O-GlcNAcylation of synaptic proteins is likely as important as phosphorylation; however, few studies have investigated its role in synaptic efficacy. We recently demonstrated that acutely increasing O-GlcNAcylation induces a novel form of LTD at CA3-CA1 synapses, O-GlcNAc LTD. Here, using hippocampal slices from young adult male rats and mice, we report that epileptiform activity at CA3-CA1 synapses, generated by GABAAR inhibition, is significantly attenuated when protein O-GlcNAcylation is pharmacologically increased. This dampening effect is lost in slices from GluA2 KO mice, indicating a requirement of GluA2-containing AMPARs, similar to expression of O-GlcNAc LTD. Furthermore, we find that increasing O-GlcNAcylation decreases spontaneous CA3 pyramidal cell activity under basal and hyperexcitable conditions. This dampening effect was also observed on cortical hyperexcitability during in vivo EEG recordings in awake mice where the effects of the proconvulsant pentylenetetrazole are attenuated by acutely increasing O-GlcNAcylation. Collectively, these data demonstrate that the post-translational modification, O-GlcNAcylation, is a novel mechanism by which neuronal and synaptic excitability can be regulated, and suggest the possibility that increasing O-GlcNAcylation could be a novel therapeutic target to treat seizure disorders and epilepsy. SIGNIFICANCE STATEMENT We recently reported that an acute pharmacological increase in protein O-GlcNAcylation induces a novel form of long-term synaptic depression at hippocampal CA3-CA1 synapses (O-GlcNAc LTD). This synaptic dampening effect on glutamatergic networks suggests that increasing O-GlcNAcylation will depress pathological hyperexcitability. Using in vitro and in vivo models of epileptiform activity, we show that acutely increasing O-GlcNAc levels can significantly attenuate ongoing epileptiform activity and prophylactically dampen subsequent seizure activity. Together, our findings support the conclusion that protein O-GlcNAcylation is a regulator of neuronal excitability, and it represents a promising target for further research on seizure disorder therapeutics. PMID:28760863

miR-191 and miR-135 are required for long-lasting spine remodelling associated with synaptic long-term depression

NASA Astrophysics Data System (ADS)

Hu, Zhonghua; Yu, Danni; Gu, Qin-Hua; Yang, Yanqin; Tu, Kang; Zhu, Jun; Li, Zheng

2014-02-01

Activity-dependent modification of dendritic spines, subcellular compartments accommodating postsynaptic specializations in the brain, is an important cellular mechanism for brain development, cognition and synaptic pathology of brain disorders. NMDA receptor-dependent long-term depression (NMDAR-LTD), a prototypic form of synaptic plasticity, is accompanied by prolonged remodelling of spines. The mechanisms underlying long-lasting spine remodelling in NMDAR-LTD, however, are largely unclear. Here we show that LTD induction causes global changes in miRNA transcriptomes affecting many cellular activities. Specifically, we show that expression changes of miR-191 and miR-135 are required for maintenance but not induction of spine restructuring. Moreover, we find that actin depolymerization and AMPA receptor exocytosis are regulated for extended periods of time by miRNAs to support long-lasting spine plasticity. These findings reveal a miRNA-mediated mechanism and a role for AMPA receptor exocytosis in long-lasting spine plasticity, and identify a number of candidate miRNAs involved in LTD.

Synaptic Tagging, Evaluation of Memories, and the Distal Reward Problem

ERIC Educational Resources Information Center

Papper, Marc; Kempter, Richard; Leibold, Christian

2011-01-01

Long-term synaptic plasticity exhibits distinct phases. The synaptic tagging hypothesis suggests an early phase in which synapses are prepared, or "tagged," for protein capture, and a late phase in which those proteins are integrated into the synapses to achieve memory consolidation. The synapse specificity of the tags is consistent with…

Aβ42-oligomer Interacting Peptide (AIP) neutralizes toxic amyloid-β42 species and protects synaptic structure and function

NASA Astrophysics Data System (ADS)

Barucker, Christian; Bittner, Heiko J.; Chang, Philip K.-Y.; Cameron, Scott; Hancock, Mark A.; Liebsch, Filip; Hossain, Shireen; Harmeier, Anja; Shaw, Hunter; Charron, François M.; Gensler, Manuel; Dembny, Paul; Zhuang, Wei; Schmitz, Dietmar; Rabe, Jürgen P.; Rao, Yong; Lurz, Rudi; Hildebrand, Peter W.; McKinney, R. Anne; Multhaup, Gerhard

2015-10-01

The amyloid-β42 (Aβ42) peptide is believed to be the main culprit in the pathogenesis of Alzheimer disease (AD), impairing synaptic function and initiating neuronal degeneration. Soluble Aβ42 oligomers are highly toxic and contribute to progressive neuronal dysfunction, loss of synaptic spine density, and affect long-term potentiation (LTP). We have characterized a short, L-amino acid Aβ-oligomer Interacting Peptide (AIP) that targets a relatively well-defined population of low-n Aβ42 oligomers, rather than simply inhibiting the aggregation of Aβ monomers into oligomers. Our data show that AIP diminishes the loss of Aβ42-induced synaptic spine density and rescues LTP in organotypic hippocampal slice cultures. Notably, the AIP enantiomer (comprised of D-amino acids) attenuated the rough-eye phenotype in a transgenic Aβ42 fly model and significantly improved the function of photoreceptors of these flies in electroretinography tests. Overall, our results indicate that specifically “trapping” low-n oligomers provides a novel strategy for toxic Aβ42-oligomer recognition and removal.

Control of synaptic function by endocannabinoid-mediated retrograde signaling.

PubMed

Kano, Masanobu

2014-01-01

Since the first reports in 2001, great advances have been made towards the understanding of endocannabinoid-mediated synaptic modulation. Electrophysiological studies have revealed that one of the two major endocannabinoids, 2-arachidonoylglycerol (2-AG), is produced from membrane lipids upon postsynaptic Ca(2+) elevation and/or activation of Gq/11-coupled receptors, and released from postsynaptic neurons. The released 2-AG then acts retrogradely onto presynaptic cannabinoid CB1 receptors and induces suppression of neurotransmitter release either transiently or persistently. These forms of 2-AG-mediated retrograde synaptic modulation are functional throughout the brain. The other major endocannabinoid, anandamide, mediates a certain form of endocannabinoid-mediated long-term depression (LTD). Anandamide also functions as an agonist for transient receptor potential vanilloid receptor type 1 (TRPV1) and mediates endocannabinoid-independent and TRPV1-dependent forms of LTD. It has also been demonstrated that the endocannabinoid system itself is plastic, which can be either up- or down-regulated by experimental or environmental conditions. In this review, I will make an overview of the mechanisms underlying endocannabinoid-mediated synaptic modulation.

Control of synaptic function by endocannabinoid-mediated retrograde signaling

PubMed Central

KANO, Masanobu

2014-01-01

Since the first reports in 2001, great advances have been made towards the understanding of endocannabinoid-mediated synaptic modulation. Electrophysiological studies have revealed that one of the two major endocannabinoids, 2-arachidonoylglycerol (2-AG), is produced from membrane lipids upon postsynaptic Ca2+ elevation and/or activation of Gq/11-coupled receptors, and released from postsynaptic neurons. The released 2-AG then acts retrogradely onto presynaptic cannabinoid CB1 receptors and induces suppression of neurotransmitter release either transiently or persistently. These forms of 2-AG-mediated retrograde synaptic modulation are functional throughout the brain. The other major endocannabinoid, anandamide, mediates a certain form of endocannabinoid-mediated long-term depression (LTD). Anandamide also functions as an agonist for transient receptor potential vanilloid receptor type 1 (TRPV1) and mediates endocannabinoid-independent and TRPV1-dependent forms of LTD. It has also been demonstrated that the endocannabinoid system itself is plastic, which can be either up- or down-regulated by experimental or environmental conditions. In this review, I will make an overview of the mechanisms underlying endocannabinoid-mediated synaptic modulation. PMID:25169670

[Changes of the neuronal membrane excitability as cellular mechanisms of learning and memory].

PubMed

Gaĭnutdinov, Kh L; Andrianov, V V; Gaĭnutdinova, T Kh

2011-01-01

In the presented review given literature and results of own studies of dynamics of electrical characteristics of neurons, which change are included in processes both an elaboration of learning, and retention of the long-term memory. Literary datas and our results allow to conclusion, that long-term retention of behavioural reactions during learning is accompanied not only by changing efficiency of synaptic transmission, as well as increasing of excitability of command neurons of the defensive reflex. This means, that in the process of learning are involved long-term changes of the characteristics a membrane of certain elements of neuronal network, dependent from the metabolism of the cells. see text). Thou phenomena possible mark as cellular (electrophysiological) correlates of long-term plastic modifications of the behaviour. The analyses of having results demonstrates an important role of membrane characteristics of neurons (their excitability) and parameters an synaptic transmission not only in initial stage of learning, as well as in long-term modifications of the behaviour (long-term memory).

Neurotoxicity and reactive astrogliosis in the anterior cingulate cortex in acute ciguatera poisoning.

PubMed

Zhang, Xu; Cao, Bing; Wang, Jun; Liu, Jin; Tung, Vivian Oi Vian; Lam, Paul Kwan Sing; Chan, Leo Lai; Li, Ying

2013-06-01

Ciguatoxins (CTXs) cause long-term disturbance of cerebral functions. The primary mechanism of neurotoxicity is related to their interaction with voltage-gated sodium channels. However, until now, the neurological targets for CTXs in the brain of intact animals have not been described. In our study, 1 day following oral exposure to 0.26 ng/g of Pacific ciguatoxin 1 (P-CTX-1), we performed in vivo electrophysiological recordings in the rat anterior cingulate cortex (ACC) and identified the increase in spontaneous firings and enhanced responses to visceral noxious stimulation. Local field recordings characterized the P-CTX-1-induced synaptic potentiation and blockage of the induction of electrical stimulation-induced long-term potentiation in the medial thalamus (MT)-ACC pathway. Furthermore, intracerebroventricular administration of P-CTX-1 at doses of 1.0, 5.0, and 10 nM produced a dose-dependent increase in ACC neuronal firings and MT-ACC synaptic transmission. Further studies showed upregulated Na(+) channel expression in astrocytes under pathological conditions. We hypothesized that the astrocytes might have been activated in the ciguatera poisoning in vivo. Increases in glial fibrillary acid protein expression were detected in reactive astrocytes in the rat ACC. The activation of astroglia was further indicated by activation of the gap junction protein connexin 43 and upregulation of excitatory amino acid transporter 2 expression suggesting that glutamate was normally rapidly cleared from the synaptic cleft during acute ciguatera poisoning. However, neurotoxicity and reactive astrogliosis were not detected in the ACC after 7 days of P-CTX-1 exposure. The present results are the first characterization of P-CTX-1-invoked brain cortex neuronal excitotoxicity in vivo and supported the theme that neuron and astroglia signals might play roles in acute ciguatera poisoning.

Long-term potentiation of synaptic response and intrinsic excitability in neurons of the rat medial vestibular nuclei.

PubMed

Pettorossi, V E; Dieni, C V; Scarduzio, M; Grassi, S

2011-07-28

Using intracellular recordings, we investigated the effects of high frequency stimulation (HFS) of the primary vestibular afferents on the evoked excitatory postsynaptic potential (EPSP) and intrinsic excitability (IE) of type-A and type-B neurons of the medial vestibular nucleus (MVN), in male rat brainstem slices. HFS induces long-term potentiation (LTP) of both EPSP and IE, which may occur in combination or separately. Synaptic LTP is characterized by an increase in the amplitude, slope and decay time constant of EPSP and IE-LTP through enhancements of spontaneous and evoked neuron firing and of input resistance (Rin). Moreover, IE-LTP is associated with a decrease in action potential afterhyperpolarization (AHP) amplitude and an increase in interspike slope steepness (ISS). The more frequent effects of HFS are EPSP-LTP in type-B neurons and IE-LTP in type-A neurons. In addition, the development of EPSP-LTP is fast in type-B neurons but slow in type-A, whereas IE-LTP develops slowly in both types. We have demonstrated that activation of N-methyl-d aspartate receptors (NMDARs) is only required for EPSP-LTP induction, whereas metabotropic glutamate receptors type-1 (mGluR1) are necessary for IE-LTP induction as well as the full development and maintenance of EPSP-LTP. Taken together, these findings demonstrate that brief and intense activation of vestibular afferent input to the MVN neurons may provoke synaptic LTP and/or IE-LTP that, induced in combination or separately, may assure the different selectivity of the MVN neuron response enhancement to the afferent signals. Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.

Nuclear and membrane estrogen receptor antagonists induce similar mTORC2 activation-reversible changes in synaptic protein expression and actin polymerization in the mouse hippocampus.

PubMed

Xing, Fang-Zhou; Zhao, Yan-Gang; Zhang, Yuan-Yuan; He, Li; Zhao, Ji-Kai; Liu, Meng-Ying; Liu, Yan; Zhang, Ji-Qiang

2018-06-01

Estrogens play pivotal roles in hippocampal synaptic plasticity through nuclear receptors (nERs; including ERα and ERβ) and the membrane receptor (mER; also called GPR30), but the underlying mechanism and the contributions of nERs and mER remain unclear. Mammalian target of rapamycin complex 2 (mTORC2) is involved in actin cytoskeleton polymerization and long-term memory, but whether mTORC2 is involved in the regulation of hippocampal synaptic plasticity by ERs is unclear. We treated animals with nER antagonists (MPP/PHTPP) or the mER antagonist (G15) alone or in combination with A-443654, an activator of mTORC2. Then, we examined the changes in hippocampal SRC-1 expression, mTORC2 signaling (rictor and phospho-AKTSer473), actin polymerization (phospho-cofilin and profilin-1), synaptic protein expression (GluR1, PSD95, spinophilin, and synaptophysin), CA1 spine density, and synapse density. All of the examined parameters except synaptophysin expression were significantly decreased by MPP/PHTPP and G15 treatment. MPP/PHTPP and G15 induced a similar decrease in most parameters except p-cofilin, GluR1, and spinophilin expression. The ER antagonist-induced decreases in these parameters were significantly reversed by mTORC2 activation, except for the change in SRC-1, rictor, and synaptophysin expression. nERs and mER contribute similarly to the changes in proteins and structures associated with synaptic plasticity, and mTORC2 may be a novel target of hippocampal-dependent dementia such as Alzheimer's disease as proposed by previous studies. © 2018 John Wiley & Sons Ltd.

Up-regulation of GLT-1 severely impairs LTD at mossy fibre--CA3 synapses.

PubMed

Omrani, Azar; Melone, Marcello; Bellesi, Michele; Safiulina, Victoria; Aida, Tomomi; Tanaka, Kohishi; Cherubini, Enrico; Conti, Fiorenzo

2009-10-01

Glutamate transporters are responsible for clearing synaptically released glutamate from the extracellular space. By this action, they maintain low levels of ambient glutamate, thus preventing excitotoxic damage, and contribute to shaping synaptic currents. We show that up-regulation of the glutamate transporter GLT-1 by ceftriaxone severely impaired mGluR-dependent long-term depression (LTD), induced at rat mossy fibre (MF)-CA3 synapses by repetitive stimulation of afferent fibres. This effect involved GLT-1, since LTD was rescued by the selective GLT-1 antagonist dihydrokainate (DHK). DHK per se produced a modest decrease in fEPSP amplitude that rapidly regained control levels after DHK wash out. Moreover, the degree of fEPSP inhibition induced by the low-affinity glutamate receptor antagonist gamma-DGG was similar during basal synaptic transmission but not during LTD, indicating that in ceftriaxone-treated rats LTD induction did not alter synaptic glutamate transient concentration. Furthermore, ceftriaxone-induced GLT-1 up-regulation significantly reduced the magnitude of LTP at MF-CA3 synapses but not at Schaffer collateral-CA1 synapses. Postembedding immunogold studies in rats showed an increased density of gold particles coding for GLT-1a in astrocytic processes and in mossy fibre terminals; in the latter, gold particles were located near and within the active zones. In both CEF-treated and untreated GLT-1 KO mice used for verifying the specificity of immunostaining, the density of gold particles in MF terminals was comparable to background levels. The enhanced expression of GLT-1 at release sites may prevent activation of presynaptic receptors, thus revealing a novel mechanism by which GLT-1 regulates synaptic plasticity in the hippocampus.

Short-term and long-term plasticity interaction in human primary motor cortex.

PubMed

Iezzi, Ennio; Suppa, Antonio; Conte, Antonella; Li Voti, Pietro; Bologna, Matteo; Berardelli, Alfredo

2011-05-01

Repetitive transcranial magnetic stimulation (rTMS) over primary motor cortex (M1) elicits changes in motor evoked potential (MEP) size thought to reflect short- and long-term forms of synaptic plasticity, resembling short-term potentiation (STP) and long-term potentiation/depression (LTP/LTD) observed in animal experiments. We designed this study in healthy humans to investigate whether STP as elicited by 5-Hz rTMS interferes with LTP/LTD-like plasticity induced by intermittent and continuous theta-burst stimulation (iTBS and cTBS). The effects induced by 5-Hz rTMS and iTBS/cTBS were indexed as changes in MEP size. We separately evaluated changes induced by 5-Hz rTMS, iTBS and cTBS applied alone and those induced by iTBS and cTBS delivered after priming 5-Hz rTMS. Interactions between 5-Hz rTMS and iTBS/cTBS were investigated under several experimental conditions by delivering 5-Hz rTMS at suprathreshold and subthreshold intensity, allowing 1 and 5 min intervals to elapse between 5-Hz rTMS and TBS, and delivering one and ten 5-Hz rTMS trains. We also investigated whether 5-Hz rTMS induces changes in intracortical excitability tested with paired-pulse transcranial magnetic stimulation. When given alone, 5-Hz rTMS induced short-lasting and iTBS/cTBS induced long-lasting changes in MEP amplitudes. When M1 was primed with 10 suprathreshold 5-Hz rTMS trains at 1 min before iTBS or cTBS, the iTBS/cTBS-induced after-effects disappeared. The 5-Hz rTMS left intracortical excitability unchanged. We suggest that STP elicited by suprathreshold 5-Hz rTMS abolishes iTBS/cTBS-induced LTP/LTD-like plasticity through non-homeostatic metaplasticity mechanisms. Our study provides new information on interactions between short-term and long-term rTMS-induced plasticity in human M1. © 2011 The Authors. European Journal of Neuroscience © 2011 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

Protective Effects of Enriched Environment Against Transient Cerebral Ischemia-Induced Impairment of Passive Avoidance Memory and Long-Term Potentiation in Rats

PubMed Central

Ahmadalipour, Ali; Sadeghzadeh, Jafar; Samaei, Seyed Afshin; Rashidy-Pour, Ali

2017-01-01

Introduction: Enriched Environment (EE), a complex novel environment, has been demonstrated to improve synaptic plasticity in both injured and intact animals. The present study investigated the capacity of an early environmental intervention to normalize the impairment of passive avoidance memory and Long-Term Potentiation (LTP) induced by transient bilateral common carotid artery occlusion (2-vessel occlusion, 2VO) in rats. Methods: After weaning, young Wistar rats (22 days old) were housed in EE or Standard Environment (SE) for 40 days. Transient (30-min) incomplete forebrain ischemia was induced 4 days before the passive avoidance memory test and LTP induction. Results: The transient forebrain ischemia led to impairment of passive avoidance memory and LTP induction in the Perforant Path-Dentate Gyrus (PP-DG) synapses. Interestingly, housing and growing in EE prior to 2VO was found to significantly reverse 2VO-induced cognitive and LTP impairments. Conclusion: Our results suggest that early housing and growing in EE exhibits therapeutic potential to normalize cognitive and LTP abnormalities induced by 2VO ischemic model in rats.

Altered gene regulation and synaptic morphology in Drosophila learning and memory mutants

PubMed Central

Guan, Zhuo; Buhl, Lauren K.; Quinn, William G.; Littleton, J. Troy

2011-01-01

Genetic studies in Drosophila have revealed two separable long-term memory pathways defined as anesthesia-resistant memory (ARM) and long-lasting long-term memory (LLTM). ARM is disrupted in radish (rsh) mutants, whereas LLTM requires CREB-dependent protein synthesis. Although the downstream effectors of ARM and LLTM are distinct, pathways leading to these forms of memory may share the cAMP cascade critical for associative learning. Dunce, which encodes a cAMP-specific phosphodiesterase, and rutabaga, which encodes an adenylyl cyclase, both disrupt short-term memory. Amnesiac encodes a pituitary adenylyl cyclase-activating peptide homolog and is required for middle-term memory. Here, we demonstrate that the Radish protein localizes to the cytoplasm and nucleus and is a PKA phosphorylation target in vitro. To characterize how these plasticity pathways may manifest at the synaptic level, we assayed synaptic connectivity and performed an expression analysis to detect altered transcriptional networks in rutabaga, dunce, amnesiac, and radish mutants. All four mutants disrupt specific aspects of synaptic connectivity at larval neuromuscular junctions (NMJs). Genome-wide DNA microarray analysis revealed ∼375 transcripts that are altered in these mutants, suggesting defects in multiple neuronal signaling pathways. In particular, the transcriptional target Lapsyn, which encodes a leucine-rich repeat cell adhesion protein, localizes to synapses and regulates synaptic growth. This analysis provides insights into the Radish-dependent ARM pathway and novel transcriptional targets that may contribute to memory processing in Drosophila. PMID:21422168

Long-term social recognition memory is mediated by oxytocin-dependent synaptic plasticity in the medial amygdala.

PubMed

Gur, Rotem; Tendler, Alex; Wagner, Shlomo

2014-09-01

Recognition of specific individuals is fundamental to mammalian social behavior and is mediated in most mammals by the main and accessory olfactory systems. Both these systems innervate the medial amygdala (MeA), where activity of the neuropeptide oxytocin is thought to mediate social recognition memory (SRM). The specific contribution of the MeA to SRM formation and the specific actions of oxytocin in the MeA are unknown. We used the social discrimination test to evaluate short-term and long-term SRM in adult Sprague-Dawley male rats (n = 38). The role of protein synthesis in the MeA was investigated by local application of the protein synthesis blocker anisomycin (n = 11). Synaptic plasticity was assessed in vivo by recording the MeA evoked field potential responses to stimulation of the main (n = 21) and accessory (n = 56) olfactory bulbs before and after theta burst stimulation. Intracerebroventricular administration of saline, oxytocin, or oxytocin receptor antagonist was used to measure the effect of oxytocin on synaptic plasticity. Anisomycin application to the MeA prevented the formation of long-term SRM. In addition, the responses of MeA neurons underwent long-term depression (LTD) after theta burst stimulation of the accessory olfactory bulb, but not the main accessory bulb, in an oxytocin-dependent manner. No LTD was found in socially isolated rats, which are known to lack long-term SRM. Finally, accessory olfactory bulb stimulation before SRM acquisition blocked long-term SRM, supporting the involvement of LTD in the MeA in formation of long-term SRM. Our results indicate that long-term SRM in rats involves protein synthesis and oxytocin-dependent LTD in the MeA. Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Sleep and protein synthesis-dependent synaptic plasticity: impacts of sleep loss and stress

PubMed Central

Grønli, Janne; Soulé, Jonathan; Bramham, Clive R.

2014-01-01

Sleep has been ascribed a critical role in cognitive functioning. Several lines of evidence implicate sleep in the consolidation of synaptic plasticity and long-term memory. Stress disrupts sleep while impairing synaptic plasticity and cognitive performance. Here, we discuss evidence linking sleep to mechanisms of protein synthesis-dependent synaptic plasticity and synaptic scaling. We then consider how disruption of sleep by acute and chronic stress may impair these mechanisms and degrade sleep function. PMID:24478645

The requirement for enhanced CREB1 expression in consolidation of long-term synaptic facilitation and long-term excitability in sensory neurons of Aplysia

PubMed Central

Liu, Rong-Yu; Cleary, Leonard J.; Byrne, John H.

2011-01-01

Accumulating evidence suggests that the transcriptional activator CREB1 is important for serotonin (5-HT)-induced long-term facilitation (LTF) of the sensorimotor synapse in Aplysia. Moreover, creb1 is among the genes activated by CREB1, suggesting a role for this protein beyond the induction phase of LTF. The time course of the requirement for CREB1 synthesis in the consolidation of long-term facilitation was examined using RNA interference (RNAi) techniques in sensorimotor co-cultures. Injection of CREB1 small-interfering RNA (siRNA) immediately or 10 h after 5-HT treatment blocked LTF when measured at 24 h and 48 h after treatment. In contrast, CREB1 siRNA did not block LTF when injected 16 h after 5-HT treatment. These results demonstrate that creb1 expression must be sustained for a relatively long time in order to support the consolidation of LTF. In addition, LTF is also accompanied by a long-term increase in the excitability (LTE) of sensory neurons (SNs). Because LTE was observed in the isolated SN after 5-HT treatment, this long-term change was intrinsic to that element of the circuit. LTE was blocked when CREB1 siRNA was injected into isolated SNs immediately after 5-HT treatment. These data suggest that 5-HT-induced CREB1 synthesis is required for consolidation of both LTF and LTE. PMID:21543617

Synaptic heterogeneity and stimulus-induced modulation of depression in central synapses.

PubMed

Hunter, J D; Milton, J G

2001-08-01

Short-term plasticity is a pervasive feature of synapses. Synapses exhibit many forms of plasticity operating over a range of time scales. We develop an optimization method that allows rapid characterization of synapses with multiple time scales of facilitation and depression. Investigation of paired neurons that are postsynaptic to the same identified interneuron in the buccal ganglion of Aplysia reveals that the responses of the two neurons differ in the magnitude of synaptic depression. Also, for single neurons, prolonged stimulation of the presynaptic neuron causes stimulus-induced increases in the early phase of synaptic depression. These observations can be described by a model that incorporates two availability factors, e.g., depletable vesicle pools or desensitizing receptor populations, with different time courses of recovery, and a single facilitation component. This model accurately predicts the responses to novel stimuli. The source of synaptic heterogeneity is identified with variations in the relative sizes of the two availability factors, and the stimulus-induced decrement in the early synaptic response is explained by a slowing of the recovery rate of one of the availability factors. The synaptic heterogeneity and stimulus-induced modifications in synaptic depression observed here emphasize that synaptic efficacy depends on both the individual properties of synapses and their past history.

Acute inhibition of estradiol synthesis impacts vestibulo-ocular reflex adaptation and cerebellar long-term potentiation in male rats.

PubMed

Dieni, Cristina V; Ferraresi, Aldo; Sullivan, Jacqueline A; Grassi, Sivarosa; Pettorossi, Vito E; Panichi, Roberto

2018-03-01

The vestibulo-ocular reflex (VOR) adaptation is an ideal model for investigating how the neurosteroid 17 beta-estradiol (E2) contributes to the modification of behavior by regulating synaptic activities. We hypothesized that E2 impacts VOR adaptation by affecting cerebellar synaptic plasticity at the parallel fiber-Purkinje cell (PF) synapse. To verify this hypothesis, we investigated the acute effect of blocking E2 synthesis on gain increases and decreases in adaptation of the VOR in male rats using an oral dose (2.5 mg/kg) of the aromatase inhibitor letrozole. We also assessed the effect of letrozole on synaptic plasticity at the PF synapse in vitro, using cerebellar slices from male rats. We found that letrozole acutely impaired both gain increases and decreases adaptation of the VOR without altering basal ocular-motor performance. Moreover, letrozole prevented long-term potentiation at the PF synapse (PF-LTP) without affecting long-term depression (PF-LTD). Thus, in male rats neurosteroid E2 has a relevant impact on VOR adaptation and affects exclusively PF-LTP. These findings suggest that E2 might regulate changes in VOR adaptation by acting locally on cerebellar and extra-cerebellar synaptic plasticity sites.

Influence of visual experience on developmental shift from long-term depression to long-term potentiation in the rat medial vestibular nuclei

PubMed Central

Grassi, Silvarosa; Dieni, Cristina; Frondaroli, Adele; Pettorossi, Vito Enrico

2004-01-01

The influence of visual experience deprivation on changes in synaptic plasticity during postnatal development was studied in the ventral part of the rat medial vestibular nuclei (vMVN). We analysed the differences in the occurrence, expressed as a percentage, of long-term depression (LTD) and long-term potentiation (LTP) induced by high frequency stimulation (HFS) of the primary vestibular afferents in rats reared in the light (LR) and those in the dark (DR). In LR rats, HFS only induced LTD in the early stages of development, but the occurrence of LTD progressively decreased to zero before their eyes opened, while that of LTP enhanced from zero to about 50%. Once the rats' eyes had opened, LTD was no longer inducible while LTP occurrence gradually reached the normal adult value (70%). In DR rats, a similar shift from LTD to LTP was observed before their eyes opened, showing only a slightly slower LTD decay and LTP growth, and the LTD annulment was delayed by 1 day. By contrast, the time courses of LTD and LTP development in DR and LR rats showed remarkable differences following eye opening. In fact, LTD occurrence increased to about 50% in a short period of time and remained high until the adult stage. In addition, the occurrence of LTP slowly decreased to less than 20%. The effect of light-deprivation was reversible, since the exposure of DR rats to light, 5 days after eye opening, caused a sudden disappearance of LTD and a partial recover of LTP occurrence. In addition, we observed that a week of light deprivation in LR adult rats did not affect the normal adult LTP occurrence. These results provide evidence that in a critical period of development visual input plays a crucial role in shaping synaptic plasticity of the vMVN, and suggest that the visual guided shift from LTD to LTP during development may be necessary to refine and consolidate vestibular circuitry. PMID:15331680

Developmental shift from long-term depression to long-term potentiation in the rat medial vestibular nuclei: role of group I metabotropic glutamate receptors.

PubMed

Puyal, Julien; Grassi, Silvarosa; Dieni, Cristina; Frondaroli, Adele; Demêmes, Danielle; Raymond, Jaqueline; Pettorossi, Vito Enrico

2003-12-01

The effects of high frequency stimulation (HFS) of the primary vestibular afferents on synaptic transmission in the ventral part of the medial vestibular nuclei (vMVN) were studied during postnatal development and compared with the changes in the expression of the group I metabotropic glutamate receptor (mGluR) subtypes, mGluR1 and mGluR5. During the first stages of development, HFS always induced a mGluR5- and GABAA-dependent long-term depression (LTD) which did not require NMDA receptor and mGluR1 activation. The probability of inducing LTD decreased progressively throughout the development and it was zero at about the end of the second postnatal week. Conversely, long-term potentiation (LTP) appeared at the beginning of the second week and its occurrence increased to reach the adult value at the end of the third week. Of interest, the sudden change in the LTP frequency occurred at the time of eye opening, about the end of the second postnatal week. LTP depended on NMDA receptor and mGluR1 activation. In parallel with the modifications in synaptic plasticity, we observed that the expression patterns and localizations of mGluR5 and mGluR1 in the medial vestibular nuclei (MVN) changed during postnatal development. At the earlier stages the mGluR1 expression was minimal, then increased progressively. In contrast, mGluR5 expression was initially high, then decreased. While mGluR1 was exclusively localized in neuronal compartments and concentrated at the postsynaptic sites at all stages observed, mGluR5 was found mainly in neuronal compartments at immature stages, then preferentially in glial compartments at mature stages. These results provide the first evidence for a progressive change from LTD to LTP accompanied by a distinct maturation expression of mGluR1 and mGluR5 during the development of the MVN.

Leptin attenuates the detrimental effects of β-amyloid on spatial memory and hippocampal later-phase long term potentiation in rats.

PubMed

Tong, Jia-Qing; Zhang, Jun; Hao, Ming; Yang, Ju; Han, Yu-Fei; Liu, Xiao-Jie; Shi, Hui; Wu, Mei-Na; Liu, Qing-Song; Qi, Jin-Shun

2015-07-01

β-Amyloid (Aβ) is the main component of amyloid plaques developed in the brain of patients with Alzheimer's disease (AD). The increasing burden of Aβ in the cortex and hippocampus is closely correlated with memory loss and cognition deficits in AD. Recently, leptin, a 16kD peptide derived mainly from white adipocyte tissue, has been appreciated for its neuroprotective function, although less is known about the effects of leptin on spatial memory and synaptic plasticity. The present study investigated the neuroprotective effects of leptin against Aβ-induced deficits in spatial memory and in vivo hippocampal late-phase long-term potentiation (L-LTP) in rats. Y maze spontaneous alternation was used to assess short term working memory, and the Morris water maze task was used to assess long term reference memory. Hippocampal field potential recordings were performed to observe changes in L-LTP. We found that chronically intracerebroventricular injection of leptin (1μg) effectively alleviated Aβ1-42 (20μg)-induced spatial memory impairments of Y maze spontaneous alternation and Morris water maze. In addition, chronic administration of leptin also reversed Aβ1-42-induced suppression of in vivo hippocampal L-LTP in rats. Together, these results suggest that chronic leptin treatments reversed Aβ-induced deficits in learning and memory and the maintenance of L-LTP. Copyright © 2015 Elsevier Inc. All rights reserved.

Insulin induces long-term depression of VTA dopamine neurons via an endocannabinoid-mediated mechanism

PubMed Central

Labouèbe, Gwenaël; Liu, Shuai; Dias, Carine; Zou, Haiyan; Wong, Jovi C.Y.; Karunakaran, Subashini; Clee, Susanne M.; Phillips, Anthony; Boutrel, Benjamin; Borgland, Stephanie L.

2014-01-01

The prevalence of obesity has drastically increased over the last few decades. Exploration into how hunger and satiety signals influence the reward system can help us to understand non-homeostatic mechanisms of feeding. Evidence suggests that insulin may act in the ventral tegmental area (VTA), a critical site for reward-seeking behavior, to suppress feeding. However, the neural mechanisms underlying insulin effects in the VTA remain unknown. We demonstrate that insulin, a circulating catabolic peptide that inhibits feeding, can induce a long-term depression (LTD) of excitatory synapses onto VTA dopamine neurons. This effect requires endocannabinoid-mediated presynaptic inhibition of glutamate release. Furthermore, after a sweetened high fat meal, which elevates endogenous insulin levels, insulin-induced LTD is occluded. Finally, insulin in the VTA reduces food anticipatory behavior and conditioned place preference for food. Taken together, these results suggest that insulin in the VTA suppresses excitatory synaptic transmission and reduces salience of food-related cues. PMID:23354329

Metabotropic Glutamate Receptors in the Trafficking of Ionotropic Glutamate and GABAA Receptors at Central Synapses

PubMed Central

Xiao, Min-Yi; Gustafsson, Bengt; Niu, Yin-Ping

2006-01-01

The trafficking of ionotropic glutamate (AMPA, NMDA and kainate) and GABAA receptors in and out of, or laterally along, the postsynaptic membrane has recently emerged as an important mechanism in the regulation of synaptic function, both under physiological and pathological conditions, such as information processing, learning and memory formation, neuronal development, and neurodegenerative diseases. Non-ionotropic glutamate receptors, primarily group I metabotropic glutamate receptors (mGluRs), co-exist with the postsynaptic ionotropic glutamate and GABAA receptors. The ability of mGluRs to regulate postsynaptic phosphorylation and Ca2+ concentration, as well as their interactions with postsynaptic scaffolding/signaling proteins, makes them well suited to influence the trafficking of ionotropic glutamate and GABAA receptors. Recent studies have provided insights into how mGluRs may impose such an influence at central synapses, and thus how they may affect synaptic signaling and the maintenance of long-term synaptic plasticity. In this review we will discuss some of the recent progress in this area: i) long-term synaptic plasticity and the involvement of mGluRs; ii) ionotropic glutamate receptor trafficking and long-term synaptic plasticity; iii) the involvement of postsynaptic group I mGluRs in regulating ionotropic glutamate receptor trafficking; iv) involvement of postsynaptic group I mGluRs in regulating GABAA receptor trafficking; v) and the trafficking of postsynaptic group I mGluRs themselves. PMID:18615134

Metabotropic glutamate receptors in the trafficking of ionotropic glutamate and GABA(A) receptors at central synapses.

PubMed

Xiao, Min-Yi; Gustafsson, Bengt; Niu, Yin-Ping

2006-01-01

The trafficking of ionotropic glutamate (AMPA, NMDA and kainate) and GABA(A) receptors in and out of, or laterally along, the postsynaptic membrane has recently emerged as an important mechanism in the regulation of synaptic function, both under physiological and pathological conditions, such as information processing, learning and memory formation, neuronal development, and neurodegenerative diseases. Non-ionotropic glutamate receptors, primarily group I metabotropic glutamate receptors (mGluRs), co-exist with the postsynaptic ionotropic glutamate and GABA(A) receptors. The ability of mGluRs to regulate postsynaptic phosphorylation and Ca(2+) concentration, as well as their interactions with postsynaptic scaffolding/signaling proteins, makes them well suited to influence the trafficking of ionotropic glutamate and GABA(A) receptors. Recent studies have provided insights into how mGluRs may impose such an influence at central synapses, and thus how they may affect synaptic signaling and the maintenance of long-term synaptic plasticity. In this review we will discuss some of the recent progress in this area: i) long-term synaptic plasticity and the involvement of mGluRs; ii) ionotropic glutamate receptor trafficking and long-term synaptic plasticity; iii) the involvement of postsynaptic group I mGluRs in regulating ionotropic glutamate receptor trafficking; iv) involvement of postsynaptic group I mGluRs in regulating GABA(A) receptor trafficking; v) and the trafficking of postsynaptic group I mGluRs themselves.

Δ9-THC-caused synaptic and memory impairments are mediated through COX-2 signaling.

PubMed

Chen, Rongqing; Zhang, Jian; Fan, Ni; Teng, Zhao-Qian; Wu, Yan; Yang, Hongwei; Tang, Ya-Ping; Sun, Hao; Song, Yunping; Chen, Chu

2013-11-21

Marijuana has been used for thousands of years as a treatment for medical conditions. However, untoward side effects limit its medical value. Here, we show that synaptic and cognitive impairments following repeated exposure to Δ(9)-tetrahydrocannabinol (Δ(9)-THC) are associated with the induction of cyclooxygenase-2 (COX-2), an inducible enzyme that converts arachidonic acid to prostanoids in the brain. COX-2 induction by Δ(9)-THC is mediated via CB1 receptor-coupled G protein βγ subunits. Pharmacological or genetic inhibition of COX-2 blocks downregulation and internalization of glutamate receptor subunits and alterations of the dendritic spine density of hippocampal neurons induced by repeated Δ(9)-THC exposures. Ablation of COX-2 also eliminates Δ(9)-THC-impaired hippocampal long-term synaptic plasticity, working, and fear memories. Importantly, the beneficial effects of decreasing β-amyloid plaques and neurodegeneration by Δ(9)-THC in Alzheimer's disease animals are retained in the presence of COX-2 inhibition. These results suggest that the applicability of medical marijuana would be broadened by concurrent inhibition of COX-2. Copyright © 2013 Elsevier Inc. All rights reserved.

Carbachol-induced long-term synaptic depression is enhanced during senescence at hippocampal CA3-CA1 synapses.

PubMed

Kumar, Ashok

2010-08-01

Dysregulation of the cholinergic transmitter system is a hallmark of Alzheimer's disease and contributes to an age-associated decline in memory performance. The current study examined the influence of carbachol, a cholinergic receptor agonist, on synaptic transmission over the course of aging. Extracellular excitatory postsynaptic field potentials were recorded from CA3-CA1 synapses in acute hippocampal slices obtained from young adult (5-8 mo) and aged (22-24 mo) male Fischer 344 rats. Bath application of carbachol elicited a transient depression of synaptic transmission, which was followed by a long-lasting depression (CCh-LTD) observed 90 min after carbachol cessation in both age groups. However, the magnitude of CCh-LTD was significantly larger in senescent animals and was attenuated by N-methyl-D-aspartate receptor blockade in aged animals. Blockade of L-type Ca(2+) channels inhibited CCh-LTD to a greater extent in aged animals compared to young adults. Finally, the expression of CCh-LTD was dependent on protein synthesis. The results indicate that altered Ca(2+) homeostasis or muscarinic activation of Ca(2+) signaling contribute to the enhanced CCh-LTD during senescence.

Atypical PKCs in Memory Maintenance: The Roles of Feedback and Redundancy

ERIC Educational Resources Information Center

Jalil, Sajiya J.; Sacktor, Todd Charlton; Shouval, Harel Z.

2015-01-01

Memories that last a lifetime are thought to be stored, at least in part, as persistent enhancement of the strength of particular synapses. The synaptic mechanism of these persistent changes, late long-term potentiation (L-LTP), depends on the state and number of specific synaptic proteins. Synaptic proteins, however, have limited dwell times due…

Long-term optical stimulation of channelrhodopsin-expressing neurons to study network plasticity

PubMed Central

Lignani, Gabriele; Ferrea, Enrico; Difato, Francesco; Amarù, Jessica; Ferroni, Eleonora; Lugarà, Eleonora; Espinoza, Stefano; Gainetdinov, Raul R.; Baldelli, Pietro; Benfenati, Fabio

2013-01-01

Neuronal plasticity produces changes in excitability, synaptic transmission, and network architecture in response to external stimuli. Network adaptation to environmental conditions takes place in time scales ranging from few seconds to days, and modulates the entire network dynamics. To study the network response to defined long-term experimental protocols, we setup a system that combines optical and electrophysiological tools embedded in a cell incubator. Primary hippocampal neurons transduced with lentiviruses expressing channelrhodopsin-2/H134R were subjected to various photostimulation protocols in a time window in the order of days. To monitor the effects of light-induced gating of network activity, stimulated transduced neurons were simultaneously recorded using multi-electrode arrays (MEAs). The developed experimental model allows discerning short-term, long-lasting, and adaptive plasticity responses of the same neuronal network to distinct stimulation frequencies applied over different temporal windows. PMID:23970852

Long-term optical stimulation of channelrhodopsin-expressing neurons to study network plasticity.

PubMed

Lignani, Gabriele; Ferrea, Enrico; Difato, Francesco; Amarù, Jessica; Ferroni, Eleonora; Lugarà, Eleonora; Espinoza, Stefano; Gainetdinov, Raul R; Baldelli, Pietro; Benfenati, Fabio

2013-01-01

Neuronal plasticity produces changes in excitability, synaptic transmission, and network architecture in response to external stimuli. Network adaptation to environmental conditions takes place in time scales ranging from few seconds to days, and modulates the entire network dynamics. To study the network response to defined long-term experimental protocols, we setup a system that combines optical and electrophysiological tools embedded in a cell incubator. Primary hippocampal neurons transduced with lentiviruses expressing channelrhodopsin-2/H134R were subjected to various photostimulation protocols in a time window in the order of days. To monitor the effects of light-induced gating of network activity, stimulated transduced neurons were simultaneously recorded using multi-electrode arrays (MEAs). The developed experimental model allows discerning short-term, long-lasting, and adaptive plasticity responses of the same neuronal network to distinct stimulation frequencies applied over different temporal windows.

Rapamycin restores BDNF-LTP and the persistence of long-term memory in a model of Down's syndrome.

PubMed

Andrade-Talavera, Yuniesky; Benito, Itziar; Casañas, Juan José; Rodríguez-Moreno, Antonio; Montesinos, María Luz

2015-10-01

Down's syndrome (DS) is the most prevalent genetic intellectual disability. Memory deficits significantly contribute to the cognitive dysfunction in DS. Previously, we discovered that mTOR-dependent local translation, a pivotal process for some forms of synaptic plasticity, is deregulated in a DS mouse model. Here, we report that these mice exhibit deficits in both synaptic plasticity (i.e., BDNF-long term potentiation) and the persistence of spatial long-term memory. Interestingly, these deficits were fully reversible using rapamycin, a Food and Drug Administration-approved specific mTOR inhibitor; therefore, rapamycin may be a novel pharmacotherapy to improve cognition in DS. Copyright © 2015 Elsevier Inc. All rights reserved.

Protection against β-amyloid induced abnormal synaptic function and cell death by Ginkgolide J

PubMed Central

Vitolo, Ottavio; Gong, Bing; Cao, Zixuan; Ishii, Hideki; Jaracz, Stanislav; Nakanishi, Koji; Arancio, Ottavio; Dzyuba, Sergei V.; Lefort, Roger; Shelanski, Michael

2009-01-01

A new Ginkgo biloba extract P8A (TTL), 70% enriched with terpene trilactones, prevents Aβ1-42 induced inhibition of long-term potentiation in the CA1 region of mouse hippocampal slices. This neuroprotective effect is attributed in large part to ginkgolide J that completely replicates the effect of the extract. Ginkgolide J is also capable of inhibiting cell death of rodent hippocampal neurons caused by Aβ1-42. This beneficial and multi-faceted mode of action of the ginkgolide makes it a new and promising lead in designing therapies against Alzheimer’s disease. PMID:17640772

The expression of plasticity-related genes in an acute model of stress is modulated by chronic desipramine in a time-dependent manner within medial prefrontal cortex.

PubMed

Nava, Nicoletta; Treccani, Giulia; Müller, Heidi Kaastrup; Popoli, Maurizio; Wegener, Gregers; Elfving, Betina

2017-01-01

It is well established that stress plays a major role in the pathogenesis of neuropsychiatric diseases. Stress-induced alteration of synaptic plasticity has been hypothesized to underlie the morphological changes observed by neuroimaging in psychiatric patients in key regions such as hippocampus and prefrontal cortex (PFC). We have recently shown that a single acute stress exposure produces significant short-term alterations of structural plasticity within medial PFC. These alterations were partially prevented by previous treatment with chronic desipramine (DMI). In the present study we evaluated the effects of acute Foot-shock (FS)-stress and pre-treatment with the traditional antidepressant DMI on the gene expression of key regulators of synaptic plasticity and structure. Expression of Homer, Shank, Spinophilin, Densin-180, and the small RhoGTPase related gene Rac1 and downstream target genes, Limk1, Cofilin1 and Rock1 were investigated 1 day (1d), 7 d and 14d after FS-stress exposure. We found that DMI specifically increases the short-term expression of Spinophilin, as well as Homer and Shank family genes, and that both acute stress and DMI exert significant long-term effects on mRNA levels of genes involved in spine plasticity. These findings support the knowledge that acute FS stress and antidepressant treatment induce both rapid and sustained time-dependent alterations in structural components of synaptic plasticity in rodent medial PFC. Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.

Mind bomb-1 is an essential modulator of long-term memory and synaptic plasticity via the Notch signaling pathway

PubMed Central

2012-01-01

Background Notch signaling is well recognized as a key regulator of the neuronal fate during embryonic development, but its function in the adult brain is still largely unknown. Mind bomb-1 (Mib1) is an essential positive regulator in the Notch pathway, acting non-autonomously in the signal-sending cells. Therefore, genetic ablation of Mib1 in mature neuron would give valuable insight to understand the cell-to-cell interaction between neurons via Notch signaling for their proper function. Results Here we show that the inactivation of Mib1 in mature neurons in forebrain results in impaired hippocampal dependent spatial memory and contextual fear memory. Consistently, hippocampal slices from Mib1-deficient mice show impaired late-phase, but not early-phase, long-term potentiation and long-term depression without change in basal synaptic transmission at SC-CA1 synapses. Conclusions These data suggest that Mib1-mediated Notch signaling is essential for long-lasting synaptic plasticity and memory formation in the rodent hippocampus. PMID:23111145

Ca currents activated by spontaneous firing and synaptic disinhibition in neurons of the cerebellar nuclei

PubMed Central

Zheng, Nan; Raman, Indira M.

2009-01-01

In neurons of the cerebellar nuclei, long-term potentiation of EPSCs is induced by high-frequency synaptic excitation by mossy fibers followed by synaptic inhibition by Purkinje cells. Induction requires activation of synaptic receptors as well as voltage-gated Ca channels. To examine how Purkinje-mediated inhibition of nuclear neurons affects Ca levels during plasticity-inducing stimuli, we have combined electrophysiology, Ca imaging, and pharmacology of cerebellar nuclear neurons in mouse cerebellar slices. We find that spontaneous firing generates tonic Ca signals in both somata and dendrites, which drop during 500-ms, 100-Hz trains of Purkinje IPSPs or hyperpolarizing steps. Although the presence of low-voltage-activated (T-type) Ca channels in nuclear neurons has fostered the inference that disinhibition activates these channels, synaptic inhibition with a physiological ECl (−75 mV) fails to hyperpolarize neurons sufficiently for T-type channels to recover substantially. Consequently, after IPSPs, Ca signals return to baseline, although firing is accelerated by ∼20 Hz for ∼300 ms. Only after hyperpolarizations beyond ECl does Ca rise gradually beyond baseline, as firing further exceeds spontaneous rates. Cd2+ (100 μM), which nearly eliminates L-type, N-type, P/Q-type, and R-type Ca currents while sparing about half the T-type current, prevents Ca changes during and after hyperpolarizations to ECl. Thus, high-frequency IPSPs in cerebellar nuclear neurons evoke little post-inhibitory current through T-type channels. Instead, inhibition regulates Ca levels simply by preventing action potentials, which usually permit Ca influx through high-voltage-activated channels. The decreases and restoration of Ca levels associated with Purkinje-mediated inhibition are likely to contribute to synaptic plasticity. PMID:19657035

AGEs induce Alzheimer-like tau pathology and memory deficit via RAGE-mediated GSK-3 activation.

PubMed

Li, Xiao-Hong; Lv, Bing-Ling; Xie, Jia-Zhao; Liu, Jing; Zhou, Xin-Wen; Wang, Jian-Zhi

2012-07-01

Accumulation of β-amyloid and hyperphosphorylated tau with synapse damage and memory deterioration are hallmark lesions of Alzheimer disease (AD), but the upstream causative factors are elusive. The advanced glycation endproducts (AGEs) are elevated in AD brains and the AGEs can stimulate β-amyloid production. Whether and how AGEs may cause AD-like tau hyperphosphorylation and memory-related deficits is not known. Here we report that AGEs induce tau hyperphosphorylation, memory deterioration, decline of synaptic proteins, and impairment of long-term potentiation (LTP) in rats. In SK-NS-H cells, upregulation of AGEs receptor (RAGE), inhibition of Akt, and activation of glycogen synthase kinase-3 (GSK-3), Erk1/2, and p38 were observed after treatment with AGEs. In rats, blockage of RAGE attenuated the AGE-induced GSK-3 activation, tau hyperphosphorylation, and memory deficit with restoration of synaptic functions, and simultaneous inhibition of GSK-3 also antagonized the AGE-induced impairments. Our data reveal that AGEs can induce tau hyperphosphorylation and impair synapse and memory through RAGE-mediated GSK-3 activation and targeting RAGE/GSK-3 pathway can efficiently improve the AD-like histopathological changes and memory deterioration. Copyright © 2012 Elsevier Inc. All rights reserved.

Synaptic Plasticity and Learning Behaviors Mimicked in Single Inorganic Synapses of Pt/HfOx/ZnOx/TiN Memristive System

NASA Astrophysics Data System (ADS)

Wang, Lai-Guo; Zhang, Wei; Chen, Yan; Cao, Yan-Qiang; Li, Ai-Dong; Wu, Di

2017-01-01

In this work, a kind of new memristor with the simple structure of Pt/HfOx/ZnOx/TiN was fabricated completely via combination of thermal-atomic layer deposition (TALD) and plasma-enhanced ALD (PEALD). The synaptic plasticity and learning behaviors of Pt/HfOx/ZnOx/TiN memristive system have been investigated deeply. Multilevel resistance states are obtained by varying the programming voltage amplitudes during the pulse cycling. The device conductance can be continuously increased or decreased from cycle to cycle with better endurance characteristics up to about 3 × 103 cycles. Several essential synaptic functions are simultaneously achieved in such a single double-layer of HfOx/ZnOx device, including nonlinear transmission properties, such as long-term plasticity (LTP), short-term plasticity (STP), and spike-timing-dependent plasticity. The transformation from STP to LTP induced by repetitive pulse stimulation is confirmed in Pt/HfOx/ZnOx/TiN memristive device. Above all, simple structure of Pt/HfOx/ZnOx/TiN by ALD technique is a kind of promising memristor device for applications in artificial neural network.

The repetition timing of high frequency afferent stimulation drives the bidirectional plasticity at central synapses in the rat medial vestibular nuclei.

PubMed

Scarduzio, M; Panichi, R; Pettorossi, V E; Grassi, S

2012-10-25

In this study we show that high frequency stimulation (HFS, 100Hz) of afferent fibers to the medial vestibular nucleus (MVN) can induce opposite long-term modifications of synaptic responses in the type B neurons depending upon the stimulation pattern. Long burst stimulation (LBS: 2s) and short burst stimulation (SBS: 0.55s) were applied with different burst number (BN) and inter-burst intervals (IBI). It results that both LBS and SBS can induce either N-methyl-d aspartate receptors (NMDARs)-mediated long-term potentiation (LTP) or long-term depression (LTD), depending on temporal organization of repetitive bursts. In particular, the IBI plays a relevant role in guiding the shift from LTP to LTD since by using both LBS and SBS LTP is induced by shorter IBI than LTD. By contrast, the sign of long-term effect does not depend on the mean impulse frequency evaluated within the entire stimulation period. Therefore, the patterns of repetitive vestibular activation with different ratios between periods of increased activity and periods of basal activity may lead to LTP or LTD probably causing different levels of postsynaptic Ca(2+). On the whole, this study demonstrates that glutamatergic vestibular synapse in the MVN can undergo NMDAR-dependent bidirectional plasticity and puts forward a new aspect for understanding the adaptive and compensatory plasticity of the oculomotor responses. Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.

Role of GABAA-Mediated Inhibition and Functional Assortment of Synapses onto Individual Layer 4 Neurons in Regulating Plasticity Expression in Visual Cortex.

PubMed

Saez, Ignacio; Friedlander, Michael J

2016-01-01

Layer 4 (L4) of primary visual cortex (V1) is the main recipient of thalamocortical fibers from the dorsal lateral geniculate nucleus (LGNd). Thus, it is considered the main entry point of visual information into the neocortex and the first anatomical opportunity for intracortical visual processing before information leaves L4 and reaches supra- and infragranular cortical layers. The strength of monosynaptic connections from individual L4 excitatory cells onto adjacent L4 cells (unitary connections) is highly malleable, demonstrating that the initial stage of intracortical synaptic transmission of thalamocortical information can be altered by previous activity. However, the inhibitory network within L4 of V1 may act as an internal gate for induction of excitatory synaptic plasticity, thus providing either high fidelity throughput to supragranular layers or transmittal of a modified signal subject to recent activity-dependent plasticity. To evaluate this possibility, we compared the induction of synaptic plasticity using classical extracellular stimulation protocols that recruit a combination of excitatory and inhibitory synapses with stimulation of a single excitatory neuron onto a L4 cell. In order to induce plasticity, we paired pre- and postsynaptic activity (with the onset of postsynaptic spiking leading the presynaptic activation by 10ms) using extracellular stimulation (ECS) in acute slices of primary visual cortex and comparing the outcomes with our previously published results in which an identical protocol was used to induce synaptic plasticity between individual pre- and postsynaptic L4 excitatory neurons. Our results indicate that pairing of ECS with spiking in a L4 neuron fails to induce plasticity in L4-L4 connections if synaptic inhibition is intact. However, application of a similar pairing protocol under GABAARs inhibition by bath application of 2μM bicuculline does induce robust synaptic plasticity, long term potentiation (LTP) or long term depression (LTD), similar to our results with pairing of pre- and postsynaptic activation between individual excitatory L4 neurons in which inhibitory connections are not activated. These results are consistent with the well-established observation that inhibition limits the capacity for induction of plasticity at excitatory synapses and that pre- and postsynaptic activation at a fixed time interval can result in a variable range of plasticity outcomes. However, in the current study by virtue of having two sets of experimental data, we have provided a new insight into these processes. By randomly mixing the assorting of individual L4 neurons according to the frequency distribution of the experimentally determined plasticity outcome distribution based on the calculated convergence of multiple individual L4 neurons onto a single postsynaptic L4 neuron, we were able to compare then actual ECS plasticity outcomes to those predicted by randomly mixing individual pairs of neurons. Interestingly, the observed plasticity profiles with ECS cannot account for the random assortment of plasticity behaviors of synaptic connections between individual cell pairs. These results suggest that connections impinging onto a single postsynaptic cell may be grouped according to plasticity states.

Differential neuronal plasticity in mouse hippocampus associated with various periods of enriched environment during postnatal development.

PubMed

Hosseiny, Salma; Pietri, Mariel; Petit-Paitel, Agnès; Zarif, Hadi; Heurteaux, Catherine; Chabry, Joëlle; Guyon, Alice

2015-11-01

Enriched environment (EE) is characterized by improved conditions for enhanced exploration, cognitive activity, social interaction and physical exercise. It has been shown that EE positively regulates the remodeling of neural circuits, memory consolidation, long-term changes in synaptic strength and neurogenesis. However, the fine mechanisms by which environment shapes the brain at different postnatal developmental stages and the duration required to induce such changes are still a matter of debate. In EE, large groups of mice were housed in bigger cages and were given toys, nesting materials and other equipment that promote physical activity to provide a stimulating environment. Weaned mice were housed in EE for 4, 6 or 8 weeks and compared with matched control mice that were raised in a standard environment. To investigate the differential effects of EE on immature and mature brains, we also housed young adult mice (8 weeks old) for 4 weeks in EE. We studied the influence of onset and duration of EE housing on the structure and function of hippocampal neurons. We found that: (1) EE enhances neurogenesis in juvenile, but not young adult mice; (2) EE increases the number of synaptic contacts at every stage; (3) long-term potentiation (LTP) and spontaneous and miniature activity at the glutamatergic synapses are affected differently by EE depending on its onset and duration. Our study provides an integrative view of the role of EE during postnatal development in various mechanisms of plasticity in the hippocampus including neurogenesis, synaptic morphology and electrophysiological parameters of synaptic connectivity. This work provides an explanation for discrepancies found in the literature about the effects of EE on LTP and emphasizes the importance of environment on hippocampal plasticity.

β-Adrenergic Control of Hippocampal Function: Subserving the Choreography of Synaptic Information Storage and Memory

PubMed Central

Hagena, Hardy; Hansen, Niels; Manahan-Vaughan, Denise

2016-01-01

Noradrenaline (NA) is a key neuromodulator for the regulation of behavioral state and cognition. It supports learning by increasing arousal and vigilance, whereby new experiences are “earmarked” for encoding. Within the hippocampus, experience-dependent information storage occurs by means of synaptic plasticity. Furthermore, novel spatial, contextual, or associative learning drives changes in synaptic strength, reflected by the strengthening of long-term potentiation (LTP) or long-term depression (LTD). NA acting on β-adrenergic receptors (β-AR) is a key determinant as to whether new experiences result in persistent hippocampal synaptic plasticity. This can even dictate the direction of change of synaptic strength. The different hippocampal subfields play different roles in encoding components of a spatial representation through LTP and LTD. Strikingly, the sensitivity of synaptic plasticity in these subfields to β-adrenergic control is very distinct (dentate gyrus > CA3 > CA1). Moreover, NA released from the locus coeruleus that acts on β-AR leads to hippocampal LTD and an enhancement of LTD-related memory processing. We propose that NA acting on hippocampal β-AR, that is graded according to the novelty or saliency of the experience, determines the content and persistency of synaptic information storage in the hippocampal subfields and therefore of spatial memories. PMID:26804338

The neurotrophin-inducible gene Vgf regulates hippocampal function and behavior through a brain-derived neurotrophic factor-dependent mechanism.

PubMed

Bozdagi, Ozlem; Rich, Erin; Tronel, Sophie; Sadahiro, Masato; Patterson, Kamara; Shapiro, Matthew L; Alberini, Cristina M; Huntley, George W; Salton, Stephen R J

2008-09-24

VGF is a neurotrophin-inducible, activity-regulated gene product that is expressed in CNS and PNS neurons, in which it is processed into peptides and secreted. VGF synthesis is stimulated by BDNF, a critical regulator of hippocampal development and function, and two VGF C-terminal peptides increase synaptic activity in cultured hippocampal neurons. To assess VGF function in the hippocampus, we tested heterozygous and homozygous VGF knock-out mice in two different learning tasks, assessed long-term potentiation (LTP) and depression (LTD) in hippocampal slices from VGF mutant mice, and investigated how VGF C-terminal peptides modulate synaptic plasticity. Treatment of rat hippocampal slices with the VGF-derived peptide TLQP62 resulted in transient potentiation through a mechanism that was selectively blocked by the BDNF scavenger TrkB-Fc, the Trk tyrosine kinase inhibitor K252a (100 nm), and tPA STOP, an inhibitor of tissue plasminogen activator (tPA), an enzyme involved in pro-BDNF cleavage to BDNF, but was not blocked by the NMDA receptor antagonist APV, anti-p75(NTR) function-blocking antiserum, or previous tetanic stimulation. Although LTP was normal in slices from VGF knock-out mice, LTD could not be induced, and VGF mutant mice were impaired in hippocampal-dependent spatial learning and contextual fear conditioning tasks. Our studies indicate that the VGF C-terminal peptide TLQP62 modulates hippocampal synaptic transmission through a BDNF-dependent mechanism and that VGF deficiency in mice impacts synaptic plasticity and memory in addition to depressive behavior.

The Neurotrophin-Inducible Gene Vgf Regulates Hippocampal Function and Behavior Through a BDNF-Dependent Mechanism

PubMed Central

Bozdagi, Ozlem; Rich, Erin; Tronel, Sophie; Sadahiro, Masato; Patterson, Kamara; Shapiro, Matthew L.; Alberini, Cristina M.; Huntley, George W.; Salton, Stephen R. J.

2009-01-01

VGF is a neurotrophin-inducible, activity-regulated gene product that is expressed in CNS and PNS neurons, where it is processed into peptides and secreted. VGF synthesis is stimulated by BDNF, a critical regulator of hippocampal development and function, and two VGF C-terminal peptides increase synaptic activity in cultured hippocampal neurons. To assess VGF function in the hippocampus, we tested heterozygous and homozygous VGF knockout mice in two different learning tasks, assessed long-term potentiation (LTP) and depression (LTD) in hippocampal slices from VGF mutant mice, and investigated how VGF C-terminal peptides modulate synaptic plasticity. Treatment of rat hippocampal slices with the VGF-derived peptide TLQP62 resulted in transient potentiation through a mechanism that was selectively blocked by the BDNF scavenger TrkB-Fc, the Trk tyrosine kinase inhibitor K252a (100 nM), and by tPASTOP, an inhibitor of tissue plasminogen activator (tPA), an enzyme involved in pro-BDNF cleavage to BDNF, but was not blocked by the NMDA receptor antagonist APV, anti-p75NTR function-blocking antiserum, nor by prior tetanic stimulation. Although LTP was normal in slices from VGF knockout mice, LTD could not be induced, and VGF mutant mice were impaired in hippocampal-dependent spatial learning and contextual fear conditioning tasks. Our studies indicate that the VGF C-terminal peptide TLQP62 modulates hippocampal synaptic transmission through a BDNF-dependent mechanism, and that VGF deficiency in mice impacts synaptic plasticity and memory in addition to depressive behavior. PMID:18815270

Addiction-like synaptic impairments in diet-induced obesity

PubMed Central

Spencer, Sade; Garcia-Keller, Constanza; Spanswick, David C; Lawrence, Andrew John; Simonds, Stephanie Elise; Schwartz, Danielle Joy; Jordan, Kelsey Ann; Jhou, Thomas Clayton; Kalivas, Peter William

2016-01-01

Background There is increasing evidence that the pathological overeating underlying some forms of obesity is compulsive in nature, and therefore contains elements of an addictive disorder. However, direct physiological evidence linking obesity to synaptic plasticity akin to that occurring in addiction is lacking. We sought to establish whether the propensity to diet-induced obesity (DIO) is associated with addictive-like behavior, as well as synaptic impairments in the nucleus accumbens core (NAcore) considered hallmarks of addiction. Methods Sprague-Dawley rats were allowed free access to a palatable diet for 8 weeks then separated by weight gain into DIO prone (OP) and resistant (OR) subgroups. Access to palatable food was then restricted to daily operant self-administration sessions using fixed (FR1, 3 and 5) and progressive ratio (PR) schedules. Subsequently, NAcore brain slices were prepared and we tested for changes in the ratio between AMPA and NMDA currents (AMPA/NMDA) and the ability to exhibit long-term depression (LTD). Results We found that propensity to develop DIO is linked to deficits in the ability to induce LTD in the NAcore, as well as increased potentiation at these synapses as measured by AMPA/NMDA currents. Consistent with these impairments, we observed addictive-like behavior in OP rats, including i) heightened motivation for palatable food (ii) excessive intake and (iii) increased food-seeking when food was unavailable. Conclusions Our results show overlap between the propensity for DIO and the synaptic changes associated with facets of addictive behavior, supporting partial coincident neurological underpinnings for compulsive overeating and drug addiction. PMID:26826876

Ethanol-mediated facilitation of AMPA receptor function in the dorsomedial striatum: implications for alcohol drinking behavior.

PubMed

Wang, Jun; Ben Hamida, Sami; Darcq, Emmanuel; Zhu, Wenheng; Gibb, Stuart L; Lanfranco, Maria Fe; Carnicella, Sebastien; Ron, Dorit

2012-10-24

We found previously that acute ex vivo as well as repeated cycles of in vivo ethanol exposure and withdrawal, including excessive voluntary consumption of ethanol, produces a long-lasting increase in the activity of NR2B-containing NMDA receptors (NR2B-NMDARs) in the dorsomedial striatum (DMS) of rats (Wang et al., 2010a). Activation of NMDARs is required for the induction of long-term potentiation (LTP) of AMPA receptor (AMPAR)-mediated synaptic response. We therefore examined whether the ethanol-mediated upregulation of NMDAR activity alters the induction of LTP in the DMS. We found that ex vivo acute exposure of striatal slices to, and withdrawal from, ethanol facilitates the induction of LTP in DMS neurons, which is abolished by the inhibition of NR2B-NMDARs. We also report that repeated systemic administration of ethanol causes an NR2B-NMDAR-dependent facilitation of LTP in the DMS. LTP is mediated by the insertion of AMPAR subunits into the synaptic membrane, and we found that repeated systemic administration of ethanol, as well as cycles of excessive ethanol consumption and withdrawal, produced a long-lasting increase in synaptic localization of the GluR1 and GluR2 subunits of AMPARs in the DMS. Importantly, we report that inhibition of AMPARs in the DMS attenuates operant self-administration of ethanol, but not of sucrose. Together, our data suggest that aberrant synaptic plasticity in the DMS induced by repeated cycles of ethanol exposure and withdrawal contributes to the molecular mechanisms underlying the development and/or maintenance of excessive ethanol consumption.

Involvement of TrkB- and p75NTR-signaling pathways in two contrasting forms of long-lasting synaptic plasticity

NASA Astrophysics Data System (ADS)

Sakuragi, Shigeo; Tominaga-Yoshino, Keiko; Ogura, Akihiko

2013-11-01

The repetition of experience is often necessary to establish long-lasting memory. However, the cellular mechanisms underlying this repetition-dependent consolidation of memory remain unclear. We previously observed in organotypic slice cultures of the rodent hippocampus that repeated inductions of long-term potentiation (LTP) led to a slowly developing long-lasting synaptic enhancement coupled with synaptogenesis. We also reported that repeated inductions of long-term depression (LTD) produced a long-lasting synaptic suppression coupled with synapse elimination. We proposed these phenomena as useful in vitro models for analyzing repetition-dependent consolidation. Here, we hypothesized that the enhancement and suppression are mediated by the brain-derived neurotrophic factor (BDNF)-TrkB signaling pathway and the proBDNF-p75NTR pathway, respectively. When we masked the respective pathways, reversals of the enhancement and suppression resulted. These results suggest the alternative activation of the p75NTR pathway by BDNF under TrkB-masking conditions and of the TrkB pathway by proBDNF under p75NTR-masking conditions, thus supporting the aforementioned hypothesis.

Estrogen's Place in the Family of Synaptic Modulators.

PubMed

Kramár, Enikö A; Chen, Lulu Y; Rex, Christopher S; Gall, Christine M; Lynch, Gary

2009-01-01

Estrogen, in addition to its genomic effects, triggers rapid synaptic changes in hippocampus and cortex. Here we summarize evidence that the acute actions of the steroid arise from actin signaling cascades centrally involved in long-term potentiation (LTP). A 10-min infusion of E2 reversibly increased fast EPSPs and promoted theta burst-induced LTP within adult hippocampal slices. The latter effect reflected a lowered threshold and an elevated ceiling for the potentiation effect. E2's actions on transmission and plasticity were completely blocked by latrunculin, a toxin that prevents actin polymerization. E2 also caused a reversible increase in spine concentrations of filamentous (F-) actin and markedly enhanced polymerization caused by theta burst stimulation (TBS). Estrogen activated the small GTPase RhoA, but not the related GTPase Rac, and phosphorylated (inactivated) synaptic cofilin, an actin severing protein targeted by RhoA. An inhibitor of RhoA kinase (ROCK) thoroughly suppressed the synaptic effects of E2. Collectively, these results indicate that E2 engages a RhoA >ROCK> cofilin> actin pathway also used by brain-derived neurotrophic factor and adenosine, and therefore belongs to a family of 'synaptic modulators' that regulate plasticity. Finally, we describe evidence that the acute signaling cascade is critical to the depression of LTP produced by ovariectomy.

Obesity in Aging Exacerbates Neuroinflammation, Dysregulating Synaptic Function-related Genes and Altering Eicosanoid Synthesis in the Mouse Hippocampus: Potential Role in Impaired Synaptic Plasticity and Cognitive Decline.

PubMed

Valcarcel-Ares, Marta Noa; Tucsek, Zsuzsanna; Kiss, Tamas; Giles, Cory B; Tarantini, Stefano; Yabluchanskiy, Andriy; Balasubramanian, Priya; Gautam, Tripti; Galvan, Veronica; Ballabh, Praveen; Richardson, Arlan; Freeman, Willard M; Wren, Jonathan D; Deak, Ferenc; Ungvari, Zoltan; Csiszar, Anna

2018-06-08

There is strong evidence that obesity has deleterious effects on cognitive function of older adults. Previous preclinical studies demonstrate that obesity in aging is associated with a heightened state of systemic inflammation, which exacerbates blood brain barrier disruption, promoting neuroinflammation and oxidative stress. To test the hypothesis that synergistic effects of obesity and aging on inflammatory processes exert deleterious effects on hippocampal function, young and aged C57BL/6 mice were rendered obese by chronic feeding of a high fat diet followed by assessment of learning and memory function, measurement of hippocampal long-term potentiation (LTP), assessment of changes in hippocampal expression of genes relevant for synaptic function and determination of synaptic density. Because there is increasing evidence that altered production of lipid mediators modulate LTP, neuroinflammation and neurovascular coupling responses, the effects of obesity on hippocampal levels of relevant eicosanoid mediators were also assessed. We found that aging exacerbates obesity-induced microglia activation, which is associated with deficits in hippocampal-dependent learning and memory tests, impaired LTP, decreased synaptic density and dysregulation of genes involved in regulation of synaptic plasticity. Obesity in aging also resulted in an altered hippocampal eicosanoid profile, including decreases in vasodilator and pro-LTP epoxy-eicosatrienoic acids (EETs). Collectively, our results taken together with previous findings suggest that obesity in aging promotes hippocampal inflammation, which in turn may contribute to synaptic dysfunction and cognitive impairment.

Memory Reactivation Enables Long-Term Prevention of Interference.

PubMed

Herszage, Jasmine; Censor, Nitzan

2017-05-22

The ability of the human brain to successively learn or perform two competing tasks constitutes a major challenge in daily function. Indeed, exposing the brain to two different competing memories within a short temporal offset can induce interference, resulting in deteriorated performance in at least one of the learned memories [1-4]. Although previous studies have investigated online interference and its effects on performance [5-13], whether the human brain can enable long-term prevention of future interference is unknown. To address this question, we utilized the memory reactivation-reconsolidation framework [2, 12] stemming from studies at the synaptic level [14-17], according to which reactivation of a memory enables its update. In a set of experiments, using the motor sequence learning task [18] we report that a unique pairing of reactivating the original memory (right hand) in synchrony with novel memory trials (left hand) prevented future interference between the two memories. Strikingly, these effects were long-term and observed a month following reactivation. Further experiments showed that preventing future interference was not due to practice per se, but rather specifically depended on a limited time window induced by reactivation of the original memory. These results suggest a mechanism according to which memory reactivation enables long-term prevention of interference, possibly by creating an updated memory trace integrating original and novel memories during the reconsolidation time window. The opportunity to induce a long-term preventive effect on memories may enable the utilization of strategies optimizing normal human learning, as well as recovery following neurological insults. Copyright © 2017 Elsevier Ltd. All rights reserved.

Magnetic Tunnel Junction Based Long-Term Short-Term Stochastic Synapse for a Spiking Neural Network with On-Chip STDP Learning

NASA Astrophysics Data System (ADS)

Srinivasan, Gopalakrishnan; Sengupta, Abhronil; Roy, Kaushik

2016-07-01

Spiking Neural Networks (SNNs) have emerged as a powerful neuromorphic computing paradigm to carry out classification and recognition tasks. Nevertheless, the general purpose computing platforms and the custom hardware architectures implemented using standard CMOS technology, have been unable to rival the power efficiency of the human brain. Hence, there is a need for novel nanoelectronic devices that can efficiently model the neurons and synapses constituting an SNN. In this work, we propose a heterostructure composed of a Magnetic Tunnel Junction (MTJ) and a heavy metal as a stochastic binary synapse. Synaptic plasticity is achieved by the stochastic switching of the MTJ conductance states, based on the temporal correlation between the spiking activities of the interconnecting neurons. Additionally, we present a significance driven long-term short-term stochastic synapse comprising two unique binary synaptic elements, in order to improve the synaptic learning efficiency. We demonstrate the efficacy of the proposed synaptic configurations and the stochastic learning algorithm on an SNN trained to classify handwritten digits from the MNIST dataset, using a device to system-level simulation framework. The power efficiency of the proposed neuromorphic system stems from the ultra-low programming energy of the spintronic synapses.

Synaptic characteristics with strong analog potentiation, depression, and short-term to long-term memory transition in a Pt/CeO2/Pt crossbar array structure

NASA Astrophysics Data System (ADS)

Kim, Hyung Jun; Park, Daehoon; Yang, Paul; Beom, Keonwon; Kim, Min Ju; Shin, Chansun; Kang, Chi Jung; Yoon, Tae-Sik

2018-06-01

A crossbar array of Pt/CeO2/Pt memristors exhibited the synaptic characteristics such as analog, reversible, and strong resistance change with a ratio of ∼103, corresponding to wide dynamic range of synaptic weight modulation as potentiation and depression with respect to the voltage polarity. In addition, it presented timing-dependent responses such as paired-pulse facilitation and the short-term to long-term memory transition by increasing amplitude, width, and repetition number of voltage pulse and reducing the interval time between pulses. The memory loss with a time was fitted with a stretched exponential relaxation model, revealing the relation of memory stability with the input stimuli strength. The resistance change was further enhanced but its stability got worse as increasing measurement temperature, indicating that the resistance was changed as a result of voltage- and temperature-dependent electrical charging and discharging to alter the energy barrier for charge transport. These detailed synaptic characteristics demonstrated the potential of crossbar array of Pt/CeO2/Pt memristors as artificial synapses in highly connected neuron-synapse network.

Synaptic characteristics with strong analog potentiation, depression, and short-term to long-term memory transition in a Pt/CeO2/Pt crossbar array structure.

PubMed

Kim, Hyung Jun; Park, Daehoon; Yang, Paul; Beom, Keonwon; Kim, Min Ju; Shin, Chansun; Kang, Chi Jung; Yoon, Tae-Sik

2018-06-29

A crossbar array of Pt/CeO 2 /Pt memristors exhibited the synaptic characteristics such as analog, reversible, and strong resistance change with a ratio of ∼10 3 , corresponding to wide dynamic range of synaptic weight modulation as potentiation and depression with respect to the voltage polarity. In addition, it presented timing-dependent responses such as paired-pulse facilitation and the short-term to long-term memory transition by increasing amplitude, width, and repetition number of voltage pulse and reducing the interval time between pulses. The memory loss with a time was fitted with a stretched exponential relaxation model, revealing the relation of memory stability with the input stimuli strength. The resistance change was further enhanced but its stability got worse as increasing measurement temperature, indicating that the resistance was changed as a result of voltage- and temperature-dependent electrical charging and discharging to alter the energy barrier for charge transport. These detailed synaptic characteristics demonstrated the potential of crossbar array of Pt/CeO 2 /Pt memristors as artificial synapses in highly connected neuron-synapse network.

Magnetic Tunnel Junction Based Long-Term Short-Term Stochastic Synapse for a Spiking Neural Network with On-Chip STDP Learning.

PubMed

Srinivasan, Gopalakrishnan; Sengupta, Abhronil; Roy, Kaushik

2016-07-13

Spiking Neural Networks (SNNs) have emerged as a powerful neuromorphic computing paradigm to carry out classification and recognition tasks. Nevertheless, the general purpose computing platforms and the custom hardware architectures implemented using standard CMOS technology, have been unable to rival the power efficiency of the human brain. Hence, there is a need for novel nanoelectronic devices that can efficiently model the neurons and synapses constituting an SNN. In this work, we propose a heterostructure composed of a Magnetic Tunnel Junction (MTJ) and a heavy metal as a stochastic binary synapse. Synaptic plasticity is achieved by the stochastic switching of the MTJ conductance states, based on the temporal correlation between the spiking activities of the interconnecting neurons. Additionally, we present a significance driven long-term short-term stochastic synapse comprising two unique binary synaptic elements, in order to improve the synaptic learning efficiency. We demonstrate the efficacy of the proposed synaptic configurations and the stochastic learning algorithm on an SNN trained to classify handwritten digits from the MNIST dataset, using a device to system-level simulation framework. The power efficiency of the proposed neuromorphic system stems from the ultra-low programming energy of the spintronic synapses.

Impairment of Release Site Clearance within the Active Zone by Reduced SCAMP5 Expression Causes Short-Term Depression of Synaptic Release.

PubMed

Park, Daehun; Lee, Unghwi; Cho, Eunji; Zhao, Haiyan; Kim, Jung Ah; Lee, Byoung Ju; Regan, Philip; Ho, Won-Kyung; Cho, Kwangwook; Chang, Sunghoe

2018-03-20

Despite being a highly enriched synaptic vesicle (SV) protein and a candidate gene for autism, the physiological function of SCAMP5 remains mostly enigmatic. Here, using optical imaging and electrophysiological experiments, we demonstrate that SCAMP5 plays a critical role in release site clearance at the active zone. Truncation analysis revealed that the 2/3 loop domain of SCAMP5 directly interacts with adaptor protein 2, and this interaction is critical for its role in release site clearance. Knockdown (KD) of SCAMP5 exhibited pronounced synaptic depression accompanied by a slower recovery of the SV pool. Moreover, it induced a strong frequency-dependent short-term depression of synaptic release, even under the condition of sufficient release-ready SVs. Super-resolution microscopy further proved the defects in SV protein clearance induced by KD. Thus, reduced expression of SCAMP5 may impair the efficiency of SV clearance at the active zone, and this might relate to the synaptic dysfunction observed in autism. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Role of motor cortex NMDA receptors in learning-dependent synaptic plasticity of behaving mice

PubMed Central

Hasan, Mazahir T.; Hernández-González, Samuel; Dogbevia, Godwin; Treviño, Mario; Bertocchi, Ilaria; Gruart, Agnès; Delgado-García, José M.

2013-01-01

The primary motor cortex has an important role in the precise execution of learned motor responses. During motor learning, synaptic efficacy between sensory and primary motor cortical neurons is enhanced, possibly involving long-term potentiation and N-methyl-D-aspartate (NMDA)-specific glutamate receptor function. To investigate whether NMDA receptor in the primary motor cortex can act as a coincidence detector for activity-dependent changes in synaptic strength and associative learning, here we generate mice with deletion of the Grin1 gene, encoding the essential NMDA receptor subunit 1 (GluN1), specifically in the primary motor cortex. The loss of NMDA receptor function impairs primary motor cortex long-term potentiation in vivo. Importantly, it impairs the synaptic efficacy between the primary somatosensory and primary motor cortices and significantly reduces classically conditioned eyeblink responses. Furthermore, compared with wild-type littermates, mice lacking primary motor cortex show slower learning in Skinner-box tasks. Thus, primary motor cortex NMDA receptors are necessary for activity-dependent synaptic strengthening and associative learning. PMID:23978820

The effects of CCK-8S on spatial memory and long-term potentiation at CA1 during induction of stress in rats.

PubMed

Sadeghi, Malihe; Reisi, Parham; Radahmadi, Maryam

2017-12-01

Cholecystokinin (CCK) has been proposed as a mediator in stress. However, it is still not fully documented what are its effects. We aimed to evaluate the effects of systemic administration of CCK exactly before induction of stress on spatial memory and synaptic plasticity at CA1 in rats. Male Wistar rats were divided into 4 groups: the control, the control-CCK, the stress and the stress-CCK. Restraint stress was induced 6 hr per day, for 24 days. Cholecystokinin sulfated octapeptide (CCK-8S) was injected (1.6 µg/kg, IP) before each session of stress induction. Spatial memory was evaluated by Morris water maze test. Long-term potentiation (LTP) in Schaffer collateral-CA1 synapses was assessed (by 100 Hz tetanization) in order to investigate synaptic plasticity. Stress impaired spatial memory significantly ( P <0.01). CCK in the control rats improved memory ( P <0.05), and prevented the impairments in the stress group. With respect to the control group, both fEPSP amplitude and slope were significantly ( P <0.05) decreased in the stress group. However, there were no differences between responses of the control-CCK and Stress-CCK groups compared to the control group. The present results suggest that high levels of CCK-8S during induction of stress can modulate the destructive effects of stress on hippocampal synaptic plasticity and memory. Therefore, the mediatory effects of CCK in stress are likely as compensatory responses.

Astrocytic Activation Generates De Novo Neuronal Potentiation and Memory Enhancement.

PubMed

Adamsky, Adar; Kol, Adi; Kreisel, Tirzah; Doron, Adi; Ozeri-Engelhard, Nofar; Melcer, Talia; Refaeli, Ron; Horn, Henrike; Regev, Limor; Groysman, Maya; London, Michael; Goshen, Inbal

2018-05-18

Astrocytes respond to neuronal activity and were shown to be necessary for plasticity and memory. To test whether astrocytic activity is also sufficient to generate synaptic potentiation and enhance memory, we expressed the Gq-coupled receptor hM3Dq in CA1 astrocytes, allowing their activation by a designer drug. We discovered that astrocytic activation is not only necessary for synaptic plasticity, but also sufficient to induce NMDA-dependent de novo long-term potentiation in the hippocampus that persisted after astrocytic activation ceased. In vivo, astrocytic activation enhanced memory allocation; i.e., it increased neuronal activity in a task-specific way only when coupled with learning, but not in home-caged mice. Furthermore, astrocytic activation using either a chemogenetic or an optogenetic tool during acquisition resulted in memory recall enhancement on the following day. Conversely, directly increasing neuronal activity resulted in dramatic memory impairment. Our findings that astrocytes induce plasticity and enhance memory may have important clinical implications for cognitive augmentation treatments. Copyright © 2018 Elsevier Inc. All rights reserved.

Aβ Damages Learning and Memory in Alzheimer's Disease Rats with Kidney-Yang Deficiency

PubMed Central

Qi, Dongmei; Qiao, Yongfa; Zhang, Xin; Yu, Huijuan; Cheng, Bin; Qiao, Haifa

2012-01-01

Previous studies demonstrated that Alzheimer's disease was considered as the consequence produced by deficiency of Kidney essence. However, the mechanism underlying the symptoms also remains elusive. Here we report that spatial learning and memory, escape, and swimming capacities were damaged significantly in Kidney-yang deficiency rats. Indeed, both hippocampal Aβ 40 and 42 increases in Kidney-yang deficiency contribute to the learning and memory impairments. Specifically, damage of synaptic plasticity is involved in the learning and memory impairment of Kidney-yang deficiency rats. We determined that the learning and memory damage in Kidney-yang deficiency due to synaptic plasticity impairment and increases of Aβ 40 and 42 was not caused via NMDA receptor internalization induced by Aβ increase. β-Adrenergic receptor agonist can rescue the impaired long-term potential (LTP) in Kidney-yang rats. Taken together, our results suggest that spatial learning and memory inhibited in Kidney-yang deficiency might be induced by Aβ increase and the decrease of β 2 receptor function in glia. PMID:22645624

Protein ubiquitination in postsynaptic densities after hypoxia in rat neostriatum is blocked by hypothermia.

PubMed

Capani, Francisco; Saraceno, Gustavo Ezequiel; Botti, Valeria; Aon-Bertolino, Laura; de Oliveira, Diêgo Madureira; Barreto, George; Galeano, Pablo; Giraldez-Alvarez, Lisandro Diego; Coirini, Héctor

2009-10-01

Synaptic dysfunction has been associated with neuronal cell death following hypoxia. The lack of knowledge on the mechanisms underlying this dysfunction prompted us to investigate the morphological changes in the postsynaptic densities (PSDs) induced by hypoxia. The results presented here demonstrate that PSDs of the rat neostriatum are highly modified and ubiquitinated 6 months after induction of hypoxia in a model of perinatal asphyxia. Using both two dimensional (2D) and three dimensional (3D) electron microscopic analyses of synapses stained with ethanolic phosphotungstic acid (E-PTA), we observed an increment of PSD thickness dependent on the duration and severity of the hypoxic insult. The PSDs showed clear signs of damage and intense staining for ubiquitin. These morphological and molecular changes were effectively blocked by hypothermia treatment, one of the most effective strategies for hypoxia-induced brain injury available today. Our data suggest that synaptic dysfunction following hypoxia may be caused by long-term misfolding and aggregation of proteins in the PSD.

Cocoa extracts reduce oligomerization of amyloid-β: implications for cognitive improvement in Alzheimer's disease.

PubMed

Wang, Jun; Varghese, Merina; Ono, Kenjiro; Yamada, Masahito; Levine, Samara; Tzavaras, Nikos; Gong, Bing; Hurst, William J; Blitzer, Robert D; Pasinetti, Giulio Maria

2014-01-01

Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder, characterized by pathological aggregates of amyloid peptide-β (Aβ) and tau protein. Currently available therapies mediate AD symptoms without modifying disease progression. Polyphenol-rich diets are reported to reduce the risk for AD. In the present study, we investigated the AD disease-modifying effects of cocoa, a rich source of flavanols, which are a class of polyphenols. We hypothesized that cocoa extracts interfere with amyloid-β oligomerization to prevent synaptic deficits. We tested the effects of three different cocoa extracts, viz. Natural, Dutched, and Lavado extracts, on Aβ42 and Aβ40 oligomerization, using photo-induced cross-linking of unmodified proteins technique. To assess the effects of cocoa extracts on synaptic function, we measured long term potentiation in mouse brain hippocampal slices exposed to oligomeric Aβ. Our results indicate that cocoa extracts are effective in preventing the oligomerization of Aβ, with Lavado extract being most effective. Lavado extract, but not Dutched extract, was effective in restoring the long term potentiation response reduced by oligomeric Aβ. Our findings indicate that cocoa extracts have multiple disease-modifying properties in AD and present a promising route of therapeutic and/or preventative initiatives.

PKMζ is necessary and sufficient for synaptic clustering of PSD-95.

PubMed

Shao, Charles Y; Sondhi, Rachna; van de Nes, Paula S; Sacktor, Todd Charlton

2012-07-01

The persistent activity of protein kinase Mzeta (PKMζ), a brain-specific, constitutively active protein kinase C isoform, maintains synaptic long-term potentiation (LTP). Structural remodeling of the postsynaptic density is believed to contribute to the expression of LTP. We therefore examined the role of PKMζ in reconfiguring PSD-95, the major postsynaptic scaffolding protein at excitatory synapses. In primary cultures of hippocampal neurons, PKMζ activity was critical for increasing the size of PSD-95 clusters during chemical LTP (cLTP). Increasing PKMζ activity by overexpressing the kinase in hippocampal neurons was sufficient to increase PSD-95 cluster size, spine size, and postsynaptic AMPAR subunit GluA2. Overexpression of an inactive mutant of PKMζ did not increase PSD-95 clustering, and applications of the ζ-pseudosubstrate inhibitor ZIP reversed the PKMζ-mediated increases in PSD-95 clustering, indicating that the activity of PKMζ is necessary to induce and maintain the increased size of PSD-95 clusters. Thus the persistent activity of PKMζ is both necessary and sufficient for maintaining increases of PSD-95 clusters, providing a unified mechanism for long-term functional and structural modifications of synapses. Copyright © 2011 Wiley Periodicals, Inc.

Single fluoxetine treatment before but not after stress prevents stress-induced hippocampal long-term depression and spatial memory retrieval impairment in rats

PubMed Central

Han, Huili; Dai, Chunfang; Dong, Zhifang

2015-01-01

A growing body of evidence has shown that chronic treatment with fluoxetine, a widely prescribed medication for treatment of depression, can affect synaptic plasticity in the adult central nervous system. However, it is not well understood whether acute fluoxetine influences synaptic plasticity, especially on hippocampal CA1 long-term depression (LTD), and if so, whether it subsequently impacts hippocampal-dependent spatial memory. Here, we reported that LTD facilitated by elevated-platform stress in hippocampal slices was completely prevented by fluoxetine administration (10 mg/kg, i.p.) 30 min before stress. The LTD was not, however, significantly inhibited by fluoxetine administration immediately after stress. Similarly, fluoxetine incubation (10 μM) during electrophysiological recordings also displayed no influence on the stress-facilitated LTD. In addition, behavioral results showed that a single fluoxetine treatment 30 min before but not after acute stress fully reversed the impairment of spatial memory retrieval in the Morris water maze paradigm. Taken together, these results suggest that acute fluoxetine treatment only before, but not after stress, can prevent hippocampal CA1 LTD and spatial memory retrieval impairment caused by behavioral stress in adult animals. PMID:26218751

Realization of synaptic learning and memory functions in Y2O3 based memristive device fabricated by dual ion beam sputtering

NASA Astrophysics Data System (ADS)

Das, Mangal; Kumar, Amitesh; Singh, Rohit; Than Htay, Myo; Mukherjee, Shaibal

2018-02-01

Single synaptic device with inherent learning and memory functions is demonstrated based on a forming-free amorphous Y2O3 (yttria) memristor fabricated by dual ion beam sputtering system. Synaptic functions such as nonlinear transmission characteristics, long-term plasticity, short-term plasticity and ‘learning behavior (LB)’ are achieved using a single synaptic device based on cost-effective metal-insulator-semiconductor (MIS) structure. An ‘LB’ function is demonstrated, for the first time in the literature, for a yttria based memristor, which bears a resemblance to certain memory functions of biological systems. The realization of key synaptic functions in a cost-effective MIS structure would promote much cheaper synapse for artificial neural network.

Nogo receptor 1 regulates formation of lasting memories.

PubMed

Karlén, Alexandra; Karlsson, Tobias E; Mattsson, Anna; Lundströmer, Karin; Codeluppi, Simone; Pham, Therese M; Bäckman, Cristina M; Ogren, Sven Ove; Aberg, Elin; Hoffman, Alexander F; Sherling, Michael A; Lupica, Carl R; Hoffer, Barry J; Spenger, Christian; Josephson, Anna; Brené, Stefan; Olson, Lars

2009-12-01

Formation of lasting memories is believed to rely on structural alterations at the synaptic level. We had found that increased neuronal activity down-regulates Nogo receptor-1 (NgR1) in brain regions linked to memory formation and storage, and postulated this to be required for formation of lasting memories. We now show that mice with inducible overexpression of NgR1 in forebrain neurons have normal long-term potentiation and normal 24-h memory, but severely impaired month-long memory in both passive avoidance and swim maze tests. Blocking transgene expression normalizes these memory impairments. Nogo, Lingo-1, Troy, endogenous NgR1, and BDNF mRNA expression levels were not altered by transgene expression, suggesting that the impaired ability to form lasting memories is directly coupled to inability to down-regulate NgR1. Regulation of NgR1 may therefore serve as a key regulator of memory consolidation. Understanding the molecular underpinnings of synaptic rearrangements that carry lasting memories may facilitate development of treatments for memory dysfunction.

Nogo receptor 1 regulates formation of lasting memories

PubMed Central

Karlén, Alexandra; Karlsson, Tobias E.; Mattsson, Anna; Lundströmer, Karin; Codeluppi, Simone; Pham, Therese M.; Bäckman, Cristina M.; Ögren, Sven Ove; Åberg, Elin; Hoffman, Alexander F.; Sherling, Michael A.; Lupica, Carl R.; Hoffer, Barry J.; Spenger, Christian; Josephson, Anna; Brené, Stefan; Olson, Lars

2009-01-01

Formation of lasting memories is believed to rely on structural alterations at the synaptic level. We had found that increased neuronal activity down-regulates Nogo receptor-1 (NgR1) in brain regions linked to memory formation and storage, and postulated this to be required for formation of lasting memories. We now show that mice with inducible overexpression of NgR1 in forebrain neurons have normal long-term potentiation and normal 24-h memory, but severely impaired month-long memory in both passive avoidance and swim maze tests. Blocking transgene expression normalizes these memory impairments. Nogo, Lingo-1, Troy, endogenous NgR1, and BDNF mRNA expression levels were not altered by transgene expression, suggesting that the impaired ability to form lasting memories is directly coupled to inability to down-regulate NgR1. Regulation of NgR1 may therefore serve as a key regulator of memory consolidation. Understanding the molecular underpinnings of synaptic rearrangements that carry lasting memories may facilitate development of treatments for memory dysfunction. PMID:19915139

Activity-dependent expression of miR-132 regulates immediate-early gene induction during olfactory learning in the greater short-nosed fruit bat, Cynopterus sphinx.

PubMed

Mukilan, Murugan; Ragu Varman, Durairaj; Sudhakar, Sivasubramaniam; Rajan, Koilmani Emmanuvel

2015-04-01

The activity-dependent expression of immediate-early genes (IEGs) and microRNA (miR)-132 has been implicated in synaptic plasticity and the formation of long-term memory (LTM). In the present study, we show that olfactory training induces the expression of IEGs (EGR-1, C-fos, C-jun) and miR-132 at similar time scale in olfactory bulb (OB) of Cynopterus sphinx. We examined the role of miR-132 in the OB using antisense oligodeoxynucleotide (AS-ODN) and demonstrated that a local infusion of AS-ODN in the OB 2h prior to training impaired olfactory memory formation in C. sphinx. However, the infusion of AS-ODN post-training did not cause a deficit in memory formation. Furthermore, the inhibition of miR-132 reduced the olfactory training-induced expression of IEGs and post synaptic density protein-95 (PSD-95) in the OB. Additionally, we show that miR-132 regulates the activation of calcium/calmodulin-dependent protein kinase-II (CaMKII) and cAMP response element binding protein (CREB), possibly through miR-148a. These data suggest that olfactory training induces the expression of miR-132 and IEGs, which in turn activates post-synaptic proteins that regulate olfactory memory formation. Copyright © 2015 Elsevier Inc. All rights reserved.

Plasticity of Neuron-Glial Transmission: Equipping Glia for Long-Term Integration of Network Activity.

PubMed

Croft, Wayne; Dobson, Katharine L; Bellamy, Tomas C

2015-01-01

The capacity of synaptic networks to express activity-dependent changes in strength and connectivity is essential for learning and memory processes. In recent years, glial cells (most notably astrocytes) have been recognized as active participants in the modulation of synaptic transmission and synaptic plasticity, implicating these electrically nonexcitable cells in information processing in the brain. While the concept of bidirectional communication between neurons and glia and the mechanisms by which gliotransmission can modulate neuronal function are well established, less attention has been focussed on the computational potential of neuron-glial transmission itself. In particular, whether neuron-glial transmission is itself subject to activity-dependent plasticity and what the computational properties of such plasticity might be has not been explored in detail. In this review, we summarize current examples of plasticity in neuron-glial transmission, in many brain regions and neurotransmitter pathways. We argue that induction of glial plasticity typically requires repetitive neuronal firing over long time periods (minutes-hours) rather than the short-lived, stereotyped trigger typical of canonical long-term potentiation. We speculate that this equips glia with a mechanism for monitoring average firing rates in the synaptic network, which is suited to the longer term roles proposed for astrocytes in neurophysiology.

mGlu5 positive allosteric modulation normalizes synaptic plasticity defects and motor phenotypes in a mouse model of Rett syndrome

PubMed Central

Gogliotti, Rocco G.; Senter, Rebecca K.; Rook, Jerri M.; Ghoshal, Ayan; Zamorano, Rocio; Malosh, Chrysa; Stauffer, Shaun R.; Bridges, Thomas M.; Bartolome, Jose M.; Daniels, J. Scott; Jones, Carrie K.; Lindsley, Craig W.; Conn, P. Jeffrey; Niswender, Colleen M.

2016-01-01

Rett syndrome (RS) is a neurodevelopmental disorder that shares many symptomatic and pathological commonalities with idiopathic autism. Alterations in protein synthesis-dependent synaptic plasticity (PSDSP) are a hallmark of a number of syndromic forms of autism; in the present work, we explore the consequences of disruption and rescue of PSDSP in a mouse model of RS. We report that expression of a key regulator of synaptic protein synthesis, the metabotropic glutamate receptor 5 (mGlu5) protein, is significantly reduced in both the brains of RS model mice and in the motor cortex of human RS autopsy samples. Furthermore, we demonstrate that reduced mGlu5 expression correlates with attenuated DHPG-induced long-term depression in the hippocampus of RS model mice, and that administration of a novel mGlu5 positive allosteric modulator (PAM), termed VU0462807, can rescue synaptic plasticity defects. Additionally, treatment of Mecp2-deficient mice with VU0462807 improves motor performance (open-field behavior and gait dynamics), corrects repetitive clasping behavior, as well as normalizes cued fear-conditioning defects. Importantly, due to the rationale drug discovery approach used in its development, our novel mGlu5 PAM improves RS phenotypes and synaptic plasticity defects without evoking the overt adverse effects commonly associated with potentiation of mGlu5 signaling (i.e. seizures), or affecting cardiorespiratory defects in RS model mice. These findings provide strong support for the continued development of mGlu5 PAMs as potential therapeutic agents for use in RS, and, more broadly, for utility in idiopathic autism. PMID:26936821

A light-stimulated synaptic transistor with synaptic plasticity and memory functions based on InGaZnO{sub x}–Al{sub 2}O{sub 3} thin film structure

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, H. K.; Chen, T. P., E-mail: echentp@ntu.edu.sg; Liu, P.

In this work, a synaptic transistor based on the indium gallium zinc oxide (IGZO)–aluminum oxide (Al{sub 2}O{sub 3}) thin film structure, which uses ultraviolet (UV) light pulses as the pre-synaptic stimulus, has been demonstrated. The synaptic transistor exhibits the behavior of synaptic plasticity like the paired-pulse facilitation. In addition, it also shows the brain's memory behaviors including the transition from short-term memory to long-term memory and the Ebbinghaus forgetting curve. The synapse-like behavior and memory behaviors of the transistor are due to the trapping and detrapping processes of the holes, which are generated by the UV pulses, at the IGZO/Al{submore » 2}O{sub 3} interface and/or in the Al{sub 2}O{sub 3} layer.« less

The eIF2a Kinase PERK Limits the Expression of Hippocampal Metabotropic Glutamate Receptor-Dependent Long-Term Depression

ERIC Educational Resources Information Center

Trinh, Mimi A.; Ma, Tao; Kaphzan, Hanoch; Bhattacharya, Aditi; Antion, Marcia D.; Cavener, Douglas R.; Hoeffer, Charles A.; Klann, Eric

2014-01-01

The proper regulation of translation is required for the expression of long-lasting synaptic plasticity. A major site of translational control involves the phosphorylation of eukaryotic initiation factor 2 a (eIF2a) by PKR-like endoplasmic reticulum (ER) kinase (PERK). To determine the role of PERK in hippocampal synaptic plasticity, we used the…

Acute Stress Suppresses Synaptic Inhibition and Increases Anxiety via Endocannabinoid Release in the Basolateral Amygdala

PubMed Central

Itoga, Christy A.; Fisher, Marc O.; Solomonow, Jonathan; Roltsch, Emily A.; Gilpin, Nicholas W.

2016-01-01

Stress and glucocorticoids stimulate the rapid mobilization of endocannabinoids in the basolateral amygdala (BLA). Cannabinoid receptors in the BLA contribute to anxiogenesis and fear-memory formation. We tested for rapid glucocorticoid-induced endocannabinoid regulation of synaptic inhibition in the rat BLA. Glucocorticoid application to amygdala slices elicited a rapid, nonreversible suppression of spontaneous, but not evoked, GABAergic synaptic currents in BLA principal neurons; the effect was also seen with a membrane-impermeant glucocorticoid, but not with intracellular glucocorticoid application, implicating a membrane-associated glucocorticoid receptor. The glucocorticoid suppression of GABA currents was not blocked by antagonists of nuclear corticosteroid receptors, or by inhibitors of gene transcription or protein synthesis, but was blocked by inhibiting postsynaptic G-protein activity, suggesting a postsynaptic nongenomic steroid signaling mechanism that stimulates the release of a retrograde messenger. The rapid glucocorticoid-induced suppression of inhibition was prevented by blocking CB1 receptors and 2-arachidonoylglycerol (2-AG) synthesis, and it was mimicked and occluded by CB1 receptor agonists, indicating it was mediated by the retrograde release of the endocannabinoid 2-AG. The rapid glucocorticoid effect in BLA neurons in vitro was occluded by prior in vivo acute stress-induced, or prior in vitro glucocorticoid-induced, release of endocannabinoid. Acute stress also caused an increase in anxiety-like behavior that was attenuated by blocking CB1 receptor activation and inhibiting 2-AG synthesis in the BLA. Together, these findings suggest that acute stress causes a long-lasting suppression of synaptic inhibition in BLA neurons via a membrane glucocorticoid receptor-induced release of 2-AG at GABA synapses, which contributes to stress-induced anxiogenesis. SIGNIFICANCE STATEMENT We provide a cellular mechanism in the basolateral amygdala (BLA) for the rapid stress regulation of anxiogenesis in rats. We demonstrate a nongenomic glucocorticoid induction of long-lasting suppression of synaptic inhibition that is mediated by retrograde endocannabinoid release at GABA synapses. The rapid glucocorticoid-induced endocannabinoid suppression of synaptic inhibition is initiated by a membrane-associated glucocorticoid receptor in BLA principal neurons. We show that acute stress increases anxiety-like behavior via an endocannabinoid-dependent mechanism centered in the BLA. The stress-induced endocannabinoid modulation of synaptic transmission in the BLA contributes, therefore, to the stress regulation of anxiety, and may play a role in anxiety disorders of the amygdala. PMID:27511017

Postsynaptic Synaptotagmins Mediate AMPA Receptor Exocytosis During LTP

PubMed Central

Wu, Dick; Bacaj, Taulant; Morishita, Wade; Goswami, Debanjan; Arendt, Kristin L.; Xu, Wei; Chen, Lu; Malenka, Robert C.; Südhof, Thomas C.

2017-01-01

Strengthening of synaptic connections by NMDA-receptor-dependent long-term potentiation (LTP) shapes neural circuits and mediates learning and memory. During NMDA-receptor-dependent LTP induction, Ca2+-influx stimulates recruitment of synaptic AMPA-receptors, thereby strengthening synapses. How Ca2+ induces AMPA-receptor recruitment, however, remains unclear. Here we show that, in pyramidal neurons of the hippocampal CA1-region, blocking postsynaptic expression of both synaptotagmin-1 and synaptotagmin-7, but not of synaptotagmin-1 or synaptotagmin-7 alone, abolished LTP. LTP was rescued by wild-type but not by Ca2+-binding-deficient mutant synaptotagmin-7. Blocking postsynaptic synaptotagmin-1/7 expression did not impair basal synaptic transmission, synaptic or extrasynaptic AMPA-receptor levels, or other AMPA-receptor trafficking events. Moreover, expression of dominant-negative mutant synaptotagmin-1 that inhibited Ca2+-dependent presynaptic vesicle exocytosis also blocked Ca2+-dependent postsynaptic AMPA-receptor exocytosis, thereby abolishing LTP. Our results suggest that postsynaptic synaptotagmin-1 and synaptotagmin-7 act as redundant Ca2+-sensors for Ca2+-dependent exocytosis of AMPA-receptors during LTP, thus delineating a simple mechanism for the recruitment of AMPA-receptors that mediates LTP. PMID:28355182

Plastic modifications induced by object recognition memory processing

PubMed Central

Clarke, Julia Rosauro; Cammarota, Martín; Gruart, Agnès; Izquierdo, Iván; Delgado-García, José María

2010-01-01

Long-term potentiation (LTP) phenomenon is widely accepted as a cellular model of memory consolidation. Object recognition (OR) is a particularly useful way of studying declarative memory in rodents because it makes use of their innate preference for novel over familiar objects. In this study, mice had electrodes implanted in the hippocampal Schaffer collaterals–pyramidal CA1 pathway and were trained for OR. Field EPSPs evoked at the CA3-CA1 synapse were recorded at the moment of training and at different times thereafter. LTP-like synaptic enhancement was found 6 h posttraining. A testing session was conducted 24 h after training, in the presence of one familiar and one novel object. Hippocampal synaptic facilitation was observed during exploration of familiar and novel objects. A short depotentiation period was observed early after the test and was followed by a later phase of synaptic efficacy enhancement. Here, we show that OR memory consolidation is accompanied by transient potentiation in the hippocampal CA3-CA1 synapses, while reconsolidation of this memory requires a short-lasting phase of depotentiation that could account for its well described vulnerability. The late synaptic enhancement phase, on the other hand, would be a consequence of memory restabilization. PMID:20133798

Long-term sensitization training in Aplysia leads to an increase in the expression of BiP, the major protein chaperon of the ER.

PubMed

Kuhl, D; Kennedy, T E; Barzilai, A; Kandel, E R

1992-12-01

Long-term memory for sensitization of the gill- and siphon-withdrawal reflexes in Aplysia californica requires RNA and protein synthesis. These long-term behavioral changes are accompanied by long-term facilitation of the synaptic connections between the gill and siphon sensory and motor neurons, which are similarly dependent on transcription and translation. In addition to showing an increase in over-all protein synthesis, long-term facilitation is associated with changes in the expression of specific early, intermediate, and late proteins, and with the growth of new synaptic connections between the sensory and motor neurons of the reflex. We previously focused on early proteins and have identified four proteins as members of the immunoglobulin family of cell adhesion molecules related to NCAM and fasciclin II. We have now cloned the cDNA corresponding to one of the late proteins, and identified it as the Aplysia homolog of BiP, an ER resident protein involved in the folding and assembly of secretory and membrane proteins. Behavioral training increases the steady-state level of BiP mRNA in the sensory neurons. The increase in the synthesis of BiP protein is first detected 3 h after the onset of facilitation, when the increase in overall protein synthesis reaches its peak and the formation of new synaptic terminals becomes apparent. These findings suggest that the chaperon function of BiP might serve to fold proteins and assemble protein complexes necessary for the structural changes characteristic of long-term memory.

Ionotropic Glutamate Receptors and Voltage-Gated Ca2+ Channels in Long-Term Potentiation of Spinal Dorsal Horn Synapses and Pain Hypersensitivity

PubMed Central

Youn, Dong-ho; Gerber, Gábor; Sather, William A.

2013-01-01

Over the last twenty years of research on cellular mechanisms of pain hypersensitivity, long-term potentiation (LTP) of synaptic transmission in the spinal cord dorsal horn (DH) has emerged as an important contributor to pain pathology. Mechanisms that underlie LTP of spinal DH neurons include changes in the numbers, activity, and properties of ionotropic glutamate receptors (AMPA and NMDA receptors) and of voltage-gated Ca2+ channels. Here, we review the roles and mechanisms of these channels in the induction and expression of spinal DH LTP, and we present this within the framework of the anatomical organization and synaptic circuitry of the spinal DH. Moreover, we compare synaptic plasticity in the spinal DH with classical LTP described for hippocampal synapses. PMID:24224102

FXR1P Limits Long-Term Memory, Long-Lasting Synaptic Potentiation, and de novo GluA2 Translation

PubMed Central

Jones, Emma V.; Altimimi, Haider F.; Farmer, W. Todd; Gandin, Valentina; Hanna, Edith; Zong, Ruiting; Barbon, Alessandro; Nelson, David L.; Topisirovic, Ivan; Rochford, Joseph; Stellwagen, David; Béïque, Jean-Claude; Murai, Keith K.

2014-01-01

SUMMARY Translational control of mRNAs allows for rapid and selective changes in synaptic protein expression, changes that are required for long-lasting plasticity and memory formation in the brain. Fragile X Related Protein 1 (FXR1P) is an RNA-binding protein that controls mRNA translation in non-neuronal cells and co-localizes with translational machinery in neurons. However, its neuronal mRNA targets and role in the brain are unknown. Here, we demonstrate that removal of FXR1P from the forebrain of postnatal mice selectively enhances long-term storage of spatial memories, hippocampal late-phase LTP (L-LTP) and de novo GluA2 synthesis. Furthermore, FXR1P binds specifically to the 5’UTR of GluA2 mRNA to repress translation and limit the amount of GluA2 incorporated at potentiated synapses. This study uncovers a new mechanism for regulating long-lasting synaptic plasticity and spatial memory formation and reveals an unexpected divergent role of FXR1P among Fragile X proteins in brain plasticity. PMID:25456134

Morvan's syndrome and the sustained absence of all sleep rhythms for months or years: An hypothesis.

PubMed

Touzet, Claude

2016-09-01

Despite the predation costs, sleep is ubiquitous in the animal realm. Humans spend a third of their life sleeping, and the quality of sleep has been related to co-morbidity, Alzheimer disease, etc. Excessive wakefulness induces rapid changes in cognitive performances, and it is claimed that one could die of sleep deprivation as quickly as by absence of water. In this context, the fact that a few people are able to go without sleep for months, even years, without displaying any cognitive troubles requires explanations. Theories ascribing sleep to memory consolidation are unable to explain such observations. It is not the case of the theory of sleep as the hebbian reinforcement of the inhibitory synapses (ToS-HRIS). Hebbian learning (Long Term Depression - LTD) guarantees that an efficient inhibitory synapse will lose its efficiency just because it is efficient at avoiding the activation of the post-synaptic neuron. This erosion of the inhibition is replenished by hebbian learning (Long Term Potentiation - LTP) when pre and post-synaptic neurons are active together - which is exactly what happens with the travelling depolarization waves of the slow-wave sleep (SWS). The best documented cases of months-long insomnia are reports of patients with Morvan's syndrome. This syndrome has an autoimmune cause that impedes - among many things - the potassium channels of the post-synaptic neurons, increasing LTP and decreasing LTD. We hypothesize that the absence of inhibitory efficiency erosion during wakefulness (thanks to a decrease of inhibitory LTD) is the cause for an absence of slow-wave sleep (SWS), which results also in the absence of REM sleep. Copyright © 2016 Elsevier Ltd. All rights reserved.

Synaptic depolarization is more effective than back-propagating action potentials during induction of associative long-term potentiation in hippocampal pyramidal neurons.

PubMed

Hardie, Jason; Spruston, Nelson

2009-03-11

Long-term potentiation (LTP) requires postsynaptic depolarization that can result from EPSPs paired with action potentials or larger EPSPs that trigger dendritic spikes. We explored the relative contribution of these sources of depolarization to LTP induction during synaptically driven action potential firing in hippocampal CA1 pyramidal neurons. Pairing of a weak test input with a strong input resulted in large LTP (approximately 75% increase) when the weak and strong inputs were both located in the apical dendrites. This form of LTP did not require somatic action potentials. When the strong input was located in the basal dendrites, the resulting LTP was smaller (< or =25% increase). Pairing the test input with somatically evoked action potentials mimicked this form of LTP. Thus, back-propagating action potentials may contribute to modest LTP, but local synaptic depolarization and/or dendritic spikes mediate a stronger form of LTP that requires spatial proximity of the associated synaptic inputs.

Persistent inhibition of hippocampal long-term potentiation in vivo by learned helplessness stress.

PubMed

Ryan, Benedict K; Vollmayr, Barbara; Klyubin, Igor; Gass, Peter; Rowan, Michael J

2010-06-01

The persistent cognitive disruptive effects of stress have been strongly implicated in the pathophysiology of depression and post-traumatic stress disorder. Here we examined factors influencing the time course of recovery from the inhibitory effect of acute inescapable stressors on the ability to induce long-term potentiation (LTP) in the dorsal hippocampus in vivo. We tested different forms of LTP, different stressors and different inbred strains of rats. Acute elevated platform stress completely, but transiently (<3 h), inhibited induction of both NMDA receptor-dependent LTP induced by a standard high frequency (200 Hz) conditioning stimulus and an additional LTP that required voltage-dependent Ca(2+) channel activation triggered by strong (400 Hz) conditioning stimulation. In contrast, acute inescapable footshock stress, used to study learned helplessness, inhibited LTP for at least 4 weeks. Contrary to expectations, there was no clear relationship between the ability of the footshock to trigger helpless behavior, a model of stress-induced depression, and the magnitude of LTP inhibition. Moreover, LTP did not appear to be affected by genetic susceptibility to learned helplessness, a model of genetic vulnerability to depression. This long-lasting synaptic plasticity disruption may underlie persistent impairment of hippocampus-dependent cognition by excessive acute inescapable stress.

The Regulation of Transcription in Memory Consolidation

PubMed Central

Alberini, Cristina M.; Kandel, Eric R.

2015-01-01

De novo transcription of DNA is a fundamental requirement for the formation of long-term memory. It is required during both consolidation and reconsolidation, the posttraining and postreactivation phases that change the state of the memory from a fragile into a stable and long-lasting form. Transcription generates both mRNAs that are translated into proteins, which are necessary for the growth of new synaptic connections, as well as noncoding RNA transcripts that have regulatory or effector roles in gene expression. The result is a cascade of events that ultimately leads to structural changes in the neurons that mediate long-term memory storage. The de novo transcription, critical for synaptic plasticity and memory formation, is orchestrated by chromatin and epigenetic modifications. The complexity of transcription regulation, its temporal progression, and the effectors produced all contribute to the flexibility and persistence of long-term memory formation. In this article, we provide an overview of the mechanisms contributing to this transcriptional regulation underlying long-term memory formation. PMID:25475090

Short-term synaptic plasticity and heterogeneity in neural systems

NASA Astrophysics Data System (ADS)

Mejias, J. F.; Kappen, H. J.; Longtin, A.; Torres, J. J.

2013-01-01

We review some recent results on neural dynamics and information processing which arise when considering several biophysical factors of interest, in particular, short-term synaptic plasticity and neural heterogeneity. The inclusion of short-term synaptic plasticity leads to enhanced long-term memory capacities, a higher robustness of memory to noise, and irregularity in the duration of the so-called up cortical states. On the other hand, considering some level of neural heterogeneity in neuron models allows neural systems to optimize information transmission in rate coding and temporal coding, two strategies commonly used by neurons to codify information in many brain areas. In all these studies, analytical approximations can be made to explain the underlying dynamics of these neural systems.

Alpha-Synuclein Produces Early Behavioral Alterations via Striatal Cholinergic Synaptic Dysfunction by Interacting With GluN2D N-Methyl-D-Aspartate Receptor Subunit.

PubMed

Tozzi, Alessandro; de Iure, Antonio; Bagetta, Vincenza; Tantucci, Michela; Durante, Valentina; Quiroga-Varela, Ana; Costa, Cinzia; Di Filippo, Massimiliano; Ghiglieri, Veronica; Latagliata, Emanuele Claudio; Wegrzynowicz, Michal; Decressac, Mickael; Giampà, Carmela; Dalley, Jeffrey W; Xia, Jing; Gardoni, Fabrizio; Mellone, Manuela; El-Agnaf, Omar Mukhtar; Ardah, Mustafa Taleb; Puglisi-Allegra, Stefano; Björklund, Anders; Spillantini, Maria Grazia; Picconi, Barbara; Calabresi, Paolo

2016-03-01

Advanced Parkinson's disease (PD) is characterized by massive degeneration of nigral dopaminergic neurons, dramatic motor and cognitive alterations, and presence of nigral Lewy bodies, whose main constituent is α-synuclein (α-syn). However, the synaptic mechanisms underlying behavioral and motor effects induced by early selective overexpression of nigral α-syn are still a matter of debate. We performed behavioral, molecular, and immunohistochemical analyses in two transgenic models of PD, mice transgenic for truncated human α-synuclein 1-120 and rats injected with the adeno-associated viral vector carrying wild-type human α-synuclein. We also investigated striatal synaptic plasticity by electrophysiological recordings from spiny projection neurons and cholinergic interneurons. We found that overexpression of truncated or wild-type human α-syn causes partial reduction of striatal dopamine levels and selectively blocks the induction of long-term potentiation in striatal cholinergic interneurons, producing early memory and motor alterations. These effects were dependent on α-syn modulation of the GluN2D-expressing N-methyl-D-aspartate receptors in cholinergic interneurons. Acute in vitro application of human α-syn oligomers mimicked the synaptic effects observed ex vivo in PD models. We suggest that striatal cholinergic dysfunction, induced by a direct interaction between α-syn and GluN2D-expressing N-methyl-D-aspartate receptors, represents a precocious biological marker of the disease. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Neuroprotective Effects of Ferruginol, Jatrophone, and Junicedric Acid Against Amyloid-β Injury in Hippocampal Neurons.

PubMed

Zolezzi, Juan M; Lindsay, Carolina B; Serrano, Felipe G; Ureta, Roxana C; Theoduloz, Cristina; Schmeda-Hirschmann, Guillermo; Inestrosa, Nibaldo C

2018-01-01

Soluble amyloid-β (Aβ) oligomers have been recognized as early neurotoxic intermediates with a key role in the synaptic dysfunction observed in Alzheimer's disease (AD). Aβ oligomers block hippocampal long-term potentiation (LTP) and impair rodent spatial memory. Additionally, the presence of Aβ oligomers is associated with imbalanced intracellular calcium levels and apoptosis in neurons. In this context, we evaluated the effects of three diterpenes (ferruginol, jatrophone, and junicedric acid) that are found in medicinal plants and have several forms of biological activity. The intracellular calcium levels in hippocampal neurons increased in the presence of ferruginol, jatrophone, and junicedric acid, a result that was consistent with the observed increase in CA1 synaptic transmission in mouse hippocampal slices. Additionally, assays using Aβ peptide demonstrated that diterpenes, particularly ferruginol, restore LTP and reduce apoptosis. Recovery of the Aβ oligomer-induced loss of the synaptic proteins PSD-95, synapsin, VGlut, and NMDA receptor subunit 2A was observed in mouse hippocampal slices treated with junicedric acid. This cascade of events may be associated with the regulation of kinases, e.g., protein kinase C (PKC) and calcium/calmodulin-dependent protein kinase II (CaMKII), in addition to the activation of the canonical Wnt signaling pathway and could thus provide protection against Aβ oligomers, which trigger synaptic dysfunction. Our results suggest a potential neuroprotective role for diterpenes against the Aβ oligomers-induced neurodegenerative alterations, which make them interesting molecules to be further studied in the context of AD.

Imbalanced pattern completion vs. separation in cognitive disease: network simulations of synaptic pathologies predict a personalized therapeutics strategy.

PubMed

Hanson, Jesse E; Madison, Daniel V

2010-08-13

Diverse Mouse genetic models of neurodevelopmental, neuropsychiatric, and neurodegenerative causes of impaired cognition exhibit at least four convergent points of synaptic malfunction: 1) Strength of long-term potentiation (LTP), 2) Strength of long-term depression (LTD), 3) Relative inhibition levels (Inhibition), and 4) Excitatory connectivity levels (Connectivity). To test the hypothesis that pathological increases or decreases in these synaptic properties could underlie imbalances at the level of basic neural network function, we explored each type of malfunction in a simulation of autoassociative memory. These network simulations revealed that one impact of impairments or excesses in each of these synaptic properties is to shift the trade-off between pattern separation and pattern completion performance during memory storage and recall. Each type of synaptic pathology either pushed the network balance towards intolerable error in pattern separation or intolerable error in pattern completion. Imbalances caused by pathological impairments or excesses in LTP, LTD, inhibition, or connectivity, could all be exacerbated, or rescued, by the simultaneous modulation of any of the other three synaptic properties. Because appropriate modulation of any of the synaptic properties could help re-balance network function, regardless of the origins of the imbalance, we propose a new strategy of personalized cognitive therapeutics guided by assay of pattern completion vs. pattern separation function. Simulated examples and testable predictions of this theorized approach to cognitive therapeutics are presented.

D-Serine rescues the deficits of hippocampal long-term potentiation and learning and memory induced by sodium fluoroacetate.

PubMed

Han, Huili; Peng, Yan; Dong, Zhifang

2015-06-01

It is well known that bidirectional glia-neuron interactions play important roles in the neurophysiological and neuropathological processes. It is reported that impairing glial functions with sodium fluoroacetate (FAC) impaired hippocampal long-term depression (LTD) and spatial memory retrieval. However, it remains unknown whether FAC impairs hippocampal long-term potentiation (LTP) and learning and/or memory, and if so, whether pharmacological treatment with exogenous d-serine can recuse the impairment. Here, we reported that systemic administration of FAC (3mg/kg, i.p.) before training resulted in dramatic impairments of spatial learning and memory in water maze and fear memory in contextual fear conditioning. Furthermore, the behavioral deficits were accompanied by impaired LTP induction in the hippocampal CA1 area of brain slices. More importantly, exogenous d-serine treatment succeeded in recusing the deficits of hippocampal LTP and learning and memory induced by FAC. Together, these results suggest that astrocytic d-serine may be essential for hippocampal synaptic plasticity and memory, and that alteration of its levels may be relevant to the induction and potentially treatment of psychiatric and neurological disorders. Copyright © 2015 Elsevier Inc. All rights reserved.

The amygdala excitatory/inhibitory balance in a valproate-induced rat autism model.

PubMed

Lin, Hui-Ching; Gean, Po-Wu; Wang, Chao-Chuan; Chan, Yun-Han; Chen, Po See

2013-01-01

The amygdala is an important structure contributing to socio-emotional behavior. However, the role of the amygdala in autism remains inconclusive. In this study, we used the 28-35 days valproate (VPA)-induced rat model of autism to observe the autistic phenotypes and evaluate their synaptic characteristics in the lateral nucleus (LA) of the amygdala. The VPA-treated offspring demonstrated less social interaction, increased anxiety, enhanced fear learning and impaired fear memory extinction. Slice preparation and electrophysiological recordings of the amygdala showed significantly enhanced long-term potentiation (LTP) while stimulating the thalamic-amygdala pathway of the LA. In addition, the pair pulse facilitation (PPF) at 30- and 60-ms intervals decreased significantly. Whole-cell recordings of the LA pyramidal neurons showed an increased miniature excitatory postsynaptic current (EPSC) frequency and amplitude. The relative contributions of the AMPA receptor and NMDA receptor to the EPSCs did not differ significantly between groups. These results suggested that the enhancement of the presynaptic efficiency of excitatory synaptic transmission might be associated with hyperexcitibility and enhanced LTP in LA pyramidal neurons. Disruption of the synaptic excitatory/inhibitory (E/I) balance in the LA of VPA-treated rats might play certain roles in the development of behaviors in the rat that may be relevant to autism. Further experiments to demonstrate the direct link are warranted.

Early Growth Response 1 (Egr-1) Regulates N-Methyl-d-aspartate Receptor (NMDAR)-dependent Transcription of PSD-95 and α-Amino-3-hydroxy-5-methyl-4-isoxazole Propionic Acid Receptor (AMPAR) Trafficking in Hippocampal Primary Neurons*

PubMed Central

Qin, Xike; Jiang, Yongjun; Tse, Yiu Chung; Wang, Yunling; Wong, Tak Pan; Paudel, Hemant K.

2015-01-01

The N-methyl-d-aspartate receptor (NMDAR) controls synaptic plasticity and memory function and is one of the major inducers of transcription factor Egr-1 in the hippocampus. However, how Egr-1 mediates the NMDAR signal in neurons has remained unclear. Here, we show that the hippocampus of mice lacking Egr-1 displays electrophysiology properties and ultrastructure that are similar to mice overexpressing PSD-95, a major scaffolding protein of postsynaptic density involved in synapse formation, synaptic plasticity, and synaptic targeting of AMPA receptors (AMPARs), which mediate the vast majority of excitatory transmission in the CNS. We demonstrate that Egr-1 is a transcription repressor of the PSD-95 gene and is recruited to the PSD-95 promoter in response to NMDAR activation. Knockdown of Egr-1 in rat hippocampal primary neurons blocks NMDAR-induced PSD-95 down-regulation and AMPAR endocytosis. Likewise, overexpression of Egr-1 in rat hippocampal primary neurons causes reduction in PSD-95 protein level and promotes AMPAR endocytosis. Our data indicate that Egr-1 is involved in NMDAR-mediated PSD-95 down-regulation and AMPAR endocytosis, a process important in the expression of long term depression. PMID:26475861

Interplay of multiple synaptic plasticity features in filamentary memristive devices for neuromorphic computing

NASA Astrophysics Data System (ADS)

La Barbera, Selina; Vincent, Adrien F.; Vuillaume, Dominique; Querlioz, Damien; Alibart, Fabien

2016-12-01

Bio-inspired computing represents today a major challenge at different levels ranging from material science for the design of innovative devices and circuits to computer science for the understanding of the key features required for processing of natural data. In this paper, we propose a detail analysis of resistive switching dynamics in electrochemical metallization cells for synaptic plasticity implementation. We show how filament stability associated to joule effect during switching can be used to emulate key synaptic features such as short term to long term plasticity transition and spike timing dependent plasticity. Furthermore, an interplay between these different synaptic features is demonstrated for object motion detection in a spike-based neuromorphic circuit. System level simulation presents robust learning and promising synaptic operation paving the way to complex bio-inspired computing systems composed of innovative memory devices.

Dendritic Spine Instability in a Mouse Model of CDKL5 Disorder Is Rescued by Insulin-like Growth Factor 1.

PubMed

Della Sala, Grazia; Putignano, Elena; Chelini, Gabriele; Melani, Riccardo; Calcagno, Eleonora; Michele Ratto, Gian; Amendola, Elena; Gross, Cornelius T; Giustetto, Maurizio; Pizzorusso, Tommaso

2016-08-15

CDKL5 (cyclin-dependent kinase-like 5) is mutated in many severe neurodevelopmental disorders, including atypical Rett syndrome. CDKL5 was shown to interact with synaptic proteins, but an in vivo analysis of the role of CDKL5 in dendritic spine dynamics and synaptic molecular organization is still lacking. In vivo two-photon microscopy of the somatosensory cortex of Cdkl5(-/y) mice was applied to monitor structural dynamics of dendritic spines. Synaptic function and plasticity were measured using electrophysiological recordings of excitatory postsynaptic currents and long-term potentiation in brain slices and assessing the expression of synaptic postsynaptic density protein 95 (PSD-95). Finally, we studied the impact of insulin-like growth factor 1 (IGF-1) treatment on CDKL5 null mice to restore the synaptic deficits. Adult mutant mice showed a significant reduction in spine density and PSD-95-positive synaptic puncta, a reduction of persistent spines, and impaired long-term potentiation. In juvenile mutants, short-term spine elimination, but not formation, was dramatically increased. Exogenous administration of IGF-1 rescued defective rpS6 phosphorylation, spine density, and PSD-95 expression. Endogenous cortical IGF-1 levels were unaffected by CDKL5 deletion. These data demonstrate that dendritic spine stabilization is strongly regulated by CDKL5. Moreover, our data suggest that IGF-1 treatment could be a promising candidate for clinical trials in CDKL5 patients. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Alleviation of N-Methyl-D-Aspartate Receptor-Dependent Long-Term Depression via Regulation of the Glycogen Synthase Kinase-3β Pathway in the Amygdala of a Valproic Acid-Induced Animal Model of Autism.

PubMed

Wu, Han-Fang; Chen, Po See; Chen, Yi-Ju; Lee, Chi-Wei; Chen, I-Tuan; Lin, Hui-Ching

2017-09-01

The amygdala plays crucial roles in socio-emotional behavior and cognition, both of which are abnormal in autism spectrum disorder (ASD). Valproic acid (VPA)-exposed rat offspring have demonstrated ASD phenotypes and amygdala excitatory/inhibitory imbalance. However, the role of glutamatergic synapses in this imbalance remains unclear. In this study, we used a VPA-induced ASD-like model to assess glutamatergic synapse-dependent long-term depression (LTD) and depotentiation (DPT) in the amygdala. We first confirmed that the VPA-exposed offspring exhibited sociability deficits, anxiety, depression-like behavior, and abnormal nociception thresholds. Then, electrophysiological examination showed a significantly decreased paired-pulse ratio in the amygdala. In addition, both NMDA-dependent LTD and DPT were absent from the amygdala. Furthermore, we found that the levels of glycogen synthase kinase3β (GSK-3β) phosphorylation and β-catenin were significantly higher in the amygdala of the experimental animals than in the controls. Local infusion of phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin into the amygdala reversed the increased phosphorylation level and impaired social behavior. Taken together, the results suggested that NMDA receptor-related synaptic plasticity is dysfunctional in VPA-exposed offspring. In addition, GSK-3β in the amygdala is critical for synaptic plasticity at the glutamatergic synapses and is related to social behavior. Its role in the underlying mechanism of ASD merits further investigation.

Single-neuron labeling with inducible cre-mediated knockout in transgenic mice

PubMed Central

Young, Paul; Qiu, Li; Wang, Dongqing; Zhao, Shengli; Gross, James; Feng, Guoping

2011-01-01

To facilitate functional analysis of neuronal connectivity in a mammalian nervous system tightly packed with billions of cells, we developed a new technique that allows inducible genetic manipulations within fluorescently labeled single neurons in mice. We term this technique SLICK for Single-neuron Labeling with Inducible Cre-mediated Knockout. SLICK is achieved by co-expressing a drug-inducible form of cre recombinase and a fluorescent protein within the same small subsets of neurons. Thus, SLICK combines the powerful cre recombinase system for conditional genetic manipulation and the fluorescent labeling of single neurons for imaging. We demonstrate efficient inducible genetic manipulation in several types of neurons using SLICK. Furthermore, we apply SLICK to eliminate synaptic transmission in a small subset of neuromuscular junctions. Our results provide evidence for the long-term stability of inactive neuromuscular synapses in adult animals. More broadly, these studies demonstrate a cre-LoxP compatible system for dissecting gene functions in single identifiable neurons. PMID:18454144

Neuronal nicotinic acetylcholine receptors: neuroplastic changes underlying alcohol and nicotine addictions

PubMed Central

Feduccia, Allison A.; Chatterjee, Susmita; Bartlett, Selena E.

2012-01-01

Addictive drugs can activate systems involved in normal reward-related learning, creating long-lasting memories of the drug's reinforcing effects and the environmental cues surrounding the experience. These memories significantly contribute to the maintenance of compulsive drug use as well as cue-induced relapse which can occur even after long periods of abstinence. Synaptic plasticity is thought to be a prominent molecular mechanism underlying drug-induced learning and memories. Ethanol and nicotine are both widely abused drugs that share a common molecular target in the brain, the neuronal nicotinic acetylcholine receptors (nAChRs). The nAChRs are ligand-gated ion channels that are vastly distributed throughout the brain and play a key role in synaptic neurotransmission. In this review, we will delineate the role of nAChRs in the development of ethanol and nicotine addiction. We will characterize both ethanol and nicotine's effects on nAChR-mediated synaptic transmission and plasticity in several key brain areas that are important for addiction. Finally, we will discuss some of the behavioral outcomes of drug-induced synaptic plasticity in animal models. An understanding of the molecular and cellular changes that occur following administration of ethanol and nicotine will lead to better therapeutic strategies. PMID:22876217

Disrupting astrocyte-neuron lactate transfer persistently reduces conditioned responses to cocaine.

PubMed

Boury-Jamot, B; Carrard, A; Martin, J L; Halfon, O; Magistretti, P J; Boutrel, B

2016-08-01

A central problem in the treatment of drug addiction is the high risk of relapse often precipitated by drug-associated cues. The transfer of glycogen-derived lactate from astrocytes to neurons is required for long-term memory. Whereas blockade of drug memory reconsolidation represents a potential therapeutic strategy, the role of astrocyte-neuron lactate transport in long-term conditioning has received little attention. By infusing an inhibitor of glycogen phosphorylase into the basolateral amygdala of rats, we report that disruption of astrocyte-derived lactate not only transiently impaired the acquisition of a cocaine-induced conditioned place preference but also persistently disrupted an established conditioning. The drug memory was rescued by L-Lactate co-administration through a mechanism requiring the synaptic plasticity-related transcription factor Zif268 and extracellular signal-regulated kinase (ERK) signalling pathway but not the brain-derived neurotrophic factor (Bdnf). The long-term amnesia induced by glycogenolysis inhibition and the concomitant decreased expression of phospho-ERK were both restored with L-Lactate co-administration. These findings reveal a critical role for astrocyte-derived lactate in positive memory formation and highlight a novel amygdala-dependent reconsolidation process, whose disruption may offer a novel therapeutic target to reduce the long-lasting conditioned responses to cocaine.

A Transcription Factor-Binding Domain of the Coactivator CBP Is Essential for Long-Term Memory and the Expression of Specific Target Genes

ERIC Educational Resources Information Center

Oliveira, Ana M. M.; Brindle, Paul K.; Abel, Ted; Wood, Marcelo A.; Attner, Michelle A.

2006-01-01

Transcriptional activation is a key process required for long-term memory formation. Recently, the transcriptional coactivator CREB-binding protein (CBP) was shown to be critical for hippocampus-dependent long-term memory and hippocampal synaptic plasticity. As a coactivator with intrinsic histone acetyltransferase activity, CBP interacts with…

Epigenetic mechanisms: critical contributors to long-term memory formation.

PubMed

Lubin, Farah D; Gupta, Swati; Parrish, R Ryley; Grissom, Nicola M; Davis, Robin L

2011-12-01

Recent advances in chromatin biology have identified a role for epigenetic mechanisms in the regulation of neuronal gene expression changes, a necessary process for proper synaptic plasticity and memory formation. Experimental evidence for dynamic chromatin remodeling influencing gene transcription in postmitotic neurons grew from initial reports describing posttranslational modifications of histones, including phosphorylation and acetylation occurring in various brain regions during memory consolidation. An accumulation of recent studies, however, has also highlighted the importance of other epigenetic modifications, such as DNA methylation and histone methylation, as playing a role in memory formation. This present review examines learning-induced gene transcription by chromatin remodeling underlying long-lasting changes in neurons, with direct implications for the study of epigenetic mechanisms in long-term memory formation and behavior. Furthermore, the study of epigenetic gene regulation, in conjunction with transcription factor activation, can provide complementary lines of evidence to further understanding transcriptional mechanisms subserving memory storage.

Nicotine Significantly Improves Chronic Stress-Induced Impairments of Cognition and Synaptic Plasticity in Mice.

PubMed

Shang, Xueliang; Shang, Yingchun; Fu, Jingxuan; Zhang, Tao

2017-08-01

The aim of this study was to examine if nicotine was able to improve cognition deficits in a mouse model of chronic mild stress. Twenty-four male C57BL/6 mice were divided into three groups: control, stress, and stress with nicotine treatment. The animal model was established by combining chronic unpredictable mild stress (CUMS) and isolated feeding. Mice were exposed to CUMS continued for 28 days, while nicotine (0.2 mg/kg) was also administrated for 28 days. Weight and sucrose consumption were measured during model establishing period. The anxiety and behavioral despair were analyzed using the forced swim test (FST) and open-field test (OFT). Spatial cognition was evaluated using Morris water maze (MWM) test. Following behavioral assessment, both long-term potentiation (LTP) and depotentiation (DEP) were recorded in the hippocampal dentate gyrus (DG) region. Both synaptic and Notch1 proteins were measured by Western. Nicotine increased stressed mouse's sucrose consumption. The MWM test showed that spatial learning and reversal learning in stressed animals were remarkably affected relative to controls, whereas nicotine partially rescued cognitive functions. Additionally, nicotine considerably alleviated the level of anxiety and the degree of behavioral despair in stressed mice. It effectively mitigated the depression-induced impairment of hippocampal synaptic plasticity, in which both the LTP and DEP were significantly inhibited in stressed mice. Moreover, nicotine enhanced the expression of synaptic and Notch1 proteins in stressed animals. The results suggest that nicotine ameliorates the depression-like symptoms and improves the hippocampal synaptic plasticity closely associated with activating transmembrane ion channel receptors and Notch signaling components. Graphical Abstract ᅟ.

Autism-linked neuroligin-3 R451C mutation differentially alters hippocampal and cortical synaptic function.

PubMed

Etherton, Mark; Földy, Csaba; Sharma, Manu; Tabuchi, Katsuhiko; Liu, Xinran; Shamloo, Mehrdad; Malenka, Robert C; Südhof, Thomas C

2011-08-16

Multiple independent mutations in neuroligin genes were identified in patients with familial autism, including the R451C substitution in neuroligin-3 (NL3). Previous studies showed that NL3(R451C) knock-in mice exhibited modestly impaired social behaviors, enhanced water maze learning abilities, and increased synaptic inhibition in the somatosensory cortex, and they suggested that the behavioral changes in these mice may be caused by a general shift of synaptic transmission to inhibition. Here, we confirm that NL3(R451C) mutant mice behaviorally exhibit social interaction deficits and electrophysiologically display increased synaptic inhibition in the somatosensory cortex. Unexpectedly, however, we find that the NL3(R451C) mutation produced a strikingly different phenotype in the hippocampus. Specifically, in the hippocampal CA1 region, the NL3(R451C) mutation caused an ∼1.5-fold increase in AMPA receptor-mediated excitatory synaptic transmission, dramatically altered the kinetics of NMDA receptor-mediated synaptic responses, induced an approximately twofold up-regulation of NMDA receptors containing NR2B subunits, and enhanced long-term potentiation almost twofold. NL3 KO mice did not exhibit any of these changes. Quantitative light microscopy and EM revealed that the NL3(R451C) mutation increased dendritic branching and altered the structure of synapses in the stratum radiatum of the hippocampus. Thus, in NL3(R451C) mutant mice, a single point mutation in a synaptic cell adhesion molecule causes context-dependent changes in synaptic transmission; these changes are consistent with the broad impact of this mutation on murine and human behaviors, suggesting that NL3 controls excitatory and inhibitory synapse properties in a region- and circuit-specific manner.

Early-life seizures alter synaptic calcium-permeable AMPA receptor function and plasticity

PubMed Central

Lippman-Bell, Jocelyn J.; Zhou, Chengwen; Sun, Hongyu; Feske, Joel S.; Jensen, Frances E.

2016-01-01

Calcium (Ca2+)-mediated1 signaling pathways are critical to synaptic plasticity. In adults, the NMDA glutamate receptor (NMDAR) represents a major route for activity-dependent synaptic Ca2+ entry. However, during neonatal development, when synaptic plasticity is high, many AMPA glutamate receptors (AMPARs) are also permeable to Ca2+ (CP-AMPAR) due to low GluA2 subunit expression, providing an additional route for activity- and glutamate-dependent Ca2+ influx and subsequent signaling. Therefore, altered hippocampal Ca2+ signaling may represent an age-specific pathogenic mechanism. We thus aimed to assess Ca2+ responses 48 hours after hypoxia-induced neonatal seizures (HS) in postnatal day (P)10 rats, a post-seizure time point at which we previously reported LTP attenuation. We found that Ca2+ responses were higher in brain slices from post-HS rats than in controls and this increase was CP-AMPAR-dependent. To determine whether synaptic CP-AMPAR expression was also altered post-HS, we assessed the expression of GluA2 at hippocampal synapses and the expression of long-term depression (LTD), which has been linked to the presence of synaptic GluA2. Here we report a decrease 48 hours after HS in synaptic GluA2 expression at synapses and LTD in hippocampal CA1. Given the potentially critical role of AMPAR trafficking in disease progression, we aimed to establish whether post-seizure in vivo AMPAR antagonist treatment prevented the enhanced Ca2+ responses, changes in GluA2 synaptic expression, and diminished LTD. We found that NBQX treatment prevents all three of these post-seizure consequences, further supporting a critical role for AMPARs as an age-specific therapeutic target. PMID:27521497

Long-Term Homeostatic Properties Complementary to Hebbian Rules in CuPc-Based Multifunctional Memristor

NASA Astrophysics Data System (ADS)

Wang, Laiyuan; Wang, Zhiyong; Lin, Jinyi; Yang, Jie; Xie, Linghai; Yi, Mingdong; Li, Wen; Ling, Haifeng; Ou, Changjin; Huang, Wei

2016-10-01

Most simulations of neuroplasticity in memristors, which are potentially used to develop artificial synapses, are confined to the basic biological Hebbian rules. However, the simplex rules potentially can induce excessive excitation/inhibition, even collapse of neural activities, because they neglect the properties of long-term homeostasis involved in the frameworks of realistic neural networks. Here, we develop organic CuPc-based memristors of which excitatory and inhibitory conductivities can implement both Hebbian rules and homeostatic plasticity, complementary to Hebbian patterns and conductive to the long-term homeostasis. In another adaptive situation for homeostasis, in thicker samples, the overall excitement under periodic moderate stimuli tends to decrease and be recovered under intense inputs. Interestingly, the prototypes can be equipped with bio-inspired habituation and sensitization functions outperforming the conventional simplified algorithms. They mutually regulate each other to obtain the homeostasis. Therefore, we develop a novel versatile memristor with advanced synaptic homeostasis for comprehensive neural functions.

A VLSI recurrent network of integrate-and-fire neurons connected by plastic synapses with long-term memory.

PubMed

Chicca, E; Badoni, D; Dante, V; D'Andreagiovanni, M; Salina, G; Carota, L; Fusi, S; Del Giudice, P

2003-01-01

Electronic neuromorphic devices with on-chip, on-line learning should be able to modify quickly the synaptic couplings to acquire information about new patterns to be stored (synaptic plasticity) and, at the same time, preserve this information on very long time scales (synaptic stability). Here, we illustrate the electronic implementation of a simple solution to this stability-plasticity problem, recently proposed and studied in various contexts. It is based on the observation that reducing the analog depth of the synapses to the extreme (bistable synapses) does not necessarily disrupt the performance of the device as an associative memory, provided that 1) the number of neurons is large enough; 2) the transitions between stable synaptic states are stochastic; and 3) learning is slow. The drastic reduction of the analog depth of the synaptic variable also makes this solution appealing from the point of view of electronic implementation and offers a simple methodological alternative to the technological solution based on floating gates. We describe the full custom analog very large-scale integration (VLSI) realization of a small network of integrate-and-fire neurons connected by bistable deterministic plastic synapses which can implement the idea of stochastic learning. In the absence of stimuli, the memory is preserved indefinitely. During the stimulation the synapse undergoes quick temporary changes through the activities of the pre- and postsynaptic neurons; those changes stochastically result in a long-term modification of the synaptic efficacy. The intentionally disordered pattern of connectivity allows the system to generate a randomness suited to drive the stochastic selection mechanism. We check by a suitable stimulation protocol that the stochastic synaptic plasticity produces the expected pattern of potentiation and depression in the electronic network.

Restoring synaptic plasticity and memory in mouse models of Alzheimer's disease by PKR inhibition.

PubMed

Hwang, Kyoung-Doo; Bak, Myeong Seong; Kim, Sang Jeong; Rhee, Sangmyung; Lee, Yong-Seok

2017-12-13

Alzheimer's disease (AD) is a neurodegenerative disorder associated with deficits in cognition and synaptic plasticity. While accumulation of amyloid β (Aβ) and hyper-phosphorylation of tau are parts of the etiology, AD can be caused by a large number of different genetic mutations and other unknown factors. Considering such a heterogeneous nature of AD, it would be desirable to develop treatment strategies that can improve memory irrespective of the individual causes. Reducing the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) was shown to enhance long-term memory and synaptic plasticity in naïve mice. Moreover, hyper-phosphorylation of eIF2α is observed in the brains of postmortem AD patients. Therefore, regulating eIF2α phosphorylation can be a plausible candidate for restoring memory in AD by targeting memory-enhancing mechanism. In this study, we examined whether PKR inhibition can rescue synaptic and learning deficits in two different AD mouse models; 5XFAD transgenic and Aβ 1-42 -injected mice. We found that the acute treatment of PKR inhibitor (PKRi) can restore the deficits in long-term memory and long-term potentiation (LTP) in both mouse models without affecting the Aβ load in the hippocampus. Our results prove the principle that targeting memory enhancing mechanisms can be a valid candidate for developing AD treatment.

Long Term Synaptic Plasticity and Learning in Neuronal Networks

DTIC Science & Technology

1989-01-14

Videomicroscopy and synaptic physiology of cultured hippocampal slices. Soc, Neurosci. Abstr. 14:246, 1988. Griffith, W.H., Brown, T.H. and Johnston, D...Chapman, P.F., Chang, V., and Brown, T.H. . Videomicroscopy of acute brain slices from hippocampus and amygdala. Brain Res. Bull, 21: 373-383, 1988

ß-Adrenergic Receptor Signaling and Modulation of Long-Term Potentiation in the Mammalian Hippocampus

ERIC Educational Resources Information Center

O'Dell, Thomas J.; Connor, Steven A.; Guglietta, Ryan; Nguyen, Peter V.

2015-01-01

Encoding new information in the brain requires changes in synaptic strength. Neuromodulatory transmitters can facilitate synaptic plasticity by modifying the actions and expression of specific signaling cascades, transmitter receptors and their associated signaling complexes, genes, and effector proteins. One critical neuromodulator in the…

Impairment in long-term memory formation and learning-dependent synaptic plasticity in mice lacking glycogen synthase in the brain

PubMed Central

Duran, Jordi; Saez, Isabel; Gruart, Agnès; Guinovart, Joan J; Delgado-García, José M

2013-01-01

Glycogen is the only carbohydrate reserve of the brain, but its overall contribution to brain functions remains unclear. Although it has traditionally been considered as an emergency energetic reservoir, increasing evidence points to a role of glycogen in the normal activity of the brain. To address this long-standing question, we generated a brain-specific Glycogen Synthase knockout (GYS1Nestin-KO) mouse and studied the functional consequences of the lack of glycogen in the brain under alert behaving conditions. These animals showed a significant deficiency in the acquisition of an associative learning task and in the concomitant activity-dependent changes in hippocampal synaptic strength. Long-term potentiation (LTP) evoked in the hippocampal CA3-CA1 synapse was also decreased in behaving GYS1Nestin-KO mice. These results unequivocally show a key role of brain glycogen in the proper acquisition of new motor and cognitive abilities and in the underlying changes in synaptic strength. PMID:23281428

Diversity in Long-Term Synaptic Plasticity at Inhibitory Synapses of Striatal Spiny Neurons

ERIC Educational Resources Information Center

Rueda-Orozco, Pavel E.; Mendoza, Ernesto; Hernandez, Ricardo; Aceves, Jose J.; Ibanez-Sandoval, Osvaldo; Galarraga, Elvira; Bargas, Jose

2009-01-01

Procedural memories and habits are posited to be stored in the basal ganglia, whose intrinsic circuitries possess important inhibitory connections arising from striatal spiny neurons. However, no information about long-term plasticity at these synapses is available. Therefore, this work describes a novel postsynaptically dependent long-term…

Protein Phosphatase 1-Dependent Transcriptional Programs for Long-Term Memory and Plasticity

ERIC Educational Resources Information Center

Graff, Johannes; Koshibu, Kyoko; Jouvenceau, Anne; Dutar, Patrick; Mansuy, Isabelle M.

2010-01-01

Gene transcription is essential for the establishment and the maintenance of long-term memory (LTM) and for long-lasting forms of synaptic plasticity. The molecular mechanisms that control gene transcription in neuronal cells are complex and recruit multiple signaling pathways in the cytoplasm and the nucleus. Protein kinases (PKs) and…

Altered Gene Regulation and Synaptic Morphology in "Drosophila" Learning and Memory Mutants

ERIC Educational Resources Information Center

Guan, Zhuo; Buhl, Lauren K.; Quinn, William G.; Littleton, J. Troy

2011-01-01

Genetic studies in "Drosophila" have revealed two separable long-term memory pathways defined as anesthesia-resistant memory (ARM) and long-lasting long-term memory (LLTM). ARM is disrupted in "radish" ("rsh") mutants, whereas LLTM requires CREB-dependent protein synthesis. Although the downstream effectors of ARM and LLTM are distinct, pathways…

Parental origin impairment of synaptic functions and behaviors in cytoplasmic FMRP interacting protein 1 (Cyfip1) deficient mice.

PubMed

Chung, Leeyup; Wang, Xiaoming; Zhu, Li; Towers, Aaron J; Cao, Xinyu; Kim, Il Hwan; Jiang, Yong-hui

2015-12-10

CYFIP1 maps to the interval between proximal breakpoint 1 (BP1) and breakpoint 2 (BP2) of chromosomal 15q11-q13 deletions that are implicated in the Angelman (AS) and Prader-Willi syndrome (PWS). There is only one breakpoint (BP3) at the distal end of deletion. CYFIP1 is deleted in AS patients with the larger class I deletion (BP1 to BP3) and the neurological presentations in these patients are more severe than that of patients with class II (BP2 to BP3) deletion. The haploinsufficiency of CYFIP1 is hypothesized to contribute to more severe clinical presentations in class I AS patients. The expression of CYFIP1 is suggested to be bi-allelic in literature but the possibility of parental origin of expression is not completely excluded. We generated and characterized Cyfip1 mutant mice. Homozygous Cyfip1 mice were early embryonic lethal. However, there was a parental origin specific effect between paternal Cyfip1 deficiency (m+/p-) and maternal deficiency (m-/p+) on both synaptic transmissions and behaviors in hippocampal CA1 synapses despite no evidence supporting the parental origin difference for the expression. Both m-/p+ and m+/p- showed the impaired input-output response and paired-pulse facilitation. While the long term-potentiation and group I mGluR mediated long term depression induced by DHPG was not different between Cyfip1 m-/p+ and m+/p- mice, the initial DHPG induced response was significantly enhanced in m-/p+ but not in m+/p- mice. m+/p- but not m-/p+ mice displayed increased freezing in cued fear conditioning and abnormal transitions in zero-maze test. The impaired synaptic transmission and behaviors in haploinsufficiency of Cyfip1 mice provide the evidence supporting the role of CYFIP1 modifying the clinical presentation of class I AS patients and in human neuropsychiatric disorders. Copyright © 2015 Elsevier B.V. All rights reserved.

Pharmacological Rescue of Long-Term Potentiation in Alzheimer Diseased Synapses

PubMed Central

Berchtold, Nicole C.; Lynch, Gary; Cotman, Carl W.

2017-01-01

Long-term potentiation (LTP) is an activity-dependent and persistent increase in synaptic transmission. Currently available techniques to measure LTP are time-intensive and require highly specialized expertise and equipment, and thus are not well suited for screening of multiple candidate treatments, even in animal models. To expand and facilitate the analysis of LTP, here we use a flow cytometry-based method to track chemically induced LTP by detecting surface AMPA receptors in isolated synaptosomes: fluorescence analysis of single-synapse long-term potentiation (FASS-LTP). First, we demonstrate that FASS-LTP is simple, sensitive, and models electrically induced LTP recorded in intact circuitries. Second, we conducted FASS-LTP analysis in two well-characterized Alzheimer's disease (AD) mouse models (3xTg and Tg2576) and, importantly, in cryopreserved human AD brain samples. By profiling hundreds of synaptosomes, our data provide the first direct evidence to support the idea that synapses from AD brain are intrinsically defective in LTP. Third, we used FASS-LTP for drug evaluation in human synaptosomes. Testing a panel of modulators of cAMP and cGMP signaling pathways, FASS-LTP identified vardenafil and Bay-73–6691 (phosphodiesterase-5 and -9 inhibitors, respectively) as potent enhancers of LTP in synaptosomes from AD cases. These results indicate that our approach could provide the basis for protocols to study LTP in both healthy and diseased human brains, a previously unattainable goal. SIGNIFICANCE STATEMENT Learning and memory depend on the ability of synapses to strengthen in response to activity. Long-term potentiation (LTP) is a rapid and persistent increase in synaptic transmission that is thought to be affected in Alzheimer's disease (AD). However, direct evidence of LTP deficits in human AD brain has been elusive, primarily due to methodological limitations. Here, we analyze LTP in isolated synapses from AD brain using a novel approach that allows testing LTP in cryopreserved brain. Our analysis of hundreds of synapses supports the idea that AD-diseased synapses are intrinsically defective in LTP. Further, we identified pharmacological agents that rescue LTP in AD, thus opening up a new avenue for drug screening and evaluation of strategies for alleviating memory impairments. PMID:27986924

Developmental shift from long-term depression to long-term potentiation in the rat medial vestibular nuclei: role of group I metabotropic glutamate receptors

PubMed Central

Puyal, Julien; Grassi, Silvarosa; Dieni, Cristina; Frondaroli, Adele; Demêmes, Danielle; Raymond, Jaqueline; Pettorossi, Vito Enrico

2003-01-01

The effects of high frequency stimulation (HFS) of the primary vestibular afferents on synaptic transmission in the ventral part of the medial vestibular nuclei (vMVN) were studied during postnatal development and compared with the changes in the expression of the group I metabotropic glutamate receptor (mGluR) subtypes, mGluR1 and mGluR5. During the first stages of development, HFS always induced a mGluR5- and GABAA-dependent long-term depression (LTD) which did not require NMDA receptor and mGluR1 activation. The probability of inducing LTD decreased progressively throughout the development and it was zero at about the end of the second postnatal week. Conversely, long-term potentiation (LTP) appeared at the beginning of the second week and its occurrence increased to reach the adult value at the end of the third week. Of interest, the sudden change in the LTP frequency occurred at the time of eye opening, about the end of the second postnatal week. LTP depended on NMDA receptor and mGluR1 activation. In parallel with the modifications in synaptic plasticity, we observed that the expression patterns and localizations of mGluR5 and mGluR1 in the medial vestibular nuclei (MVN) changed during postnatal development. At the earlier stages the mGluR1 expression was minimal, then increased progressively. In contrast, mGluR5 expression was initially high, then decreased. While mGluR1 was exclusively localized in neuronal compartments and concentrated at the postsynaptic sites at all stages observed, mGluR5 was found mainly in neuronal compartments at immature stages, then preferentially in glial compartments at mature stages. These results provide the first evidence for a progressive change from LTD to LTP accompanied by a distinct maturation expression of mGluR1 and mGluR5 during the development of the MVN. PMID:12972627

Long-term potentiation in the rat medial vestibular nuclei depends on locally synthesized 17beta-estradiol.

PubMed

Grassi, Silvarosa; Frondaroli, Adele; Dieni, Cristina; Scarduzio, Mariangela; Pettorossi, Vito E

2009-08-26

In male rat brainstem slices, we investigated the involvement of locally synthesized 17beta-estradiol (E(2)) in the induction in the medial vestibular nucleus (MVN) of long-term potentiation (LTP) by high-frequency stimulation (HFS) of the primary vestibular afferents. We demonstrated that the blockade of aromatase by letrozole or of E(2) receptors (ERalpha and ERbeta) by ICI 182,780 prevented the HFS-induced LTP of the N1 wave of the evoked field potential (FP) without affecting baseline responses. Only prolonged afferent activation could induce low LTP. In contrast, HFS applied under a combined blockade of GABA(A) receptors and aromatase or ERs was still able to induce LTP, but it was significantly lower and slower. These findings demonstrate that E(2) does not have a tonic influence on the activity of the MVN neurons and provide the first evidence of the crucial role played by local synthesis of E(2) in inducing LTP. We suggest that the synthesis of E(2) occurs after aromatase activation during HFS and facilitates the development of vestibular synaptic plasticity by influencing glutamate and GABA transmission.

Antiepileptic effects of levetiracetam in a rodent neonatal seizure model.

PubMed

Talos, Delia M; Chang, Meayoung; Kosaras, Bela; Fitzgerald, Erin; Murphy, Andrew; Folkerth, Rebecca Dunn; Jensen, Frances E

2013-01-01

Neonatal seizures can result in chronic epilepsy and long-term behavioral and cognitive deficits. Levetiracetam (LEV), an antiepileptic drug that binds to the synaptic vesicle protein 2A (SV2A), has been increasingly used off-label for the therapy of neonatal seizures. Preclinical data regarding the acute or long-term efficacy of LEV are lacking. We tested the anticonvulsant efficacy of LEV in a rat model of hypoxia-induced neonatal seizures. In addition, we evaluated the protective effects of postnatal day (P)10 LEV treatment on later-life kainic acid (KA)-induced seizure susceptibility and seizure-induced neuronal injury. Western blot and immunohistochemistry were used to assess the developmental regulation of SV2A in the rat and human brain. LEV pretreatment at P10 significantly decreased the cumulative duration of behavioral and electrographic seizures at both 25 and 50 mg/kg. At P40, KA-induced seizures and neuronal loss were significantly diminished in rats previously treated with LEV. LEV target SV2A is present in both neonatal rat and human brain and increases steadily to adulthood. LEV suppressed acute seizures induced by perinatal hypoxia and diminished later-life seizure susceptibility and seizure-induced neuronal injury, providing evidence for disease modification. These results support consideration of a clinical trial of LEV in neonatal seizures.

A Synaptic Basis for Memory Storage in the Cerebral Cortex

NASA Astrophysics Data System (ADS)

Bear, Mark F.

1996-11-01

A cardinal feature of neurons in the cerebral cortex is stimulus selectivity, and experience-dependent shifts in selectivity are a common correlate of memory formation. We have used a theoretical ``learning rule,'' devised to account for experience-dependent shifts in neuronal selectivity, to guide experiments on the elementary mechanisms of synaptic plasticity in hippocampus and neocortex. These experiments reveal that many synapses in hippocampus and neocortex are bidirectionally modifiable, that the modifications persist long enough to contribute to long-term memory storage, and that key variables governing the sign of synaptic plasticity are the amount of NMDA receptor activation and the recent history of cortical activity.

TLR4 response mediates ethanol-induced neurodevelopment alterations in a model of fetal alcohol spectrum disorders.

PubMed

Pascual, María; Montesinos, Jorge; Montagud-Romero, Sandra; Forteza, Jerónimo; Rodríguez-Arias, Marta; Miñarro, José; Guerri, Consuelo

2017-07-24

Inflammation during brain development participates in the pathogenesis of early brain injury and cognitive dysfunctions. Prenatal ethanol exposure affects the developing brain and causes neural impairment, cognitive and behavioral effects, collectively known as fetal alcohol spectrum disorders (FASD). Our previous studies demonstrate that ethanol activates the innate immune response and TLR4 receptor and causes neuroinflammation, brain damage, and cognitive defects in the developmental brain stage of adolescents. We hypothesize that by activating the TLR4 response, maternal alcohol consumption during pregnancy triggers the release of cytokines and chemokines in both the maternal sera and brains of fetuses/offspring, which impairs brain ontogeny and causes cognitive dysfunction. WT and TLR4-KO female mice treated with or without 10% ethanol in the drinking water during gestation and lactation were used. Cytokine/chemokine levels were determined by ELISA in the amniotic fluid, maternal serum, and cerebral cortex, as well as in the offspring cerebral cortex. Microglial and neuronal markers (evaluated by western blotting), myelin proteins (immunohistochemical and western blotting) and synaptic parameters (western blotting and electron microscopy) were assessed in the cortices of the WT and TLR4-KO pups on PND 0, 20, and 66. Behavioral tests (elevated plus maze and passive avoidance) were performed in the WT and TLR4-KO mice on PND 66 exposed or not to ethanol. We show that alcohol intake during gestation and lactation increases the levels of several cytokines/chemokines (IL-1β, IL-17, MIP-1α, and fractalkine) in the maternal sera, amniotic fluid, and brains of fetuses and offspring. The upregulation of cytokines/chemokines is associated with an increase in activated microglia markers (CD11b and MHC-II), and with a reduction in some synaptic (synaptotagmin, synapsin IIa) and myelin (MBP, PLP) proteins in the brains of offspring on days 0, 20, and 66 (long-term effects). These changes are associated with long-term behavioral impairments, in the 66-day-old alcohol-exposed pups. TLR4-deficient mice are protected against ethanol-induced cytokine/chemokine production in alcohol-treated dams and offspring, along with synaptic and myelin alterations, and the log-term behavioral dysfunction induced by ethanol in offspring. These results suggest that the immune system activation, through the TLR4 response, might play an important role in the neurodevelopmental defects in FASD.

Long-term Treatment with Oriental Medicinal Herb Artemisia princeps Alters Neuroplasticity in a Rat Model of Ovarian Hormone Deficiency.

PubMed

Kim, Hyun-Bum; Kwon, Byeong-Jae; Cho, Hyun-Ji; Kim, Ji-Won; Chon, Jeong-Woo; Do, Moon-Ho; Park, Sang-Yong; Kim, Sun-Yeou; Maeng, Sung-Ho; Park, Yoo-Kyoung; Park, Ji-Ho

2015-03-01

Artemisia princeps (AP) is a flowering perennial used as a traditional medicine and dietary supplement across East Asia. No study has yet assessed its effects on synaptic plasticity in hippocampus and much less in a model of ovarian hormone deficiency. We examined the influence of chronic oral AP ethanol extract treatment in ovariectomized rats on the induction of long-term depression in a representative synapse (CA3-CA1) of the hippocampus. Ovariectomized rats demonstrated lower trabecular mean bone mineral densities than sham, validating the establishment of pathology. Against this background of pathology, AP-treated ovariectomized rats exhibited attenuated long-term depression (LTD) in CA1 relative to water-treated controls as measured by increased field excitatory post-synaptic potentials (fEPSP) activation averages over the post-stimulation period. While pathological significance of long-term depression (LTD) in ovariectomized rats is conflicting, that AP treatment significantly affected its induction offers justification for further study of its influences on plasticity and its related disorders.

Sleep deprivation during a specific 3-hour time window post-training impairs hippocampal synaptic plasticity and memory

PubMed Central

Prince, Toni-Moi; Wimmer, Mathieu; Choi, Jennifer; Havekes, Robbert; Aton, Sara; Abel, Ted

2014-01-01

Sleep deprivation disrupts hippocampal function and plasticity. In particular, long-term memory consolidation is impaired by sleep deprivation, suggesting that a specific critical period exists following learning during which sleep is necessary. To elucidate the impact of sleep deprivation on long-term memory consolidation and synaptic plasticity, long-term memory was assessed when mice were sleep deprived following training in the hippocampus-dependent object place recognition task. We found that 3 hours of sleep deprivation significantly impaired memory when deprivation began 1 hour after training. In contrast, 3 hours of deprivation beginning immediately post-training did not impair spatial memory. Furthermore, a 3-hour sleep deprivation beginning 1 hour after training impaired hippocampal long-term potentiation (LTP), whereas sleep deprivation immediately after training did not affect LTP. Together, our findings define a specific 3-hour critical period, extending from 1 to 4 hours after training, during which sleep deprivation impairs hippocampal function. PMID:24380868

The A-Current Modulates Learning via NMDA Receptors Containing the NR2B Subunit

PubMed Central

Fontán-Lozano, Ángela; Suárez-Pereira, Irene; González-Forero, David; Carrión, Ángel Manuel

2011-01-01

Synaptic plasticity involves short- and long-term events, although the molecular mechanisms that underlie these processes are not fully understood. The transient A-type K+ current (IA) controls the excitability of the dendrites from CA1 pyramidal neurons by regulating the back-propagation of action potentials and shaping synaptic input. Here, we have studied how decreases in IA affect cognitive processes and synaptic plasticity. Using wild-type mice treated with 4-AP, an IA inhibitor, and mice lacking the DREAM protein, a transcriptional repressor and modulator of the IA, we demonstrate that impairment of IA decreases the stimulation threshold for learning and the induction of early-LTP. Hippocampal electrical recordings in both models revealed alterations in basal electrical oscillatory properties toward low-theta frequencies. In addition, we demonstrated that the facilitated learning induced by decreased IA requires the activation of NMDA receptors containing the NR2B subunit. Together, these findings point to a balance between the IA and the activity of NR2B-containing NMDA receptors in the regulation of learning. PMID:21966384

Radiation-induced alterations in synaptic neurotransmission of dentate granule cells depend on the dose and species of charged particles.

PubMed

Marty, V N; Vlkolinsky, R; Minassian, N; Cohen, T; Nelson, G A; Spigelman, I

2014-12-01

The evaluation of potential health risks associated with neuronal exposure to space radiation is critical for future long duration space travel. The purpose of this study was to evaluate and compare the effects of low-dose proton and high-energy charged particle (HZE) radiation on electrophysiological parameters of the granule cells in the dentate gyrus (DG) of the hippocampus and its associated functional consequences. We examined excitatory and inhibitory neurotransmission in DG granule cells (DGCs) in dorsal hippocampal slices from male C57BL/6 mice at 3 months after whole body irradiation with accelerated proton, silicon or iron particles. Multielectrode arrays were used to investigate evoked field synaptic potentials, an extracellular measurement of synaptic excitability in the perforant path to DG synaptic pathway. Whole-cell patch clamp recordings were used to measure miniature excitatory postsynaptic currents (mEPSCs) and miniature inhibitory postsynaptic currents (mIPSCs) in DGCs. Exposure to proton radiation increased synaptic excitability and produced dose-dependent decreases in amplitude and charge transfer of mIPSCs, without affecting the expression of γ-aminobutyric acid type A receptor α2, β3 and γ2 subunits determined by Western blotting. Exposure to silicon radiation had no significant effects on synaptic excitability, mEPSCs or mIPSCs of DGCs. Exposure to iron radiation had no effect on synaptic excitability and mIPSCs, but significantly increased mEPSC frequency at 1 Gy, without changes in mEPSC kinetics, suggesting a presynaptic mechanism. Overall, the data suggest that proton and HZE exposure results in radiation dose- and species-dependent long-lasting alterations in synaptic neurotransmission, which could cause radiation-induced impairment of hippocampal-dependent cognitive functions.

The effect of acute swim stress and training in the water maze on hippocampal synaptic activity as well as plasticity in the dentate gyrus of freely moving rats: revisiting swim-induced LTP reinforcement.

PubMed

Tabassum, Heena; Frey, Julietta U

2013-12-01

Hippocampal long-term potentiation (LTP) is a cellular model of learning and memory. An early form of LTP (E-LTP) can be reinforced into its late form (L-LTP) by various behavioral interactions within a specific time window ("behavioral LTP-reinforcement"). Depending on the type and procedure used, various studies have shown that stress differentially affects synaptic plasticity. Under low stress, such as novelty detection or mild foot shocks, E-LTP can be transformed into L-LTP in the rat dentate gyrus (DG). A reinforcing effect of a 2-min swim, however, has only been shown in (Korz and Frey (2003) J Neurosci 23:7281-7287; Korz and Frey (2005) J Neurosci 25:7393-7400; Ahmed et al. (2006) J Neurosci 26:3951-3958; Sajikumar et al., (2007) J Physiol 584.2:389-400) so far. We have reinvestigated these studies using the same as well as an improved recording technique which allowed the recording of field excitatory postsynaptic potentials (fEPSP) and the population spike amplitude (PSA) at their places of generation in freely moving rats. We show that acute swim stress led to a long-term depression (LTD) in baseline values of PSA and partially fEPSP. In contrast to earlier studies a LTP-reinforcement by swimming could never be reproduced. Our results indicate that 2-min swim stress influenced synaptic potentials as well as E-LTP negatively. Copyright © 2013 Wiley Periodicals, Inc.

Associative spike timing-dependent potentiation of the basal dendritic excitatory synapses in the hippocampus in vivo.

PubMed

Fung, Thomas K; Law, Clayton S; Leung, L Stan

2016-06-01

Spike timing-dependent plasticity in the hippocampus has rarely been studied in vivo. Using extracellular potential and current source density analysis in urethane-anesthetized adult rats, we studied synaptic plasticity at the basal dendritic excitatory synapse in CA1 after excitation-spike (ES) pairing; E was a weak basal dendritic excitation evoked by stratum oriens stimulation, and S was a population spike evoked by stratum radiatum apical dendritic excitation. We hypothesize that positive ES pairing-generating synaptic excitation before a spike-results in long-term potentiation (LTP) while negative ES pairing results in long-term depression (LTD). Pairing (50 pairs at 5 Hz) at ES intervals of -10 to 0 ms resulted in significant input-specific LTP of the basal dendritic excitatory sink, lasting 60-120 min. Pairing at +10- to +20-ms ES intervals, or unpaired 5-Hz stimulation, did not induce significant basal dendritic or apical dendritic LTP or LTD. No basal dendritic LTD was found after stimulation of stratum oriens with 200 pairs of high-intensity pulses at 25-ms interval. Pairing-induced LTP was abolished by pretreatment with an N-methyl-d-aspartate receptor antagonist, 3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), which also reduced spike bursting during 5-Hz pairing. Pairing at 0.5 Hz did not induce spike bursts or basal dendritic LTP. In conclusion, ES pairing at 5 Hz resulted in input-specific basal dendritic LTP at ES intervals of -10 ms to 0 ms but no LTD at ES intervals of -20 to +20 ms. Associative LTP likely occurred because of theta-rhythmic coincidence of subthreshold excitation with a backpropagated spike burst, which are conditions that can occur naturally in the hippocampus. Copyright © 2016 the American Physiological Society.

Associative spike timing-dependent potentiation of the basal dendritic excitatory synapses in the hippocampus in vivo

PubMed Central

Fung, Thomas K.; Law, Clayton S.

2016-01-01

Spike timing-dependent plasticity in the hippocampus has rarely been studied in vivo. Using extracellular potential and current source density analysis in urethane-anesthetized adult rats, we studied synaptic plasticity at the basal dendritic excitatory synapse in CA1 after excitation-spike (ES) pairing; E was a weak basal dendritic excitation evoked by stratum oriens stimulation, and S was a population spike evoked by stratum radiatum apical dendritic excitation. We hypothesize that positive ES pairing—generating synaptic excitation before a spike—results in long-term potentiation (LTP) while negative ES pairing results in long-term depression (LTD). Pairing (50 pairs at 5 Hz) at ES intervals of −10 to 0 ms resulted in significant input-specific LTP of the basal dendritic excitatory sink, lasting 60–120 min. Pairing at +10- to +20-ms ES intervals, or unpaired 5-Hz stimulation, did not induce significant basal dendritic or apical dendritic LTP or LTD. No basal dendritic LTD was found after stimulation of stratum oriens with 200 pairs of high-intensity pulses at 25-ms interval. Pairing-induced LTP was abolished by pretreatment with an N-methyl-d-aspartate receptor antagonist, 3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), which also reduced spike bursting during 5-Hz pairing. Pairing at 0.5 Hz did not induce spike bursts or basal dendritic LTP. In conclusion, ES pairing at 5 Hz resulted in input-specific basal dendritic LTP at ES intervals of −10 ms to 0 ms but no LTD at ES intervals of −20 to +20 ms. Associative LTP likely occurred because of theta-rhythmic coincidence of subthreshold excitation with a backpropagated spike burst, which are conditions that can occur naturally in the hippocampus. PMID:27052581

Synaptic Glutamate Spillover Due to Impaired Glutamate Uptake Mediates Heroin Relapse

PubMed Central

Scofield, Michael D.; Boger, Heather; Hensley, Megan; Kalivas, Peter W.

2014-01-01

Reducing the enduring vulnerability to relapse is a therapeutic goal in treating drug addiction. Studies with animal models of drug addiction show a marked increase in extrasynaptic glutamate in the core subcompartment of the nucleus accumbens (NAcore) during reinstated drug seeking. However, the synaptic mechanisms linking drug-induced changes in extrasynaptic glutamate to relapse are poorly understood. Here, we discovered impaired glutamate elimination in rats extinguished from heroin self-administration that leads to spillover of synaptically released glutamate into the nonsynaptic extracellular space in NAcore and investigated whether restoration of glutamate transport prevented reinstated heroin seeking. Through multiple functional assays of glutamate uptake and analyzing NMDA receptor-mediated currents, we show that heroin self-administration produced long-lasting downregulation of glutamate uptake and surface expression of the transporter GLT-1. This downregulation was associated with spillover of synaptic glutamate to extrasynaptic NMDA receptors within the NAcore. Ceftriaxone restored glutamate uptake and prevented synaptic glutamate spillover and cue-induced heroin seeking. Ceftriaxone-induced inhibition of reinstated heroin seeking was blocked by morpholino-antisense targeting GLT-1 synthesis. These data reveal that the synaptic glutamate spillover in the NAcore results from reduced glutamate transport and is a critical pathophysiological mechanism underling reinstated drug seeking in rats extinguished from heroin self-administration. PMID:24741055

Late onset deficits in synaptic plasticity in the valproic acid rat model of autism.

PubMed

Martin, Henry G S; Manzoni, Olivier J

2014-01-01

Valproic acid (VPA) is a frequently used drug in the treatment of epilepsy, bipolar disorders and migraines; however it is also a potent teratogen. Prenatal exposure increases the risk of childhood malformations and can result in cognitive deficits. In rodents in utero exposure to VPA also causes neurodevelopmental abnormalities and is an important model of autism. In early postnatal life VPA exposed rat pups show changes in medial prefrontal cortex (mPFC) physiology and synaptic connectivity. Specifically, principal neurons show decreased excitability but increased local connectivity, coupled with an increase in long-term potentiation (LTP) due to an up-regulation of NMDA receptor (NMDAR) expression. However recent evidence suggests compensatory homeostatic mechanisms lead to normalization of synaptic NMDARs during later postnatal development. Here we have extended study of mPFC synaptic physiology into adulthood to better understand the longitudinal consequences of early developmental abnormalities in VPA exposed rats. Surprisingly in contrast to early postnatal life and adolescence, we find that adult VPA exposed rats show reduced synaptic function. Both NMDAR mediated currents and LTP are lower in adult VPA rats, although spontaneous activity and endocannabinoid dependent long-term depression are normal. We conclude that rather than correcting, synaptic abnormalities persist into adulthood in VPA exposed rats, although a quite different synaptic phenotype is present. This switch from hyper to hypo function in mPFC may be linked to some of the neurodevelopmental defects found in prenatal VPA exposure and autism spectrum disorders in general.

Repeated pulses of serotonin required for long-term facilitation activate mitogen-activated protein kinase in sensory neurons of Aplysia

PubMed Central

Michael, Dan; Martin, Kelsey C.; Seger, Rony; Ning, Ming-Ming; Baston, Rene; Kandel, Eric R.

1998-01-01

Long-term facilitation of the connections between the sensory and motor neurons of the gill-withdrawal reflex in Aplysia requires five repeated pulses of serotonin (5-HT). The repeated pulses of 5-HT initiate a cascade of gene activation that leads ultimately to the growth of new synaptic connections. Several genes in this process have been identified, including the transcriptional regulators apCREB-1, apCREB-2, apC/EBP, and the cell adhesion molecule apCAM, which is thought to be involved in the formation of new synaptic connections. Here we report that the transcriptional regulators apCREB-2 and apC/EBP, as well as a peptide derived from the cytoplasmic domain of apCAM, are phosphorylated in vitro by Aplysia mitogen-activated protein kinase (apMAPK). We have cloned the cDNA encoding apMAPK and show that apMAPK activity is increased in sensory neurons treated with repeated pulses of 5-HT and by the cAMP pathway. These results suggest that apMAPK may participate with cAMP-dependent protein kinase during long-term facilitation in sensory cells by modifying some of the key elements involved in the consolidation of short- to long-lasting changes in synaptic strength. PMID:9465108

Calcium Input Frequency, Duration and Amplitude Differentially Modulate the Relative Activation of Calcineurin and CaMKII

PubMed Central

Li, Lu; Stefan, Melanie I.; Le Novère, Nicolas

2012-01-01

NMDA receptor dependent long-term potentiation (LTP) and long-term depression (LTD) are two prominent forms of synaptic plasticity, both of which are triggered by post-synaptic calcium elevation. To understand how calcium selectively stimulates two opposing processes, we developed a detailed computational model and performed simulations with different calcium input frequencies, amplitudes, and durations. We show that with a total amount of calcium ions kept constant, high frequencies of calcium pulses stimulate calmodulin more efficiently. Calcium input activates both calcineurin and Ca2+/calmodulin-dependent protein kinase II (CaMKII) at all frequencies, but increased frequencies shift the relative activation from calcineurin to CaMKII. Irrespective of amplitude and duration of the inputs, the total amount of calcium ions injected adjusts the sensitivity of the system to calcium input frequencies. At a given frequency, the quantity of CaMKII activated is proportional to the total amount of calcium. Thus, an input of a small amount of calcium at high frequencies can induce the same activation of CaMKII as a larger amount, at lower frequencies. Finally, the extent of activation of CaMKII signals with high calcium frequency is further controlled by other factors, including the availability of calmodulin, and by the potency of phosphatase inhibitors. PMID:22962589

Restoration of long-term potentiation in middle-aged hippocampus after induction of brain-derived neurotrophic factor.

PubMed

Rex, Christopher S; Lauterborn, Julie C; Lin, Ching-Yi; Kramár, Eniko A; Rogers, Gary A; Gall, Christine M; Lynch, Gary

2006-08-01

Restoration of neuronal viability and synaptic plasticity through increased trophic support is widely regarded as a potential therapy for the cognitive declines that characterize aging. Previous studies have shown that in the hippocampal CA1 basal dendritic field deficits in the stabilization of long-term potentiation (LTP) are evident by middle age. The present study tested whether increasing endogenous brain-derived neurotrophic factor (BDNF) could reverse this age-related change. We report here that in middle-aged (8- to 10-mo-old) rats, in vivo treatments with a positive AMPA-type glutamate receptor modulator both increase BDNF protein levels in the cortical telencephalon and restore stabilization of basal dendritic LTP as assessed in acute hippocampal slices 18 h after the last drug treatment. These effects were not attributed to enhanced synaptic transmission or to facilitation of burst responses used to induce LTP. Increasing extracellular levels of BDNF by exogenous application to slices of middle-aged rats was also sufficient to rescue the stabilization of basal dendritic LTP. Finally, otherwise stable LTP in ampakine-treated middle-aged rats can be eliminated by infusion of the extracellular BDNF scavenger TrkB-Fc. Together these results indicate that increases in endogenous BDNF signaling can offset deficits in the postinduction processes that stabilize LTP.

Could Perinatal Asphyxia Induce a Synaptopathy? New Highlights from an Experimental Model

PubMed Central

Herrera, María Inés; Udovin, Lucas Daniel; Kusnier, Carlos; Kölliker-Frers, Rodolfo; de Souza, Wanderley

2017-01-01

Birth asphyxia also termed perinatal asphyxia is an obstetric complication that strongly affects brain structure and function. Central nervous system is highly susceptible to oxidative damage caused by perinatal asphyxia while activation and maturity of the proper pathways are relevant to avoiding abnormal neural development. Perinatal asphyxia is associated with high morbimortality in term and preterm neonates. Although several studies have demonstrated a variety of biochemical and molecular pathways involved in perinatal asphyxia physiopathology, little is known about the synaptic alterations induced by perinatal asphyxia. Nearly 25% of the newborns who survive perinatal asphyxia develop neurological disorders such as cerebral palsy and certain neurodevelopmental and learning disabilities where synaptic connectivity disturbances may be involved. Accordingly, here we review and discuss the association of possible synaptic dysfunction with perinatal asphyxia on the basis of updated evidence from an experimental model. PMID:28326198

Importance of stimulation paradigm in determining facilitation and effects of neuromodulation.

PubMed

Crider, M E; Cooper, R L

1999-09-25

Evoked synaptic activity within the CNS and at the neuromuscular junction in most in vivo preparations studied occurs not with single isolated stimuli, but with trains, or bursts, of stimuli. Although for ease in studying the mechanisms of vesicular synaptic transmission one often uses single discrete stimuli, the true mechanisms in the animal may be far more complex. When repetitive stimuli are present at a nerve terminal, often a heightened (i.e., facilitated) postsynaptic potential can be as a result. Facilitation is commonly used as an index of synaptic function and plasticity induced by chronic stimulation or by neuromodulation. The mechanisms that give rise to facilitation are thought to be the same that may underlie short-term learning and memory [C.H. Bailey, E.R. Kandel, Structural changes accompanying memory storage. Annu. Rev. Physiol. 55 (1993) 397-426.]. Differences in short term facilitation (STF) are seen depending on the conventional stimulation paradigm (twin pulse, train, or continuous) used to induce facilitation. Thus, a battery of paradigms should be used to characterize synaptic function to obtain a closer understanding of the possible in vivo conditions.

Matrix metalloproteinase 9 (MMP-9) is indispensable for long term potentiation in the central and basal but not in the lateral nucleus of the amygdala.

PubMed

Gorkiewicz, Tomasz; Balcerzyk, Marcin; Kaczmarek, Leszek; Knapska, Ewelina

2015-01-01

It has been shown that matrix metalloproteinase 9 (MMP-9) is required for synaptic plasticity, learning and memory. In particular, MMP-9 involvement in long-term potentiation (LTP, the model of synaptic plasticity) in the hippocampus and prefrontal cortex has previously been demonstrated. Recent data suggest the role of MMP-9 in amygdala-dependent learning and memory. Nothing is known, however, about its physiological correlates in the specific pathways in the amygdala. In the present study we show that LTP in the basal and central but not lateral amygdala (LA) is affected by MMP-9 knock-out. The MMP-9 dependency of LTP was confirmed in brain slices treated with a specific MMP-9 inhibitor. The results suggest that MMP-9 plays different roles in synaptic plasticity in different nuclei of the amygdala.

Tetrahydrohyperforin prevents cognitive deficit, Aβ deposition, tau phosphorylation and synaptotoxicity in the APPswe/PSEN1ΔE9 model of Alzheimer's disease: a possible effect on APP processing

PubMed Central

Inestrosa, N C; Tapia-Rojas, C; Griffith, T N; Carvajal, F J; Benito, M J; Rivera-Dictter, A; Alvarez, A R; Serrano, F G; Hancke, J L; Burgos, P V; Parodi, J; Varela-Nallar, L

2011-01-01

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive deterioration of cognitive abilities, amyloid-β peptide (Aβ) accumulation and synaptic alterations. Previous studies indicated that hyperforin, a component of the St John's Wort, prevents Aβ neurotoxicity and some behavioral impairments in a rat model of AD. In this study we examined the ability of tetrahydrohyperforin (IDN5607), a stable hyperforin derivative, to prevent the cognitive deficit and synaptic impairment in an in vivo model of AD. In double transgenic APPswe/PSEN1ΔE9 mice, IDN5706 improves memory and prevents the impairment of synaptic plasticity in a dose-dependent manner, inducing a recovery of long-term potentiation. In agreement with these findings, IDN5706 prevented the decrease in synaptic proteins in hippocampus and cortex. In addition, decreased levels of tau hyperphosphorylation, astrogliosis, and total fibrillar and oligomeric forms of Aβ were determined in double transgenic mice treated with IDN5706. In cultured cells, IDN5706 decreased the proteolytic processing of the amyloid precursor protein that leads to Aβ peptide generation. These findings indicate that IDN5706 ameliorates AD neuropathology and could be considered of therapeutic relevance in AD treatment. PMID:22832522

Crucial Role of Postsynaptic Syntaxin 4 in Mediating Basal Neurotransmission and Synaptic Plasticity in Hippocampal CA1 Neurons.

PubMed

Bin, Na-Ryum; Ma, Ke; Harada, Hidekiyo; Tien, Chi-Wei; Bergin, Fiona; Sugita, Kyoko; Luyben, Thomas T; Narimatsu, Masahiro; Jia, Zhengping; Wrana, Jeffrey L; Monnier, Philippe P; Zhang, Liang; Okamoto, Kenichi; Sugita, Shuzo

2018-06-05

Trafficking of neurotransmitter receptors on postsynaptic membranes is critical for basal neurotransmission and synaptic plasticity, yet the underlying mechanisms remain elusive. Here, we investigated the role of syntaxin 4 in postsynaptic hippocampal CA1 neurons by analyzing conditional knockout (syntaxin 4 cKO) mice. We show that syntaxin 4 cKO resulted in reduction of basal neurotransmission without changes in paired-pulse ratios. Both α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-d-aspartic acid (NMDA) receptor-mediated charge transfers were diminished. Patch-clamp experiments revealed that amplitudes, but not frequencies, of spontaneous excitatory postsynaptic currents are reduced. Syntaxin 4 knockout (KO) caused drastic reduction in expression of surface α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-d-aspartic acid (NMDA) receptors in cultured hippocampal neurons. Furthermore, cKO caused defects in theta-burst stimulation induced long-term potentiation and spatial learning as assessed by a water maze task, indicating that synaptic plasticity was altered. Our data reveal a crucial role of syntaxin 4 in trafficking of ionotropic glutamate receptors that are essential for basal neurotransmission, synaptic plasticity, and spatial memory. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Dissecting the Components of Long-Term Potentiation

PubMed Central

Blundon, Jay A.; Zakharenko, Stanislav S.

2009-01-01

The formation of memories relies on plastic changes at synapses between neurons. Although the mechanisms of synaptic plasticity have been studied extensively over several decades, many aspects of this process remain controversial. The cellular locus of expression of long-term potentiation (LTP), a major form of synaptic plasticity, is one of the most important unresolved phenomena. In this article, we summarize some recent advances in this area made possible by the development of new imaging tools. These studies have demonstrated that LTP is compound in nature and consists of both presynaptic and postsynaptic components. We also review some features of presynaptic and postsynaptic changes during compound LTP. PMID:18940785

From the Cover: 7,8-Dihydroxyflavone Rescues Lead-Induced Impairment of Vesicular Release: A Novel Therapeutic Approach for Lead Intoxicated Children.

PubMed

Zhang, Xiao-Lei; McGlothan, Jennifer L; Miry, Omid; Stansfield, Kirstie H; Loth, Meredith K; Stanton, Patric K; Guilarte, Tomás R

2018-01-01

Childhood lead (Pb2+) intoxication is a public health problem of global proportion. Lead exposure during development produces multiple effects on the central nervous system including impaired synapse formation, altered synaptic plasticity, and learning deficits. In primary hippocampal neurons in culture and hippocampal slices, Pb2+ exposure inhibits vesicular release and reduces the number of fast-releasing sites, an effect associated with Pb2+ inhibition of NMDA receptor-mediated trans-synaptic Brain-Derived Neurotrophic Factor (BDNF) signaling. The objective of this study was to determine if activation of TrkB, the cognate receptor for BDNF, would rescue Pb2+-induced impairments of vesicular release. Rats were chronically exposed to Pb2+ prenatally and postnatally until 50 days of age. This chronic Pb2+ exposure paradigm enhanced paired-pulse facilitation of synaptic potentials in Schaffer collateral-CA1 synapses in the hippocampus, a phenomenon indicative of reduced vesicular release probability. Decreased vesicular release probability was confirmed by both mean-variance analysis and direct 2-photon imaging of vesicular release from hippocampal slices of rats exposed to Pb2+in vivo. We also found a Pb2+-induced impairment of calcium influx in Schaffer collateral-CA1 synaptic terminals. Intraperitoneal injections of Pb2+ rats with the TrkB receptor agonist 7,8-dihydroxyflavone (5 mg/kg) for 14-15 days starting at postnatal day 35, reversed all Pb2+-induced impairments of presynaptic transmitter release at Schaffer collateral-CA1 synapses. This study demonstrates for the first time that in vivo pharmacological activation of TrkB receptors by small molecules such as 7,8-dihydroxyflavone can reverse long-term effects of chronic Pb2+ exposure on presynaptic terminals, pointing to TrkB receptor activation as a promising therapeutic intervention in Pb2+-intoxicated children. © The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Synaptic plasticity and memory functions achieved in a WO3-x-based nanoionics device by using the principle of atomic switch operation

NASA Astrophysics Data System (ADS)

Yang, Rui; Terabe, Kazuya; Yao, Yiping; Tsuruoka, Tohru; Hasegawa, Tsuyoshi; Gimzewski, James K.; Aono, Masakazu

2013-09-01

A compact neuromorphic nanodevice with inherent learning and memory properties emulating those of biological synapses is the key to developing artificial neural networks rivaling their biological counterparts. Experimental results showed that memorization with a wide time scale from volatile to permanent can be achieved in a WO3-x-based nanoionics device and can be precisely and cumulatively controlled by adjusting the device’s resistance state and input pulse parameters such as the amplitude, interval, and number. This control is analogous to biological synaptic plasticity including short-term plasticity, long-term potentiation, transition from short-term memory to long-term memory, forgetting processes for short- and long-term memory, learning speed, and learning history. A compact WO3-x-based nanoionics device with a simple stacked layer structure should thus be a promising candidate for use as an inorganic synapse in artificial neural networks due to its striking resemblance to the biological synapse.

Brief Embryonic Strychnine Exposure in Zebrafish Causes Long-Term Adult Behavioral Impairment with Indications of Embryonic Synaptic Changes

PubMed Central

Roy, Nicole M.; Arpie, Brianna; Lugo, Joseph; Linney, Elwood; Levin, Edward D.; Cerutti, Daniel

2015-01-01

Zebrafish provide a powerful model of the impacts of embryonic toxicant exposure on neural development that may result in long-term behavioral dysfunction. In this study, zebrafish embryos were treated with 1.5 mM strychnine for short embryonic time windows to induce transient changes in inhibitory neural signaling, and were subsequently raised in untreated water until adulthood. PCR analysis showed indications that strychnine exposure altered expression of some genes related to glycinergic, GABAergic and glutamatergic neuronal synapses during embryonic development. In adulthood, treated fish showed significant changes in swimming speed and tank diving behavior compared to controls. Taken together, these data show that a short embryonic exposure to a neurotoxicant can alter development of neural synapses and lead to changes in adult behavior. PMID:23022260

Brief embryonic strychnine exposure in zebrafish causes long-term adult behavioral impairment with indications of embryonic synaptic changes.

PubMed

Roy, Nicole M; Arpie, Brianna; Lugo, Joseph; Linney, Elwood; Levin, Edward D; Cerutti, Daniel

2012-01-01

Zebrafish provide a powerful model of the impacts of embryonic toxicant exposure on neural development that may result in long-term behavioral dysfunction. In this study, zebrafish embryos were treated with 1.5mM strychnine for short embryonic time windows to induce transient changes in inhibitory neural signaling, and were subsequently raised in untreated water until adulthood. PCR analysis showed indications that strychnine exposure altered expression of some genes related to glycinergic, GABAergic and glutamatergic neuronal synapses during embryonic development. In adulthood, treated fish showed significant changes in swimming speed and tank diving behavior compared to controls. Taken together, these data show that a short embryonic exposure to a neurotoxicant can alter development of neural synapses and lead to changes in adult behavior. Copyright © 2012 Elsevier Inc. All rights reserved.

mGluR2/3 in the Lateral Amygdala is Required for Fear Extinction: Cortical Input Synapses onto the Lateral Amygdala as a Target Site of the mGluR2/3 Action

PubMed Central

Kim, Jihye; An, Bobae; Kim, Jeongyeon; Park, Sewon; Park, Sungmo; Hong, Ingie; Lee, Sukwon; Park, Kyungjoon; Choi, Sukwoo

2015-01-01

Various subtypes of metabotropic glutamate receptors (mGluRs) have been implicated in fear extinction, but mGluR2/3 subtype has not been tested. Here, we found that microinjection of an mGluR2/3 antagonist, LY341495, into the lateral amygdala (LA), but not into the adjacent central amygdala (CeA), impaired extinction retention without affecting within-session extinction. In contrast, we failed to detect any significant changes in motility and anxiety during a period when extinction training or retention was performed after LY341495 injection, suggesting that the effect of LY341495 is specific to conditioned responses. Subsequently, on the basis of a previous finding that a long-term potentiation of presynaptic efficacy at cortical input synapses onto the lateral amygdala (C-LA synapses) supports conditioned fear, we tested the hypothesis that activation of mGluR2/3 leads to fear extinction via a long-term weakening of presynaptic functions at C-LA synapses. Fear extinction produced a decrease in C-LA synaptic efficacy, whereas LY341495 infusion into the LA blocked this extinction-induced C-LA efficacy decrease without altering synaptic efficacy at other LA synapses. Furthermore, extinction enhanced paired pulse ratio (PPR) of EPSCs, which inversely correlates with presynaptic release probability, whereas LY341495 infusion into the LA attenuated the extinction-induced increase in PPR, suggesting the presence of mGluR2/3-dependent presynaptic changes after extinction. Consistently, extinction occluded a presynaptic form of depression at C-LA synapses, whereas the LY341495 infusion into the LA rescued this occlusion. Together, our findings suggest that mGluR2/3 is required for extinction retention and that the mGluR2/3 action is mediated by the long-term weakening of release probability at C-LA synapses. PMID:26081171

Histone acetylation rescues contextual fear conditioning in nNOS KO mice and accelerates extinction of cued fear conditioning in wild type mice.

PubMed

Itzhak, Yossef; Anderson, Karen L; Kelley, Jonathan B; Petkov, Martin

2012-05-01

Epigenetic regulation of chromatin structure is an essential molecular mechanism that contributes to the formation of synaptic plasticity and long-term memory (LTM). An important regulatory process of chromatin structure is acetylation and deacetylation of histone proteins. Inhibition of histone deacetylase (HDAC) increases acetylation of histone proteins and facilitate learning and memory. Nitric oxide (NO) signaling pathway has a role in synaptic plasticity, LTM and regulation of histone acetylation. We have previously shown that NO signaling pathway is required for contextual fear conditioning. The present study investigated the effects of systemic administration of the HDAC inhibitor sodium butyrate (NaB) on fear conditioning in neuronal nitric oxide synthase (nNOS) knockout (KO) and wild type (WT) mice. The effect of single administration of NaB on total H3 and H4 histone acetylation in hippocampus and amygdala was also investigated. A single administration of NaB prior to fear conditioning (a) rescued contextual fear conditioning of nNOS KO mice and (b) had long-term (weeks) facilitatory effect on the extinction of cued fear memory of WT mice. The facilitatory effect of NaB on extinction of cued fear memory of WT mice was confirmed in a study whereupon NaB was administered during extinction. Results suggest that (a) the rescue of contextual fear conditioning in nNOS KO mice is associated with NaB-induced increase in H3 histone acetylation and (b) the accelerated extinction of cued fear memory in WT mice is associated with NaB-induced increase in H4 histone acetylation. Hence, a single administration of HDAC inhibitor may rescue NO-dependent cognitive deficits and afford a long-term accelerating effect on extinction of fear memory of WT mice. Copyright © 2012 Elsevier Inc. All rights reserved.

Sustained neuronal activity generated by glial plasticity

PubMed Central

Pirttimaki, Tiina M.; Hall, Stephen D.; Parri, H. Rheinallt

2011-01-01

Astrocytes release gliotransmitters, notably glutamate, that can affect neuronal and synaptic activity. In particular, astrocytic glutamate release results in the generation of N-methyl D-aspartate receptor (NMDA-R) mediated slow inward currents (SICs) in neurons. However, factors underlying the emergence of SICs, and their physiological roles are largely unknown. Here we show that, in acute slices of rat somatosensory thalamus, stimulation of Lemniscal or cortical afferents results in a sustained increase of SICs in thalamocortical (TC) neurons that outlasts the duration of the stimulus by an hour. This long term enhancement (LTE) of astrocytic glutamate release is induced by group I metabotropic glutamate receptors (mGluRs), and is dependent on astrocytic intracellular calcium ([Ca2+]i). Neuronal SICs are mediated by extrasynaptic NR2B subunit-containing NMDA-Rs and are capable of eliciting bursts. These are distinct from T-type Ca2+ channel dependent bursts of action potentials, and are synchronized in neighboring TC neurons. These findings describe a previously unrecognized form of excitatory, non-synaptic plasticity in the central nervous system (CNS) that feeds forward to generate local neuronal firing long after stimulus termination. PMID:21613477

Iron-mediated redox modulation in neural plasticity

PubMed Central

Muñoz, Pablo

2012-01-01

The role of iron in brain physiology has focused on the neuropathological, effects due to iron-induced oxidative stress. However, our recent work has established a physiological relationship between the iron-mediated oxidative modification and normal neuronal function. Our results obtained from hippocampal neurons, suggest that iron-generated reactive species oxygen (ROS) are involved in calcium signaling initiated by stimulation of NMDA receptors. This signal is amplified by ryanodine receptors (RyR), a redox- sensitive calcium channel, allowing the phosphorylation and nuclear translocation of ERK1/2. Furthermore, using electrophysiological approaches, we showed that iron is required for basal synaptic transmission and full expression of long-term potentiation, a type of synaptic plasticity. Our data combined suggest that the oxidative effect of iron is critical to activate processes that are downstream of NMDAR activation. Finally, due to the high reactivity of DNA with iron-generated ROS, we hypothesize an additional function of iron in gene regulation. PMID:22808323

Hyperexcitability of Rat Thalamocortical Networks after Exposure to General Anesthesia during Brain Development

PubMed Central

DiGruccio, Michael R.; Joksimovic, Srdjan; Joksovic, Pavle M.; Lunardi, Nadia; Salajegheh, Reza; Jevtovic-Todorovic, Vesna; Beenhakker, Mark P.; Goodkin, Howard P.

2015-01-01

Prevailing literature supports the idea that common general anesthetics (GAs) cause long-term cognitive changes and neurodegeneration in the developing mammalian brain, especially in the thalamus. However, the possible role of GAs in modifying ion channels that control neuronal excitability has not been taken into consideration. Here we show that rats exposed to GAs at postnatal day 7 display a lasting reduction in inhibitory synaptic transmission, an increase in excitatory synaptic transmission, and concomitant increase in the amplitude of T-type calcium currents (T-currents) in neurons of the nucleus reticularis thalami (nRT). Collectively, this plasticity of ionic currents leads to increased action potential firing in vitro and increased strength of pharmacologically induced spike and wave discharges in vivo. Selective blockade of T-currents reversed neuronal hyperexcitability in vitro and in vivo. We conclude that drugs that regulate thalamic excitability may improve the safety of GAs used during early brain development. PMID:25632125

A single exposure to severe stressors causes long-term desensitisation of the physiological response to the homotypic stressor.

PubMed

Armario, Antonio; Vallès, Astrid; Dal-Zotto, Silvina; Márquez, Cristina; Belda, Xavier

2004-09-01

Although some laboratories have reported that a single session of stress is able to induce a long-lasting sensitisation of the hypothalamic-pituitary-adrenal (HPA) response to further exposures to stress, we have found that a single exposure to severe emotional (immobilisation, restraint or shock) or systemic (endotoxin) stressors reduces the responsiveness of the HPA to the same, but not to a novel (heterotypic), stressor, in which case a slight sensitisation was observed. Long-term desensitisation has been found to reduce not only secretion of peripheral HPA hormones (ACTH and corticosterone), but also to reduce responses of central components of the HPA axis (c-fos and CRF gene expression at the level of the paraventricular nucleus of the hypothalamus, PVN). In addition, desensitisation also applies to the impact of the stressor on food intake and, probably, to stress-induced hyperglycaemia. The development of long-term desensitisation of the HPA axis does not appear to be a universal consequence of exposure to severe stressors as it was not observed in response to insulin-induced hypoglycaemia. Whether or not the development of long-term effects of stress depend on the specific pathways activated by particular stressors remains to be tested. The observed desensitisation of the HPA axis in response to the homotypic stressor shows two special features which makes it difficult to be interpreted in terms of an habituation-like process: (a) the effect increased with time (days to weeks) elapsed between the first and second exposure to the stressor, suggesting a progressive maturational process; and (b) the stronger the stressor the greater the long-term desensitisation. Therefore, it is possible that desensitisation of the HPA axis is the sum of two different phenomena: long-term effects and habituation-like processes. The contribution of the former may be more relevant with severe stressors and longer inter-stress intervals, and that of the latter with mild stressors and repeated exposures. Long-term stress-induced changes may not take place at the level of the PVN itself, but in brain nuclei showing synaptic plasticity and putatively involved in the control of the HPA axis and other physiological responses. As for the precise areas involved, these remain to be characterized.

Orchestrated Regulation of Nogo Receptors, Lotus, AMPA Receptors and BDNF in an ECT Model Suggests Opening and Closure of a Window of Synaptic Plasticity

PubMed Central

Nordgren, Max; Karlsson, Tobias; Svensson, Maria; Koczy, Josefin; Josephson, Anna; Olson, Lars; Tingström, Anders; Brené, Stefan

2013-01-01

Electroconvulsive therapy (ECT) is an efficient and relatively fast acting treatment for depression. However, one severe side effect of the treatment is retrograde amnesia, which in certain cases can be long-term. The mechanisms behind the antidepressant effect and the amnesia are not well understood. We hypothesized that ECT causes transient downregulation of key molecules needed to stabilize synaptic structure and to prevent Ca2+ influx, and a simultaneous increase in neurotrophic factors, thus providing a short time window of increased structural synaptic plasticity. Here we followed regulation of NgR1, NgR3, LOTUS, BDNF, and AMPA subunits GluR1 and GluR2 flip and flop mRNA levels in hippocampus at 2, 4, 12, 24, and 72 hours after a single episode of induced electroconvulsive seizures (ECS) in rats. NgR1 and LOTUS mRNA levels were transiently downregulated in the dentate gyrus 2, 4, 12 and 4, 12, 24 h after ECS treatment, respectively. GluR2 flip, flop and GluR1 flop were downregulated at 4 h. GluR2 flip remained downregulated at 12 h. In contrast, BDNF, NgR3 and GluR1 flip mRNA levels were upregulated. Thus, ECS treatment induces a transient regulation of factors important for neuronal plasticity. Our data provide correlations between ECS treatment and molecular events compatible with the hypothesis that both effects and side effects of ECT may be caused by structural synaptic rearrangements. PMID:24244357

Orchestrated regulation of Nogo receptors, LOTUS, AMPA receptors and BDNF in an ECT model suggests opening and closure of a window of synaptic plasticity.

PubMed

Nordgren, Max; Karlsson, Tobias; Svensson, Maria; Koczy, Josefin; Josephson, Anna; Olson, Lars; Tingström, Anders; Brené, Stefan

2013-01-01

Electroconvulsive therapy (ECT) is an efficient and relatively fast acting treatment for depression. However, one severe side effect of the treatment is retrograde amnesia, which in certain cases can be long-term. The mechanisms behind the antidepressant effect and the amnesia are not well understood. We hypothesized that ECT causes transient downregulation of key molecules needed to stabilize synaptic structure and to prevent Ca2+ influx, and a simultaneous increase in neurotrophic factors, thus providing a short time window of increased structural synaptic plasticity. Here we followed regulation of NgR1, NgR3, LOTUS, BDNF, and AMPA subunits GluR1 and GluR2 flip and flop mRNA levels in hippocampus at 2, 4, 12, 24, and 72 hours after a single episode of induced electroconvulsive seizures (ECS) in rats. NgR1 and LOTUS mRNA levels were transiently downregulated in the dentate gyrus 2, 4, 12 and 4, 12, 24 h after ECS treatment, respectively. GluR2 flip, flop and GluR1 flop were downregulated at 4 h. GluR2 flip remained downregulated at 12 h. In contrast, BDNF, NgR3 and GluR1 flip mRNA levels were upregulated. Thus, ECS treatment induces a transient regulation of factors important for neuronal plasticity. Our data provide correlations between ECS treatment and molecular events compatible with the hypothesis that both effects and side effects of ECT may be caused by structural synaptic rearrangements.

An Activity-Regulated microRNA, miR-188, Controls Dendritic Plasticity and Synaptic Transmission by Downregulating Neuropilin-2

PubMed Central

AN, Kyongman; Ryu, Junghwa; Cho, Kwangwook; Suh, Yoo-Hun; Kim, Hye-Sun

2016-01-01

MicroRNAs (miRNAs) have recently come to be viewed as critical players that modulate a number of cellular features in various biological systems including the mature central nervous system by exerting regulatory control over the stability and translation of mRNAs. Despite considerable evidence for the regulatory functions of miRNAs, the identities of the miRNA species that are involved in the regulation of synaptic transmission and plasticity and the mechanisms by which these miRNAs exert functional roles remain largely unknown. In the present study, the expression of microRNA-188 (miR-188) was found to be upregulated by the induction of long-term potentiation (LTP). The protein level of neuropilin-2 (Nrp-2), one of the possible molecular targets for miR-188, was decreased during LTP induction. We also confirmed that the luciferase activity of the 3’-UTR of Nrp-2 was diminished by treatment with a miR-188 oligonucleotide but not with a scrambled miRNA oligonucleotide. Nrp-2 serves as a receptor for semaphorin 3F, which is a negative regulator of spine development and synaptic structure. In addition, miR-188 specifically rescued the reduction in dendritic spine density induced by Nrp-2 expression in hippocampal neurons from rat primary culture. Furthermore, miR-188 counteracted the decrease in the miniature EPSC frequency induced by Nrp-2 expression in hippocampal neurons from rat primary culture. These findings suggest that miR-188 serves to fine-tune synaptic plasticity by regulating Nrp-2 expression. PMID:22514329

An activity-regulated microRNA, miR-188, controls dendritic plasticity and synaptic transmission by downregulating neuropilin-2.

PubMed

Lee, Kihwan; Kim, Joung-Hun; Kwon, Oh-Bin; An, Kyongman; Ryu, Junghwa; Cho, Kwangwook; Suh, Yoo-Hun; Kim, Hye-Sun

2012-04-18

MicroRNAs (miRNAs) have recently come to be viewed as critical players that modulate a number of cellular features in various biological systems including the mature CNS by exerting regulatory control over the stability and translation of mRNAs. Despite considerable evidence for the regulatory functions of miRNAs, the identities of the miRNA species that are involved in the regulation of synaptic transmission and plasticity and the mechanisms by which these miRNAs exert functional roles remain largely unknown. In the present study, the expression of microRNA-188 (miR-188) was found to be upregulated by the induction of long-term potentiation (LTP). The protein level of neuropilin-2 (Nrp-2), one of the possible molecular targets for miR-188, was decreased during LTP induction. We also confirmed that the luciferase activity of the 3'-UTR of Nrp-2 was diminished by treatment with a miR-188 oligonucleotide but not with a scrambled miRNA oligonucleotide. Nrp-2 serves as a receptor for semaphorin 3F, which is a negative regulator of spine development and synaptic structure. In addition, miR-188 specifically rescued the reduction in dendritic spine density induced by Nrp-2 expression in hippocampal neurons from rat primary culture. Furthermore, miR-188 counteracted the decrease in the miniature EPSC frequency induced by Nrp-2 expression in hippocampal neurons from rat primary culture. These findings suggest that miR-188 serves to fine-tune synaptic plasticity by regulating Nrp-2 expression.

Long-term hippocampal glutamate synapse and astrocyte dysfunctions underlying the altered phenotype induced by adolescent THC treatment in male rats.

PubMed

Zamberletti, Erica; Gabaglio, Marina; Grilli, Massimo; Prini, Pamela; Catanese, Alberto; Pittaluga, Anna; Marchi, Mario; Rubino, Tiziana; Parolaro, Daniela

2016-09-01

Cannabis use has been frequently associated with sex-dependent effects on brain and behavior. We previously demonstrated that adult female rats exposed to delta-9-tetrahydrocannabinol (THC) during adolescence develop long-term alterations in cognitive performances and emotional reactivity, whereas preliminary evidence suggests the presence of a different phenotype in male rats. To thoroughly depict the behavioral phenotype induced by adolescent THC exposure in male rats, we treated adolescent animals with increasing doses of THC twice a day (PND 35-45) and, at adulthood, we performed a battery of behavioral tests to measure affective- and psychotic-like symptoms as well as cognition. Poorer memory performance and psychotic-like behaviors were present after adolescent THC treatment in male rats, without alterations in the emotional component. At cellular level, the expression of the NMDA receptor subunit, GluN2B, as well as the levels of the AMPA subunits, GluA1 and GluA2, were significantly increased in hippocampal post-synaptic fractions from THC-exposed rats compared to controls. Furthermore, increases in the levels of the pre-synaptic marker, synaptophysin, and the post-synaptic marker, PSD95, were also present. Interestingly, KCl-induced [(3)H]D-ASP release from hippocampal synaptosomes, but not gliosomes, was significantly enhanced in THC-treated rats compared to controls. Moreover, in the same brain region, adolescent THC treatment also resulted in a persistent neuroinflammatory state, characterized by increased expression of the astrocyte marker, GFAP, increased levels of the pro-inflammatory markers, TNF-α, iNOS and COX-2, as well as a concomitant reduction of the anti-inflammatory cytokine, IL-10. Notably, none of these alterations was observed in the prefrontal cortex (PFC). Together with our previous findings in females, these data suggest that the sex-dependent detrimental effects induced by adolescent THC exposure on adult behavior may rely on its ability to trigger different region-dependent changes in glutamate synapse and glial cells. The phenotype observed in males is mainly associated with marked dysregulations in the hippocampus, whereas the prevalence of alterations in the emotional sphere in females is associated with profound changes in the PFC. Copyright © 2016 Elsevier Ltd. All rights reserved.

Postsynaptic density 95 (PSD-95) serine 561 phosphorylation regulates a conformational switch and bidirectional dendritic spine structural plasticity.

PubMed

Wu, Qian; Sun, Miao; Bernard, Laura P; Zhang, Huaye

2017-09-29

Postsynaptic density 95 (PSD-95) is a major synaptic scaffolding protein that plays a key role in bidirectional synaptic plasticity, which is a process important for learning and memory. It is known that PSD-95 shows increased dynamics upon induction of plasticity. However, the underlying structural and functional changes in PSD-95 that mediate its role in plasticity remain unclear. Here we show that phosphorylation of PSD-95 at Ser-561 in its guanylate kinase (GK) domain, which is mediated by the partitioning-defective 1 (Par1) kinases, regulates a conformational switch and is important for bidirectional plasticity. Using a fluorescence resonance energy transfer (FRET) biosensor, we show that a phosphomimetic mutation of Ser-561 promotes an intramolecular interaction between GK and the nearby Src homology 3 (SH3) domain, leading to a closed conformation, whereas a non-phosphorylatable S561A mutation or inhibition of Par1 kinase activity decreases SH3-GK interaction, causing PSD-95 to adopt an open conformation. In addition, S561A mutation facilitates the interaction between PSD-95 and its binding partners. Fluorescence recovery after photobleaching imaging reveals that the S561A mutant shows increased stability, whereas the phosphomimetic S561D mutation increases PSD-95 dynamics at the synapse. Moreover, molecular replacement of endogenous PSD-95 with the S561A mutant blocks dendritic spine structural plasticity during chemical long-term potentiation and long-term depression. Endogenous Ser-561 phosphorylation is induced by synaptic NMDA receptor activation, and the SH3-GK domains exhibit a Ser-561 phosphorylation-dependent switch to a closed conformation during synaptic plasticity. Our results provide novel mechanistic insight into the regulation of PSD-95 in dendritic spine structural plasticity through phosphorylation-mediated regulation of protein dynamics and conformation. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Possible Mechanisms Underlying the Therapeutic Effects of Transcranial Magnetic Stimulation

PubMed Central

Chervyakov, Alexander V.; Chernyavsky, Andrey Yu.; Sinitsyn, Dmitry O.; Piradov, Michael A.

2015-01-01

Transcranial magnetic stimulation (TMS) is an effective method used to diagnose and treat many neurological disorders. Although repetitive TMS (rTMS) has been used to treat a variety of serious pathological conditions including stroke, depression, Parkinson’s disease, epilepsy, pain, and migraines, the pathophysiological mechanisms underlying the effects of long-term TMS remain unclear. In the present review, the effects of rTMS on neurotransmitters and synaptic plasticity are described, including the classic interpretations of TMS effects on synaptic plasticity via long-term potentiation and long-term depression. We also discuss the effects of rTMS on the genetic apparatus of neurons, glial cells, and the prevention of neuronal death. The neurotrophic effects of rTMS on dendritic growth and sprouting and neurotrophic factors are described, including change in brain-derived neurotrophic factor concentration under the influence of rTMS. Also, non-classical effects of TMS related to biophysical effects of magnetic fields are described, including the quantum effects, the magnetic spin effects, genetic magnetoreception, the macromolecular effects of TMS, and the electromagnetic theory of consciousness. Finally, we discuss possible interpretations of TMS effects according to dynamical systems theory. Evidence suggests that a rTMS-induced magnetic field should be considered a separate physical factor that can be impactful at the subatomic level and that rTMS is capable of significantly altering the reactivity of molecules (radicals). It is thought that these factors underlie the therapeutic benefits of therapy with TMS. Future research on these mechanisms will be instrumental to the development of more powerful and reliable TMS treatment protocols. PMID:26136672

Possible Mechanisms Underlying the Therapeutic Effects of Transcranial Magnetic Stimulation.

PubMed

Chervyakov, Alexander V; Chernyavsky, Andrey Yu; Sinitsyn, Dmitry O; Piradov, Michael A

2015-01-01

Transcranial magnetic stimulation (TMS) is an effective method used to diagnose and treat many neurological disorders. Although repetitive TMS (rTMS) has been used to treat a variety of serious pathological conditions including stroke, depression, Parkinson's disease, epilepsy, pain, and migraines, the pathophysiological mechanisms underlying the effects of long-term TMS remain unclear. In the present review, the effects of rTMS on neurotransmitters and synaptic plasticity are described, including the classic interpretations of TMS effects on synaptic plasticity via long-term potentiation and long-term depression. We also discuss the effects of rTMS on the genetic apparatus of neurons, glial cells, and the prevention of neuronal death. The neurotrophic effects of rTMS on dendritic growth and sprouting and neurotrophic factors are described, including change in brain-derived neurotrophic factor concentration under the influence of rTMS. Also, non-classical effects of TMS related to biophysical effects of magnetic fields are described, including the quantum effects, the magnetic spin effects, genetic magnetoreception, the macromolecular effects of TMS, and the electromagnetic theory of consciousness. Finally, we discuss possible interpretations of TMS effects according to dynamical systems theory. Evidence suggests that a rTMS-induced magnetic field should be considered a separate physical factor that can be impactful at the subatomic level and that rTMS is capable of significantly altering the reactivity of molecules (radicals). It is thought that these factors underlie the therapeutic benefits of therapy with TMS. Future research on these mechanisms will be instrumental to the development of more powerful and reliable TMS treatment protocols.

Oscillatory power decreases and long-term memory: the information via desynchronization hypothesis

PubMed Central

Hanslmayr, Simon; Staudigl, Tobias; Fellner, Marie-Christin

2012-01-01

The traditional belief is that brain oscillations are important for human long-term memory, because they induce synchronized firing between cell assemblies which shapes synaptic plasticity. Therefore, most prior studies focused on the role of synchronization for episodic memory, as reflected in theta (∼5 Hz) and gamma (>40 Hz) power increases. These studies, however, neglect the role that is played by neural desynchronization, which is usually reflected in power decreases in the alpha and beta frequency band (8–30 Hz). In this paper we present a first idea, derived from information theory that gives a mechanistic explanation of how neural desynchronization aids human memory encoding and retrieval. Thereby we will review current studies investigating the role of alpha and beta power decreases during long-term memory tasks and show that alpha and beta power decreases play an important and active role for human memory. Applying mathematical models of information theory, we demonstrate that neural desynchronization is positively related to the richness of information represented in the brain, thereby enabling encoding and retrieval of long-term memories. This information via desynchronization hypothesis makes several predictions, which can be tested in future experiments. PMID:22514527

Oscillatory power decreases and long-term memory: the information via desynchronization hypothesis.

PubMed

Hanslmayr, Simon; Staudigl, Tobias; Fellner, Marie-Christin

2012-01-01

The traditional belief is that brain oscillations are important for human long-term memory, because they induce synchronized firing between cell assemblies which shapes synaptic plasticity. Therefore, most prior studies focused on the role of synchronization for episodic memory, as reflected in theta (∼5 Hz) and gamma (>40 Hz) power increases. These studies, however, neglect the role that is played by neural desynchronization, which is usually reflected in power decreases in the alpha and beta frequency band (8-30 Hz). In this paper we present a first idea, derived from information theory that gives a mechanistic explanation of how neural desynchronization aids human memory encoding and retrieval. Thereby we will review current studies investigating the role of alpha and beta power decreases during long-term memory tasks and show that alpha and beta power decreases play an important and active role for human memory. Applying mathematical models of information theory, we demonstrate that neural desynchronization is positively related to the richness of information represented in the brain, thereby enabling encoding and retrieval of long-term memories. This information via desynchronization hypothesis makes several predictions, which can be tested in future experiments.

[Progress on metaplasticity and its role in learning and memory].

PubMed

Wang, Shao-Li; Lu, Wei

2016-08-25

Long-term potentiation (LTP) and long-term depression (LTD) are two major forms of synaptic plasticity that are widely considered as important cellular models of learning and memory. Metaplasticity is defined as the plasticity of synaptic plasticity and thus is an advanced form of plasticity. The history of synaptic activity can affect the subsequent synaptic plasticity induction. Therefore, it is important to study metaplasticity to explore new mechanisms underlying various brain functions including learning and memory. Since the concept of metaplasticity was proposed, it has aroused widespread concerns and attracted numerous researchers to dig more details on this topic. These new-found experimental phenomena and cellular mechanisms have established the basis of theoretical studies on metaplasticity. In recent years, researchers have found that metaplasticity can not only affect the synaptic plasticity, but also regulate the neural network to encode specific content and enhance the learning and memory. These findings have greatly enriched our knowledge on plasticity and opened a new route to study the mechanism of learning and memory. In this review, we discuss the recent progress on metaplasticity on following three aspects: (1) the molecular mechanisms of metaplasticity; (2) the role of metaplasticity in learning and memory; and (3) the outlook of future study on metaplasticity.

Persistent improvement in synaptic and cognitive functions in an Alzheimer mouse model after rolipram treatment

PubMed Central

Gong, Bing; Vitolo, Ottavio V.; Trinchese, Fabrizio; Liu, Shumin; Shelanski, Michael; Arancio, Ottavio

2004-01-01

Evidence suggests that Alzheimer disease (AD) begins as a disorder of synaptic function, caused in part by increased levels of amyloid β-peptide 1–42 (Aβ42). Both synaptic and cognitive deficits are reproduced in mice double transgenic for amyloid precursor protein (AA substitution K670N,M671L) and presenilin-1 (AA substitution M146V). Here we demonstrate that brief treatment with the phosphodiesterase 4 inhibitor rolipram ameliorates deficits in both long-term potentiation (LTP) and contextual learning in the double-transgenic mice. Most importantly, this beneficial effect can be extended beyond the duration of the administration. One course of long-term systemic treatment with rolipram improves LTP and basal synaptic transmission as well as working, reference, and associative memory deficits for at least 2 months after the end of the treatment. This protective effect is possibly due to stabilization of synaptic circuitry via alterations in gene expression by activation of the cAMP-dependent protein kinase (PKA)/cAMP regulatory element–binding protein (CREB) signaling pathway that make the synapses more resistant to the insult inflicted by Aβ. Thus, agents that enhance the cAMP/PKA/CREB pathway have potential for the treatment of AD and other diseases associated with elevated Aβ42 levels. PMID:15578094

Microelectrode array recordings of cultured hippocampal networks reveal a simple model for transcription and protein synthesis-dependent plasticity

PubMed Central

Arnold, Fiona JL; Hofmann, Frank; Bengtson, C. Peter; Wittmann, Malte; Vanhoutte, Peter; Bading, Hilmar

2005-01-01

A simplified cell culture system was developed to study neuronal plasticity. As changes in synaptic strength may alter network activity patterns, we grew hippocampal neurones on a microelectrode array (MEA) and monitored their collective behaviour with 60 electrodes simultaneously. We found that exposure of the network for 15 min to the GABAA receptor antagonist bicuculline induced an increase in synaptic efficacy at excitatory synapses that was associated with an increase in the frequency of miniature AMPA receptor-mediated EPSCs and a change in network activity from uncoordinated firing of neurones (lacking any recognizable pattern) to a highly organized, periodic and synchronous burst pattern. Induction of recurrent synchronous bursting was dependent on NMDA receptor activation and required extracellular signal-regulated kinase (ERK)1/2 signalling and translation of pre-existing mRNAs. Once induced, the burst pattern persisted for several days; its maintenance phase (> 4 h) was dependent on gene transcription taking place in a critical period of 120 min following induction. Thus, cultured hippocampal neurones display a simple, transcription and protein synthesis-dependent form of plasticity. The non-invasive nature of MEA recordings provides a significant advantage over traditional assays for synaptic connectivity (i.e. long-term potentiation in brain slices) and facilitates the search for activity-regulated genes critical for late-phase plasticity. PMID:15618268

Early Growth Response 1 (Egr-1) Regulates N-Methyl-d-aspartate Receptor (NMDAR)-dependent Transcription of PSD-95 and α-Amino-3-hydroxy-5-methyl-4-isoxazole Propionic Acid Receptor (AMPAR) Trafficking in Hippocampal Primary Neurons.

PubMed

Qin, Xike; Jiang, Yongjun; Tse, Yiu Chung; Wang, Yunling; Wong, Tak Pan; Paudel, Hemant K

2015-12-04

The N-methyl-d-aspartate receptor (NMDAR) controls synaptic plasticity and memory function and is one of the major inducers of transcription factor Egr-1 in the hippocampus. However, how Egr-1 mediates the NMDAR signal in neurons has remained unclear. Here, we show that the hippocampus of mice lacking Egr-1 displays electrophysiology properties and ultrastructure that are similar to mice overexpressing PSD-95, a major scaffolding protein of postsynaptic density involved in synapse formation, synaptic plasticity, and synaptic targeting of AMPA receptors (AMPARs), which mediate the vast majority of excitatory transmission in the CNS. We demonstrate that Egr-1 is a transcription repressor of the PSD-95 gene and is recruited to the PSD-95 promoter in response to NMDAR activation. Knockdown of Egr-1 in rat hippocampal primary neurons blocks NMDAR-induced PSD-95 down-regulation and AMPAR endocytosis. Likewise, overexpression of Egr-1 in rat hippocampal primary neurons causes reduction in PSD-95 protein level and promotes AMPAR endocytosis. Our data indicate that Egr-1 is involved in NMDAR-mediated PSD-95 down-regulation and AMPAR endocytosis, a process important in the expression of long term depression. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Microelectrode array recordings of cultured hippocampal networks reveal a simple model for transcription and protein synthesis-dependent plasticity.

PubMed

Arnold, Fiona J L; Hofmann, Frank; Bengtson, C Peter; Wittmann, Malte; Vanhoutte, Peter; Bading, Hilmar

2005-04-01

A simplified cell culture system was developed to study neuronal plasticity. As changes in synaptic strength may alter network activity patterns, we grew hippocampal neurones on a microelectrode array (MEA) and monitored their collective behaviour with 60 electrodes simultaneously. We found that exposure of the network for 15 min to the GABA(A) receptor antagonist bicuculline induced an increase in synaptic efficacy at excitatory synapses that was associated with an increase in the frequency of miniature AMPA receptor-mediated EPSCs and a change in network activity from uncoordinated firing of neurones (lacking any recognizable pattern) to a highly organized, periodic and synchronous burst pattern. Induction of recurrent synchronous bursting was dependent on NMDA receptor activation and required extracellular signal-regulated kinase (ERK)1/2 signalling and translation of pre-existing mRNAs. Once induced, the burst pattern persisted for several days; its maintenance phase (> 4 h) was dependent on gene transcription taking place in a critical period of 120 min following induction. Thus, cultured hippocampal neurones display a simple, transcription and protein synthesis-dependent form of plasticity. The non-invasive nature of MEA recordings provides a significant advantage over traditional assays for synaptic connectivity (i.e. long-term potentiation in brain slices) and facilitates the search for activity-regulated genes critical for late-phase plasticity.

Neonatal isolation delays the developmental decline of long-term depression in the CA1 region of rat hippocampus.

PubMed

Ku, Hsiao-Yun; Huang, Yu-Fei; Chao, Pei-Hsuan; Huang, Chiung-Chun; Hsu, Kuei-Sen

2008-11-01

Activity-dependent alterations of synaptic efficacy or connectivity are essential for the development, signal processing, and learning and memory functions of the nervous system. It was observed that, in particular in the CA1 region of the hippocampus, low-frequency stimulation (LFS) became progressively less effective at inducing long-term depression (LTD) with advancing developmental age. The physiological factors regulating this developmental plasticity change, however, have not yet been elucidated. Here we examined the hypothesis that neonatal isolation (once per day for 1 h from postnatal days 1-7) is able to alter processes underlying the developmental decline of LTD. We confirm that the magnitude of LTD induced by LFS (900 stimuli at 1 Hz) protocol correlates negatively with developmental age and illustrates that neonatal isolation delays this developmental decline via the activation of corticotrophin-releasing factor (CRF) system. Furthermore, this modulation appears to be mediated by an increased transcription of N-methyl-D-aspartate receptor NR2B subunits. We also demonstrate that intracerebroventricular injection of CRF postnatally mimicked the effect of neonatal isolation to increase the expression of NR2B subunits and delayed the developmental decline of LTD, which was specifically blocked by CRF receptor 1 antagonist NBI27914 pretreatment. These results suggest a novel role for CRF in regulating developmental events in the hippocampus and indicate that although maternal deprivation is stressful for neonate, appropriate neonatal isolation can serve to promote an endocrine state that may regulate the gradual developmental change in the induction rules for synaptic plasticity in the hippocampal CA1 region.

Artificial Synaptic Devices Based on Natural Chicken Albumen Coupled Electric-Double-Layer Transistors

NASA Astrophysics Data System (ADS)

Wu, Guodong; Feng, Ping; Wan, Xiang; Zhu, Liqiang; Shi, Yi; Wan, Qing

2016-03-01

Recent progress in using biomaterials to fabricate functional electronics has got growing attention for the new generation of environmentally friendly and biocompatible electronic devices. As a kind of biological material with rich source, proteins are essential natural component of all organisms. At the same time, artificial synaptic devices are of great significance for neuromorphic systems because they can emulate the signal process and memory behaviors of biological synapses. In this report, natural chicken albumen with high proton conductivity was used as the coupling electrolyte film for organic/inorganic hybrid synaptic devices fabrication. Some important synaptic functions including paired-pulse facilitation, dynamic filtering, short-term to long-term memory transition and spatial summation and shunting inhibition were successfully mimicked. Our results are very interesting for biological friendly artificial neuron networks and neuromorphic systems.

A Novel Cysteine-Rich Neurotrophic Factor in "Aplysia" Facilitates Growth, MAPK Activation, and Long-Term Synaptic Facilitation

ERIC Educational Resources Information Center

Pu, Lu; Kopec, Ashley M.; Boyle, Heather D.; Carew, Thomas J.

2014-01-01

Neurotrophins are critically involved in developmental processes such as neuronal cell survival, growth, and differentiation, as well as in adult synaptic plasticity contributing to learning and memory. Our previous studies examining neurotrophins and memory formation in "Aplysia" showed that a TrkB ligand is required for MAPK…

The Extracellular Protease Matrix Metalloproteinase-9 Is Activated by Inhibitory Avoidance Learning and Required for Long-Term Memory

ERIC Educational Resources Information Center

Nagy, Vanja; Bozdagi, Ozlem; Huntley, George W.

2007-01-01

Matrix metalloproteinases (MMPs) are a family of extracellularly acting proteolytic enzymes with well-recognized roles in plasticity and remodeling of synaptic circuits during brain development and following brain injury. However, it is now becoming increasingly apparent that MMPs also function in normal, nonpathological synaptic plasticity of the…

"Silent" Priming of Translation-Dependent LTP by [Beta]-Adrenergic Receptors Involves Phosphorylation and Recruitment of AMPA Receptors

ERIC Educational Resources Information Center

Tenorio, Gustavo; Connor, Steven A.; Guevremont, Diane; Abraham, Wickliffe C.; Williams, Joanna; O'Dell, Thomas J.; Nguyen, Peter V.

2010-01-01

The capacity for long-term changes in synaptic efficacy can be altered by prior synaptic activity, a process known as "metaplasticity." Activation of receptors for modulatory neurotransmitters can trigger downstream signaling cascades that persist beyond initial receptor activation and may thus have metaplastic effects. Because activation of…

Long-Term Exercise Is Needed to Enhance Synaptic Plasticity in the Hippocampus

ERIC Educational Resources Information Center

Patten, Anna R.; Sickmann, Helle; Hryciw, Brett N.; Kucharsky, Tessa; Parton, Roberta; Kernick, Aimee; Christie, Brian R.

2013-01-01

Exercise can have many benefits for the body, but it also benefits the brain by increasing neurogenesis, synaptic plasticity, and performance on learning and memory tasks. The period of exercise needed to realize the structural and functional benefits for the brain have not been well delineated, and previous studies have used periods of exercise…

BISPHENOL A INTERFERES WITH SYNAPTIC REMODELING

PubMed Central

Hajszan, Tibor; Leranth, Csaba

2010-01-01

The potential adverse effects of Bisphenol A (BPA), a synthetic xenoestrogen, have long been debated. Although standard toxicology tests have revealed no harmful effects, recent research highlighted what was missed so far: BPA-induced alterations in the nervous system. Since 2004, our laboratory has been investigating one of the central effects of BPA, which is interference with gonadal steroid-induced synaptogenesis and the resulting loss of spine synapses. We have shown in both rats and nonhuman primates that BPA completely negates the ~70–100% increase in the number of hippocampal and prefrontal spine synapses induced by both estrogens and androgens. Synaptic loss of this magnitude may have significant consequences, potentially causing cognitive decline, depression, and schizophrenia, to mention those that our laboratory has shown to be associated with synaptic loss. Finally, we discuss why children may particularly be vulnerable to BPA, which represents future direction of research in our laboratory. PMID:20609373

Role of nitric oxide in long-term potentiation of the rat medial vestibular nuclei.

PubMed

Grassi, S; Pettorossi, V E

2000-01-01

In rat brainstem slices, we investigated the role of nitric oxide in long-term potentiation induced in the ventral portion of the medial vestibular nuclei by high-frequency stimulation of the primary vestibular afferents. The nitric oxide scavenger [2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide ] and the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester were administered before and after induction of potentiation. Both drugs completely prevented long-term potentiation, whereas they did not impede the potentiation build-up, or affect the already established potentiation. These results demonstrate that the induction, but not the maintenance of vestibular long-term potentiation, depends on the synthesis and release into the extracellular medium of nitric oxide. In addition, we analysed the effect of the nitric oxide donor sodium nitroprusside on vestibular responses. Sodium nitroprusside induced long-term potentiation, as evidenced through the field potential enhancement and unit peak latency decrease. This potentiation was impeded by D, L-2-amino-5-phosphonopentanoic acid, and was reduced under blockade of synaptosomal platelet-activating factor receptors by ginkgolide B and group I metabotropic glutamate receptors by (R,S)-1-aminoindan-1, 5-dicarboxylic acid. When reduced, potentiation fully developed following the washout of antagonist, demonstrating an involvement of platelet-activating factor and group I metabotropic glutamate receptors in its full development. Potentiation induced by sodium nitroprusside was also associated with a decrease in the paired-pulse facilitation ratio, which persisted under ginkgolide B, indicating that nitric oxide increases glutamate release independently of platelet-activating factor-mediated presynaptic events. We suggest that nitric oxide, released after the activation of N-methyl-D-aspartate receptors, acts as a retrograde messenger leading to an enhancement of glutamate release to a sufficient level for triggering potentiation. Once the synaptic efficacy has changed, it becomes a long-lasting phenomenon only through a subsequent action of platelet-activating factor.

SPIN90 Modulates Long-Term Depression and Behavioral Flexibility in the Hippocampus

PubMed Central

Kim, Dae Hwan; Kang, Minkyung; Kim, Chong-Hyun; Huh, Yun Hyun; Cho, In Ha; Ryu, Hyun-Hee; Chung, Kyung Hwun; Park, Chul-Seung; Rhee, Sangmyung; Lee, Yong-Seok; Song, Woo Keun

2017-01-01

The importance of actin-binding proteins (ABPs) in the regulation of synapse morphology and plasticity has been well established. SH3 protein interacting with Nck, 90 kDa (SPIN90), an Nck-interacting protein highly expressed in synapses, is essential for actin remodeling and dendritic spine morphology. Synaptic targeting of SPIN90 to spine heads or dendritic shafts depends on its phosphorylation state, leading to blockage of cofilin-mediated actin depolymerization and spine shrinkage. However, the physiological role of SPIN90 in long-term plasticity, learning and memory are largely unknown. In this study, we demonstrate that Spin90-knockout (KO) mice exhibit substantial deficits in synaptic plasticity and behavioral flexibility. We found that loss of SPIN90 disrupted dendritic spine density in CA1 neurons of the hippocampus and significantly impaired long-term depression (LTD), leaving basal synaptic transmission and long-term potentiation (LTP) intact. These impairments were due in part to deficits in AMPA receptor endocytosis and its pre-requisites, GluA1 dephosphorylation and postsynaptic density (PSD) 95 phosphorylation, but also by an intrinsic activation of Akt-GSK3β signaling as a result of Spin90-KO. In accordance with these defects, mice lacking SPIN90 were found to carry significant deficits in object-recognition and behavioral flexibility, while learning ability was largely unaffected. Collectively, these findings demonstrate a novel modulatory role for SPIN90 in hippocampal LTD and behavioral flexibility. PMID:28979184

The metabotropic glutamate receptor mGluR3 is critically required for hippocampal long-term depression and modulates long-term potentiation in the dentate gyrus of freely moving rats.

PubMed

Pöschel, Beatrice; Wroblewska, Barbara; Heinemann, Uwe; Manahan-Vaughan, Denise

2005-09-01

Group II metabotropic glutamate receptors (mGluRs) play an important role in the regulation of hippocampal synaptic plasticity in vivo: long-term potentiation (LTP) is inhibited and long-term depression (LTD) is enhanced by activation of these receptors. The contribution, in vivo, of the individual group II mGluR subtypes has not been characterized. We analysed the involvement of the subtype mGluR3 in LTD and LTP. Rats were implanted with electrodes to enable chronic measurement of evoked potentials from medial perforant path-dentate gyrus synapses. Neither the selective mGluR3 agonist, N-acetylaspartylglutamate (NAAG), nor the antagonist beta-NAAG, given intracerebrally, affected basal synaptic transmission. beta-NAAG significantly inhibited LTD expression. NAAG exhibited transient inhibitory effects on the intermediate phase of LTD. Whereas NAAG altered paired-pulse responses, beta-NAAG had no effect, suggesting that antagonism of mGluR3 prevents LTD via a postsynaptic mechanism, whereas agonist activation of mGluR3 modulates LTD at a presynaptic locus. NAAG impaired the expression of LTP, whereas beta-NAAG had no effect. NAAG effects on LTP were blocked by EGLU, a selective group II mGluR antagonist. Our data suggest an essential role for mGluR3 in LTD, and a modulatory role for mGluR3 in LTP, with effects being mediated by distinct pre- and post-synaptic loci.

A role for synaptic and network plasticity in controlling epileptiform activity in CA1 in the kainic acid-lesioned rat hippocampus in vitro.

PubMed Central

Bernard, C; Wheal, H V

1996-01-01

1. Stimulation of the surviving afferents in the stratum radiatum of the CA1 area in kainic acid-lesioned hippocampal slices produced graded epileptiform activity, part of which (> 20%) involved the activation of N-methyl-D-aspartate (NMDA) receptors. There was also a failure of synaptic inhibition in this region. In this preparation, we have tested the effects of low-frequency stimulation (LFS; 1 Hz for 15 min) on synaptic responses and epileptiform activity. 2. LFS resulted in long-term depression (LTD) of excitatory synaptic potentials (EPSPs), long-term decrease of population spike amplitudes (PSAs) and EPSP-spike (E-S) potentiation. Evoked epileptiform activity was reduced but neurons had a higher probability of discharge. LTD could be reversed by subsequent tetanic stimulation whereas E-S dissociation remained unchanged. Synaptic and network responses could be saturated towards either potentiation or depression. However, E-S potentiation was maximal following the first conditioning stimulus. 3. NMDA receptor-mediated responses were pharmacologically isolated. LFS resulted in LTD of synaptic responses, long-term decrease of PSAs and E-S depression. These depressions could not be reversed by subsequent tetanic stimulation. alpha-Amino-3-hydroxy-5-methylisoxazolepropionic acid (AMPA) and NMDA receptor-mediated responses were then measured in isolation before and following conditioning stimuli. LFS was shown to simultaneously produce LTD of AMPA and NMDA receptor-mediated responses. E-S potentiation of the AMPA component and E-S depression of the NMDA component occurred coincidentally. 4. LTD of AMPA and NMDA receptor-mediated responses were shown to be NMDA dependent. In contrast, E-S potentiation and depression occurred even when NMDA receptors were pharmacologically blocked. 5. These findings indicate that synaptic responses could be modified bidirectionally in the CA1 area of kainic acid-lesioned rat hippocampus in an NMDA receptor-dependent manner. However, E-S dissociations were independent of the activation of NMDA receptors, hinting at mechanisms different from those of synaptic LTD. We suggest that changes in E-S coupling were caused by a modification of the firing threshold of the CA1 pyramidal neurons. Furthermore, the firing mechanisms controlling NMDA and AMPA receptor-mediated network activity appeared to be different. The possible use of LFS applied to the hippocampus as a clinical intervention to suppress epileptiform activity is discussed. PMID:8866357

Postsynaptic activity reverses the sign of the acetylcholine-induced long-term plasticity of GABAA inhibition

PubMed Central

Domínguez, Soledad; Fernández de Sevilla, David; Buño, Washington

2014-01-01

Acetylcholine (ACh) regulates forms of plasticity that control cognitive functions but the underlying mechanisms remain largely unknown. ACh controls the intrinsic excitability, as well as the synaptic excitation and inhibition of CA1 hippocampal pyramidal cells (PCs), cells known to participate in circuits involved in cognition and spatial navigation. However, how ACh regulates inhibition in function of postsynaptic activity has not been well studied. Here we show that in rat PCs, a brief pulse of ACh or a brief stimulation of cholinergic septal fibers combined with repeated depolarization induces strong long-term enhancement of GABAA inhibition (GABAA-LTP). Indeed, this enhanced inhibition is due to the increased activation of α5βγ2 subunit-containing GABAA receptors by the GABA released. GABAA-LTP requires the activation of M1-muscarinic receptors and an increase in cytosolic Ca2+. In the absence of PC depolarization ACh triggered a presynaptic depolarization-induced suppression of inhibition (DSI), revealing that postsynaptic activity gates the effects of ACh from presynaptic DSI to postsynaptic LTP. These results provide key insights into mechanisms potentially linked with cognitive functions, spatial navigation, and the homeostatic control of abnormal hyperexcitable states. PMID:24938789

Wasp uses venom cocktail to manipulate the behavior of its cockroach prey.

PubMed

Libersat, F

2003-07-01

The sting of the parasitoid wasp Ampulex compressa is unusual, as it induces a transient paralysis of the front legs followed by grooming behavior and then by a long-term hypokinesia of its cockroach prey. Because the wasp's goal is to provide a living meal for its newborn larva, the behavioral changes in the prey are brought about by manipulating the host behavior in a way beneficial to the wasp and its offspring. To this end, the wasp injects its venom cocktail with two consecutive stings directly into the host's central nervous system. The first sting in the thorax causes a transient front leg paralysis lasting a few minutes. This paralysis is due to the presence of a venom component that induces a postsynaptic block of central cholinergic synaptic transmission. Following the head sting, dopamine identified in the venom appears to induce 30 min of intense grooming. During the long-term hypokinesia that follows the grooming, specific behaviors of the prey are inhibited while others are unaffected. We propose that the venom represses the activity of head ganglia neurons thereby removing the descending excitatory drive to the thoracic neurons.

Epigenetic stability in the adult mouse cortex under conditions of pharmacologically induced histone acetylation.

PubMed

Benoit, Jamie; Ayoub, Albert; Rakic, Pasko

2016-11-01

Histone acetylation is considered a major epigenetic process that affects brain development and synaptic plasticity, as well as learning and memory. The transcriptional effectors and morphological changes responsible for plasticity as a result of long-term modifications to histone acetylation are not fully understood. To this end, we pharmacologically inhibited histone deacetylation using Trichostatin A in adult (6-month-old) mice and found significant increases in the levels of the acetylated histone marks H3Lys9, H3Lys14 and H4Lys12. High-resolution transcriptome analysis of diverse brain regions uncovered few differences in gene expression between treated and control animals, none of which were plasticity related. Instead, after increased histone acetylation, we detected a large number of novel transcriptionally active regions, which correspond to long non-coding RNAs (lncRNAs). We also surprisingly found no significant changes in dendritic spine plasticity in layers 1 and 2/3 of the visual cortex using long-term in vivo two-photon imaging. Our results indicate that chronic pharmacologically induced histone acetylation can be decoupled from gene expression and instead, may potentially exert a post-transcriptional effect through the differential production of lncRNAs.

Synapse Specificity of Long-Term Potentiation Breaks Down with Aging

ERIC Educational Resources Information Center

Ris, Laurence; Godaux, Emile

2007-01-01

Memory shows age-related decline. According to the current prevailing theoretical model, encoding of memories relies on modifications in the strength of the synapses connecting the different cells within a neuronal network. The selective increases in synaptic weight are thought to be biologically implemented by long-term potentiation (LTP). Here,…

Object-Place Recognition Learning Triggers Rapid Induction of Plasticity-Related Immediate Early Genes and Synaptic Proteins in the Rat Dentate Gyrus

PubMed Central

Soulé, Jonathan; Penke, Zsuzsa; Kanhema, Tambudzai; Alme, Maria Nordheim; Laroche, Serge; Bramham, Clive R.

2008-01-01

Long-term recognition memory requires protein synthesis, but little is known about the coordinate regulation of specific genes. Here, we examined expression of the plasticity-associated immediate early genes (Arc, Zif268, and Narp) in the dentate gyrus following long-term object-place recognition learning in rats. RT-PCR analysis from dentate gyrus tissue collected shortly after training did not reveal learning-specific changes in Arc mRNA expression. In situ hybridization and immunohistochemistry were therefore used to assess possible sparse effects on gene expression. Learning about objects increased the density of granule cells expressing Arc, and to a lesser extent Narp, specifically in the dorsal blade of the dentate gyrus, while Zif268 expression was elevated across both blades. Thus, object-place recognition triggers rapid, blade-specific upregulation of plasticity-associated immediate early genes. Furthermore, Western blot analysis of dentate gyrus homogenates demonstrated concomitant upregulation of three postsynaptic density proteins (Arc, PSD-95, and α-CaMKII) with key roles in long-term synaptic plasticity and long-term memory. PMID:19190776

Long-term Treatment with Oriental Medicinal Herb Artemisia princeps Alters Neuroplasticity in a Rat Model of Ovarian Hormone Deficiency

PubMed Central

Kim, Hyun-Bum; Kwon, Byeong-Jae; Cho, Hyun-Ji; Kim, Ji-Won; Chon, Jeong-Woo; Do, Moon-Ho; Park, Sang-Yong; Kim, Sun-Yeou; Maeng, Sung-Ho; Park, Yoo-Kyoung

2015-01-01

Artemisia princeps (AP) is a flowering perennial used as a traditional medicine and dietary supplement across East Asia. No study has yet assessed its effects on synaptic plasticity in hippocampus and much less in a model of ovarian hormone deficiency. We examined the influence of chronic oral AP ethanol extract treatment in ovariectomized rats on the induction of long-term depression in a representative synapse (CA3-CA1) of the hippocampus. Ovariectomized rats demonstrated lower trabecular mean bone mineral densities than sham, validating the establishment of pathology. Against this background of pathology, AP-treated ovariectomized rats exhibited attenuated long-term depression (LTD) in CA1 relative to water-treated controls as measured by increased field excitatory post-synaptic potentials (fEPSP) activation averages over the post-stimulation period. While pathological significance of long-term depression (LTD) in ovariectomized rats is conflicting, that AP treatment significantly affected its induction offers justification for further study of its influences on plasticity and its related disorders. PMID:25792871

mTOR signaling: at the crossroads of plasticity, memory and disease.

PubMed

Hoeffer, Charles A; Klann, Eric

2010-02-01

Mammalian target of rapamycin (mTOR) is a protein kinase involved in translation control and long-lasting synaptic plasticity. mTOR functions as the central component of two multi-protein signaling complexes, mTORC1 and mTORC2, which can be distinguished from each other based on their unique compositions and substrates. Although the majority of evidence linking mTOR function to synaptic plasticity comes from studies utilizing rapamycin, studies in genetically modified mice also suggest that mTOR couples receptors to the translation machinery for establishing long-lasting synaptic changes that are the basis for higher order brain function, including long-term memory. Finally, perturbation of the mTOR signaling cascade appears to be a common pathophysiological feature of human neurological disorders, including mental retardation syndromes and autism spectrum disorders. (c) 2009 Elsevier Ltd. All rights reserved.

mTOR Signaling: At the Crossroads of Plasticity, Memory, and Disease

PubMed Central

Hoeffer, Charles A.; Klann, Eric

2009-01-01

Mammalian target of rapamycin (mTOR) is a protein kinase involved in translation control and long-lasting synaptic plasticity. mTOR functions as the central component of two multi-protein signaling complexes, mTORC1 and mTORC2, which can be distinguished from each other based on their unique compositions and substrates. Although majority of evidence linking mTOR function to synaptic plasticity comes from studies utilizing rapamycin, studies in genetically-modified mice also suggest that mTOR couples receptors to the translation machinery for establishing long-lasting synaptic changes that are the basis for higher order brain function, including long-term memory. Finally, perturbation of the mTOR signaling cascade appears to be a common pathophysiological feature of human neurological disorders, including mental retardation syndromes and autism spectrum disorders. PMID:19963289

Short-term plasticity and long-term potentiation mimicked in single inorganic synapses

NASA Astrophysics Data System (ADS)

Ohno, Takeo; Hasegawa, Tsuyoshi; Tsuruoka, Tohru; Terabe, Kazuya; Gimzewski, James K.; Aono, Masakazu

2011-08-01

Memory is believed to occur in the human brain as a result of two types of synaptic plasticity: short-term plasticity (STP) and long-term potentiation (LTP; refs , , , ). In neuromorphic engineering, emulation of known neural behaviour has proven to be difficult to implement in software because of the highly complex interconnected nature of thought processes. Here we report the discovery of a Ag2S inorganic synapse, which emulates the synaptic functions of both STP and LTP characteristics through the use of input pulse repetition time. The structure known as an atomic switch, operating at critical voltages, stores information as STP with a spontaneous decay of conductance level in response to intermittent input stimuli, whereas frequent stimulation results in a transition to LTP. The Ag2S inorganic synapse has interesting characteristics with analogies to an individual biological synapse, and achieves dynamic memorization in a single device without the need of external preprogramming. A psychological model related to the process of memorizing and forgetting is also demonstrated using the inorganic synapses. Our Ag2S element indicates a breakthrough in mimicking synaptic behaviour essential for the further creation of artificial neural systems that emulate characteristics of human memory.

Synaptic damage underlies EEG abnormalities in postanoxic encephalopathy: A computational study.

PubMed

Ruijter, B J; Hofmeijer, J; Meijer, H G E; van Putten, M J A M

2017-09-01

In postanoxic coma, EEG patterns indicate the severity of encephalopathy and typically evolve in time. We aim to improve the understanding of pathophysiological mechanisms underlying these EEG abnormalities. We used a mean field model comprising excitatory and inhibitory neurons, local synaptic connections, and input from thalamic afferents. Anoxic damage is modeled as aggravated short-term synaptic depression, with gradual recovery over many hours. Additionally, excitatory neurotransmission is potentiated, scaling with the severity of anoxic encephalopathy. Simulations were compared with continuous EEG recordings of 155 comatose patients after cardiac arrest. The simulations agree well with six common categories of EEG rhythms in postanoxic encephalopathy, including typical transitions in time. Plausible results were only obtained if excitatory synapses were more severely affected by short-term synaptic depression than inhibitory synapses. In postanoxic encephalopathy, the evolution of EEG patterns presumably results from gradual improvement of complete synaptic failure, where excitatory synapses are more severely affected than inhibitory synapses. The range of EEG patterns depends on the excitation-inhibition imbalance, probably resulting from long-term potentiation of excitatory neurotransmission. Our study is the first to relate microscopic synaptic dynamics in anoxic brain injury to both typical EEG observations and their evolution in time. Copyright © 2017 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.

Synaptic behaviors of thin-film transistor with a Pt/HfO x /n-type indium-gallium-zinc oxide gate stack.

PubMed

Yang, Paul; Park, Daehoon; Beom, Keonwon; Kim, Hyung Jun; Kang, Chi Jung; Yoon, Tae-Sik

2018-07-20

We report a variety of synaptic behaviors in a thin-film transistor (TFT) with a metal-oxide-semiconductor gate stack that has a Pt/HfO x /n-type indium-gallium-zinc oxide (n-IGZO) structure. The three-terminal synaptic TFT exhibits a tunable synaptic weight with a drain current modulation upon repeated application of gate and drain voltages. The synaptic weight modulation is analog, voltage-polarity dependent reversible, and strong with a dynamic range of multiple orders of magnitude (>10 4 ). This modulation process emulates biological synaptic potentiation, depression, excitatory-postsynaptic current, paired-pulse facilitation, and short-term to long-term memory transition behaviors as a result of repeated pulsing with respect to the pulse amplitude, width, repetition number, and the interval between pulses. These synaptic behaviors are interpreted based on the changes in the capacitance of the Pt/HfO x /n-IGZO gate stack, the channel mobility, and the threshold voltage that result from the redistribution of oxygen ions by the applied gate voltage. These results demonstrate the potential of this structure for three-terminal synaptic transistor using the gate stack composed of the HfO x gate insulator and the IGZO channel layer.

Synaptic behaviors of thin-film transistor with a Pt/HfO x /n-type indium–gallium–zinc oxide gate stack

NASA Astrophysics Data System (ADS)

Yang, Paul; Park, Daehoon; Beom, Keonwon; Kim, Hyung Jun; Kang, Chi Jung; Yoon, Tae-Sik

2018-07-01

We report a variety of synaptic behaviors in a thin-film transistor (TFT) with a metal-oxide-semiconductor gate stack that has a Pt/HfO x /n-type indium–gallium–zinc oxide (n-IGZO) structure. The three-terminal synaptic TFT exhibits a tunable synaptic weight with a drain current modulation upon repeated application of gate and drain voltages. The synaptic weight modulation is analog, voltage-polarity dependent reversible, and strong with a dynamic range of multiple orders of magnitude (>104). This modulation process emulates biological synaptic potentiation, depression, excitatory-postsynaptic current, paired-pulse facilitation, and short-term to long-term memory transition behaviors as a result of repeated pulsing with respect to the pulse amplitude, width, repetition number, and the interval between pulses. These synaptic behaviors are interpreted based on the changes in the capacitance of the Pt/HfO x /n-IGZO gate stack, the channel mobility, and the threshold voltage that result from the redistribution of oxygen ions by the applied gate voltage. These results demonstrate the potential of this structure for three-terminal synaptic transistor using the gate stack composed of the HfO x gate insulator and the IGZO channel layer.

The Corticohippocampal Circuit, Synaptic Plasticity, and Memory

PubMed Central

Basu, Jayeeta; Siegelbaum, Steven A.

2015-01-01

Synaptic plasticity serves as a cellular substrate for information storage in the central nervous system. The entorhinal cortex (EC) and hippocampus are interconnected brain areas supporting basic cognitive functions important for the formation and retrieval of declarative memories. Here, we discuss how information flow in the EC–hippocampal loop is organized through circuit design. We highlight recently identified corticohippocampal and intrahippocampal connections and how these long-range and local microcircuits contribute to learning. This review also describes various forms of activity-dependent mechanisms that change the strength of corticohippocampal synaptic transmission. A key point to emerge from these studies is that patterned activity and interaction of coincident inputs gives rise to associational plasticity and long-term regulation of information flow. Finally, we offer insights about how learning-related synaptic plasticity within the corticohippocampal circuit during sensory experiences may enable adaptive behaviors for encoding spatial, episodic, social, and contextual memories. PMID:26525152

Cornering the fear engram: long-term synaptic changes in the lateral nucleus of the amygdala after fear conditioning.

PubMed

Kwon, Jeong-Tae; Choi, June-Seek

2009-08-05

Use-dependent synaptic modifications in the lateral nucleus of the amygdala (LA) have been suggested to be the cellular analog of memory trace after pavlovian fear conditioning. However, whether neurophysiological changes in the LA are produced as a direct consequence of associative learning awaits additional proof. Using microstimulation of the medial geniculate nucleus of the thalamus as the conditioned stimulus (CS), we demonstrated that contingent pairings of the brain-stimulation CS and a footshock unconditioned stimulus lead to enhanced synaptic efficacy in the thalamic input to the LA, supporting the hypothesis that localized synaptic alterations underlie fear memory formation.

Temporary microglia-depletion after cosmic radiation modifies phagocytic activity and prevents cognitive deficits.

PubMed

Krukowski, Karen; Feng, Xi; Paladini, Maria Serena; Chou, Austin; Sacramento, Kristen; Grue, Katherine; Riparip, Lara-Kirstie; Jones, Tamako; Campbell-Beachler, Mary; Nelson, Gregory; Rosi, Susanna

2018-05-18

Microglia are the main immune component in the brain that can regulate neuronal health and synapse function. Exposure to cosmic radiation can cause long-term cognitive impairments in rodent models thereby presenting potential obstacles for astronauts engaged in deep space travel. The mechanism/s for how cosmic radiation induces cognitive deficits are currently unknown. We find that temporary microglia depletion, one week after cosmic radiation, prevents the development of long-term memory deficits. Gene array profiling reveals that acute microglia depletion alters the late neuroinflammatory response to cosmic radiation. The repopulated microglia present a modified functional phenotype with reduced expression of scavenger receptors, lysosome membrane protein and complement receptor, all shown to be involved in microglia-synapses interaction. The lower phagocytic activity observed in the repopulated microglia is paralleled by improved synaptic protein expression. Our data provide mechanistic evidence for the role of microglia in the development of cognitive deficits after cosmic radiation exposure.

Learning, memory and long-term potentiation are altered in Nedd4 heterozygous mice.

PubMed

Camera, Daria; Coleman, Harold A; Parkington, Helena C; Jenkins, Trisha A; Pow, David V; Boase, Natasha; Kumar, Sharad; Poronnik, Philip

2016-04-15

The consolidation of short-term memory into long-term memory involves changing protein level and activity for the synaptic plasticity required for long-term potentiation (LTP). AMPA receptor trafficking is a key determinant of LTP and recently ubiquitination by Nedd4 has been shown to play an important role via direct action on the GluA1 subunit, although the physiological relevance of these findings are yet to be determined. We therefore investigated learning and memory in Nedd4(+/-) mice that have a 50% reduction in levels of Nedd4. These mice showed decreased long-term spatial memory as evidenced by significant increases in the time taken to learn the location of and subsequently find a platform in the Morris water maze. In contrast, there were no significant differences between Nedd4(+/+) and Nedd4(+/-) mice in terms of short-term spatial memory in a Y-maze test. Nedd4(+/-) mice also displayed a significant reduction in post-synaptic LTP measured in hippocampal brain slices. Immunofluorescence of Nedd4 in the hippocampus confirmed its expression in hippocampal neurons of the CA1 region. These findings indicate that reducing Nedd4 protein by 50% significantly impairs LTP and long-term memory thereby demonstrating an important role for Nedd4 in these processes. Copyright © 2016 Elsevier B.V. All rights reserved.

Postsynaptic Regulation of Long-Term Facilitation in Aplysia

PubMed Central

Cai, Diancai; Chen, Shanping; Glanzman, David L.

2009-01-01

Summary Repeated exposure to serotonin (5-HT), an endogenous neurotransmitter that mediates behavioral sensitization in Aplysia [1–3], induces long-term facilitation (LTF) of the Aplysia sensorimotor synapse [4]. LTF, a prominent form of invertebrate synaptic plasticity, is believed to play a major role in long-term learning in Aplysia [5]. Until now, LTF has been thought to be due predominantly to cellular processes activated by 5-HT within the presynaptic sensory neuron [6]. Recent work indicates that LTF depends on the increased expression and release of a sensory neuron-specific neuropeptide, sensorin [7]. Sensorin released during LTF appears to bind to autoreceptors on the sensory neuron, thereby activating critical presynaptic signals, including mitogen-activated protein kinase (MAPK) [8, 9]. Here, we show that LTF depends on elevated postsynaptic Ca2+ and postsynaptic protein synthesis. Furthermore, we find that the increased expression of presynaptic sensorin due to 5-HT stimulation requires elevation of postsynaptic intracellular Ca2+. Our results represent perhaps the strongest evidence to date that the increased expression of a specific presynaptic neuropeptide during LTF is regulated by retrograde signals. PMID:18571411

A Reaction-Diffusion Model for Synapse Growth and Long-Term Memory

NASA Astrophysics Data System (ADS)

Liu, Kang; Lisman, John; Hagan, Michael

Memory storage involves strengthening of synaptic transmission known as long-term potentiation (LTP). The late phase of LTP is associated with structural processes that enlarge the synapse. Yet, synapses must be stable, despite continual subunit turnover, over the lifetime of an encoded memory. These considerations suggest that synapses are variable-size stable structure (VSSS), meaning they can switch between multiple metastable structures with different sizes. The mechanisms underlying VSSS are poorly understood. While experiments and theory have suggested that the interplay between diffusion and receptor-scaffold interactions can lead to a preferred stable size for synaptic domains, such a mechanism cannot explain how synapses adopt widely different sizes. Here we develop a minimal reaction-diffusion model of VSSS for synapse growth, incorporating the recent observation from super-resolution microscopy that neural activity can build compositional heterogeneities within synaptic domains. We find that introducing such heterogeneities can change the stable domain size in a controlled manner. We discuss a potential connection between this model and experimental data on synapse sizes, and how it provides a possible mechanism to structurally encode graded long-term memory. We acknowledge the support from NSF INSPIRE Award number IOS-1526941 (KL, MFH, JL) and the Brandeis Center for Bioinspired Soft Materials, an NSF MRSEC, DMR- 1420382 (MFH).

The Less Things Change, the More They Are Different: Contributions of Long-Term Synaptic Plasticity and Homeostasis to Memory

ERIC Educational Resources Information Center

Schacher, Samuel; Hu, Jiang-Yuan

2014-01-01

An important cellular mechanism contributing to the strength and duration of memories is activity-dependent alterations in the strength of synaptic connections within the neural circuit encoding the memory. Reversal of the memory is typically correlated with a reversal of the cellular changes to levels expressed prior to the stimulation. Thus, for…

Mice Overexpressing Type 1 Adenylyl Cyclase Show Enhanced Spatial Memory Flexibility in the Absence of Intact Synaptic Long-Term Depression

ERIC Educational Resources Information Center

Zhang, Ming; Wang, Hongbing

2013-01-01

There is significant interest in understanding the contribution of intracellular signaling and synaptic substrates to memory flexibility, which involves new learning and suppression of obsolete memory. Here, we report that enhancement of Ca[superscript 2+]-stimulated cAMP signaling by overexpressing type 1 adenylyl cyclase (AC1) facilitated…

Possible Contributions of a Novel Form of Synaptic Plasticity in "Aplysia" to Reward, Memory, and Their Dysfunctions in Mammalian Brain

ERIC Educational Resources Information Center

Hawkins, Robert D.

2013-01-01

Recent studies in "Aplysia" have identified a new variation of synaptic plasticity in which modulatory transmitters enhance spontaneous release of glutamate, which then acts on postsynaptic receptors to recruit mechanisms of intermediate- and long-term plasticity. In this review I suggest the hypothesis that similar plasticity occurs in…

Spatial Object Recognition Enables Endogenous LTD that Curtails LTP in the Mouse Hippocampus

PubMed Central

Goh, Jinzhong Jeremy

2013-01-01

Although synaptic plasticity is believed to comprise the cellular substrate for learning and memory, limited direct evidence exists that hippocampus-dependent learning actually triggers synaptic plasticity. It is likely, however, that long-term potentiation (LTP) works in concert with its counterpart, long-term depression (LTD) in the creation of spatial memory. It has been reported in rats that weak synaptic plasticity is facilitated into persistent plasticity if afferent stimulation is coupled with a novel spatial learning event. It is not known if this phenomenon also occurs in other species. We recorded from the hippocampal CA1 of freely behaving mice and observed that novel spatial learning triggers endogenous LTD. Specifically, we observed that LTD is enabled when test-pulse afferent stimulation is given during the learning of object constellations or during a spatial object recognition task. Intriguingly, LTP is significantly impaired by the same tasks, suggesting that LTD is the main cellular substrate for this type of learning. These data indicate that learning-facilitated plasticity is not exclusive to rats and that spatial learning leads to endogenous LTD in the hippocampus, suggesting an important role for this type of synaptic plasticity in the creation of hippocampus-dependent memory. PMID:22510536

Synaptic Plasticity Enables Adaptive Self-Tuning Critical Networks

PubMed Central

Stepp, Nigel; Plenz, Dietmar; Srinivasa, Narayan

2015-01-01

During rest, the mammalian cortex displays spontaneous neural activity. Spiking of single neurons during rest has been described as irregular and asynchronous. In contrast, recent in vivo and in vitro population measures of spontaneous activity, using the LFP, EEG, MEG or fMRI suggest that the default state of the cortex is critical, manifested by spontaneous, scale-invariant, cascades of activity known as neuronal avalanches. Criticality keeps a network poised for optimal information processing, but this view seems to be difficult to reconcile with apparently irregular single neuron spiking. Here, we simulate a 10,000 neuron, deterministic, plastic network of spiking neurons. We show that a combination of short- and long-term synaptic plasticity enables these networks to exhibit criticality in the face of intrinsic, i.e. self-sustained, asynchronous spiking. Brief external perturbations lead to adaptive, long-term modification of intrinsic network connectivity through long-term excitatory plasticity, whereas long-term inhibitory plasticity enables rapid self-tuning of the network back to a critical state. The critical state is characterized by a branching parameter oscillating around unity, a critical exponent close to -3/2 and a long tail distribution of a self-similarity parameter between 0.5 and 1. PMID:25590427

Long-term avoidance memory formation is associated with a transient increase in mushroom body synaptic complexes in leaf-cutting ants

PubMed Central

Falibene, Agustina; Roces, Flavio; Rössler, Wolfgang

2015-01-01

Long-term behavioral changes related to learning and experience have been shown to be associated with structural remodeling in the brain. Leaf-cutting ants learn to avoid previously preferred plants after they have proved harmful for their symbiotic fungus, a process that involves long-term olfactory memory. We studied the dynamics of brain microarchitectural changes after long-term olfactory memory formation following avoidance learning in Acromyrmex ambiguus. After performing experiments to control for possible neuronal changes related to age and body size, we quantified synaptic complexes (microglomeruli, MG) in olfactory regions of the mushroom bodies (MBs) at different times after learning. Long-term avoidance memory formation was associated with a transient change in MG densities. Two days after learning, MG density was higher than before learning. At days 4 and 15 after learning—when ants still showed plant avoidance—MG densities had decreased to the initial state. The structural reorganization of MG triggered by long-term avoidance memory formation clearly differed from changes promoted by pure exposure to and collection of novel plants with distinct odors. Sensory exposure by the simultaneous collection of several, instead of one, non-harmful plant species resulted in a decrease in MG densities in the olfactory lip. We hypothesize that while sensory exposure leads to MG pruning in the MB olfactory lip, the formation of long-term avoidance memory involves an initial growth of new MG followed by subsequent pruning. PMID:25904854

Dopamine Promotes Motor Cortex Plasticity and Motor Skill Learning via PLC Activation

PubMed Central

Rioult-Pedotti, Mengia-Seraina; Pekanovic, Ana; Atiemo, Clement Osei; Marshall, John; Luft, Andreas Rüdiger

2015-01-01

Dopaminergic neurons in the ventral tegmental area, the major midbrain nucleus projecting to the motor cortex, play a key role in motor skill learning and motor cortex synaptic plasticity. Dopamine D1 and D2 receptor antagonists exert parallel effects in the motor system: they impair motor skill learning and reduce long-term potentiation. Traditionally, D1 and D2 receptor modulate adenylyl cyclase activity and cyclic adenosine monophosphate accumulation in opposite directions via different G-proteins and bidirectionally modulate protein kinase A (PKA), leading to distinct physiological and behavioral effects. Here we show that D1 and D2 receptor activity influences motor skill acquisition and long term synaptic potentiation via phospholipase C (PLC) activation in rat primary motor cortex. Learning a new forelimb reaching task is severely impaired in the presence of PLC, but not PKA-inhibitor. Similarly, long term potentiation in motor cortex, a mechanism involved in motor skill learning, is reduced when PLC is inhibited but remains unaffected by the PKA inhibitor. Skill learning deficits and reduced synaptic plasticity caused by dopamine antagonists are prevented by co-administration of a PLC agonist. These results provide evidence for a role of intracellular PLC signaling in motor skill learning and associated cortical synaptic plasticity, challenging the traditional view of bidirectional modulation of PKA by D1 and D2 receptors. These findings reveal a novel and important action of dopamine in motor cortex that might be a future target for selective therapeutic interventions to support learning and recovery of movement resulting from injury and disease. PMID:25938462

Heterosynaptic changes accompany long-term but not short-term potentiation of the perforant path in the anaesthetized rat.

PubMed

Abraham, W C; Bliss, T V; Goddard, G V

1985-06-01

Brief high-frequency trains of electrical stimulation delivered to the perforant path result in long-term potentiation (l.t.p.) of field potentials recorded extracellularly from granule cells of the dentate gyrus. L.t.p. of the population spike is often disproportionately greater than l.t.p. of the population excitatory post-synaptic potential (e.p.s.p.). We have investigated the basis of this effect in rats anaesthetized with sodium pentobarbitone. A series of graded stimuli were given before and after tetanization of the perforant path. From data obtained in this way, we plotted stimulus-response curves, and the relation (E-S curve) between the slope of the population e.p.s.p. (E) and the amplitude of the population spike (S). Curves relating spike onset latency to the slope of the e.p.s.p. were also constructed. Tetanization of the combined medial and lateral components of the perforant path led to long-term changes in the relation between the e.p.s.p. and the population spike. For a given e.p.s.p., the corresponding population spike was of greater amplitude and earlier onset. This E-S potentiation was marked by a shift to the left of the E-S amplitude curve and a downward displacement of the E-S latency curve. Tetanization of the lateral component of the perforant path had two long-term effects on responses evoked by test stimuli to the untetanized medial component: (1) long-term depression of the medial e.p.s.p. and (2) long-term E-S potentiation. The net result of these two heterosynaptically induced effects was to leave unaltered information transfer across medial perforant path-granule cell synapses; for a given test volley the e.p.s.p. was smaller, but because of E-S potentiation the population spike remained relatively unaffected. Short-term potentiation, which has a time course of only a few minutes and is presumed to be mediated by presynaptic mechanisms, was not accompanied by E-S potentiation or by corresponding changes in spike latency. Possible mechanisms of long-term heterosynaptic depression of the e.p.s.p. and of homo- and heterosynaptic E-S potentiation, are discussed. We conclude that although these effects probably reflect a generalized post-synaptic change, this change is unlikely to be a prolonged reduction in the membrane potential of granule cells.

Selective effects of aniracetam across receptor types and forms of synaptic facilitation in hippocampus.

PubMed

Xiao, P; Staubli, U; Kessler, M; Lynch, G

1991-10-01

Aniracetam reversibly increased synaptic responses mediated by the AMPA but not the NMDA subclass of glutamate receptors in hippocampus and was considerably more potent than structurally similar nootropics. The drug had greater effects on field excitatory postsynaptic potentials (EPSPs) in the dentate gyrus and CA1 region than it did in the CA3 region, suggesting that it differentiates between variants of the AMPA receptor. Ligand binding to glutamate receptors in synaptosomal membrane fractions was minimally changed by aniracetam. Finally, the percent facilitation produced by aniracetam in the CA1 region was not reduced by any of three treatments (4-aminopyridine, changes in extracellular calcium concentrations, paired-pulse stimulation) that affect release but, in accord with a previous report, was substantially decreased by long-term potentiation. These results support the conclusion that aniracetam selectively increases the conductance of a subgroup of synaptic AMPA receptors in hippocampus and suggest that receptor changes underlie the expression of long-term potentiation.

Using Inspiration from Synaptic Plasticity Rules to Optimize Traffic Flow in Distributed Engineered Networks.

PubMed

Suen, Jonathan Y; Navlakha, Saket

2017-05-01

Controlling the flow and routing of data is a fundamental problem in many distributed networks, including transportation systems, integrated circuits, and the Internet. In the brain, synaptic plasticity rules have been discovered that regulate network activity in response to environmental inputs, which enable circuits to be stable yet flexible. Here, we develop a new neuro-inspired model for network flow control that depends only on modifying edge weights in an activity-dependent manner. We show how two fundamental plasticity rules, long-term potentiation and long-term depression, can be cast as a distributed gradient descent algorithm for regulating traffic flow in engineered networks. We then characterize, both by simulation and analytically, how different forms of edge-weight-update rules affect network routing efficiency and robustness. We find a close correspondence between certain classes of synaptic weight update rules derived experimentally in the brain and rules commonly used in engineering, suggesting common principles to both.

Increased Training Intensity Induces Proper Membrane Localization of Actin Remodeling Proteins in the Hippocampus Preventing Cognitive Deficits: Implications for Fragile X Syndrome.

PubMed

Martinez, L A; Tejada-Simon, Maria Victoria

2018-06-01

Behavioral intervention therapy has proven beneficial in the treatment of autism and intellectual disabilities (ID), raising the possibility of certain changes in molecular mechanisms activated by these interventions that may promote learning. Fragile X syndrome (FXS) is a neurodevelopmental disorder characterized by autistic features and intellectual disability and can serve as a model to examine mechanisms that promote learning. FXS results from mutations in the fragile X mental retardation 1 gene (Fmr1) that prevents expression of the Fmr1 protein (FMRP), a messenger RNA (mRNA) translation regulator at synapses. Among many other functions, FMRP organizes a complex with the actin cytoskeleton-regulating small Rho GTPase Rac1. As in humans, Fmr1 KO mice lacking FMRP display autistic-like behaviors and deformities of actin-rich synaptic structures in addition to impaired hippocampal learning and synaptic plasticity. These features have been previously linked to proper function of actin remodeling proteins that includes Rac1. An important step in Rac1 activation and function is its translocation to the membrane, where it can influence synaptic actin cytoskeleton remodeling during hippocampus-dependent learning. Herein, we report that Fmr1 KO mouse hippocampus exhibits increased levels of membrane-bound Rac1, which may prevent proper learning-induced synaptic changes. We also determine that increasing training intensity during fear conditioning (FC) training restores contextual memory in Fmr1 KO mice and reduces membrane-bound Rac1 in Fmr1 KO hippocampus. Increased training intensity also results in normalized long-term potentiation in hippocampal slices taken from Fmr1 KO mice. These results point to interventional treatments providing new therapeutic options for FXS-related cognitive dysfunction.

Amyloid-beta oligomers impair fear conditioned memory in a calcineurin-dependent fashion in mice.

PubMed

Dineley, Kelly T; Kayed, Rakez; Neugebauer, Volker; Fu, Yu; Zhang, Wenru; Reese, Lindsay C; Taglialatela, Giulio

2010-10-01

Soluble oligomeric aggregates of the amyloid-beta (A beta) peptide are believed to be the most neurotoxic A beta species affecting the brain in Alzheimer disease (AD), a terminal neurodegenerative disorder involving severe cognitive decline underscored by initial synaptic dysfunction and later extensive neuronal death in the CNS. Recent evidence indicates that A beta oligomers are recruited at the synapse, oppose expression of long-term potentiation (LTP), perturb intracellular calcium balance, disrupt dendritic spines, and induce memory deficits. However, the molecular mechanisms behind these outcomes are only partially understood; achieving such insight is necessary for the comprehension of A beta-mediated neuronal dysfunction. We have investigated the role of the phosphatase calcineurin (CaN) in these pathological processes of AD. CaN is especially abundant in the CNS, where it is involved in synaptic activity, LTP, and memory function. Here, we describe how oligomeric A beta treatment causes memory deficits and depresses LTP expression in a CaN-dependent fashion. Mice given a single intracerebroventricular injection of A beta oligomers exhibited increased CaN activity and decreased pCREB, a transcription factor involved in proper synaptic function, accompanied by decreased memory in a fear conditioning task. These effects were reversed by treatment with the CaN inhibitor FK506. We further found that expression of hippocampal LTP in acutely cultured rodent brain slices was opposed by A beta oligomers and that this effect was also reversed by FK506. Collectively, these results indicate that CaN activation may play a central role in mediating synaptic and memory disruption induced by acute oligomeric A beta treatment in mice. (c) 2010 Wiley-Liss, Inc.

Chronic Intermittent Ethanol Exposure Enhances the Excitability and Synaptic Plasticity of Lateral Orbitofrontal Cortex Neurons and Induces a Tolerance to the Acute Inhibitory Actions of Ethanol

PubMed Central

Nimitvilai, Sudarat; Lopez, Marcelo F; Mulholland, Patrick J; Woodward, John J

2016-01-01

Alcoholism is associated with changes in brain reward and control systems, including the prefrontal cortex. In prefrontal areas, the orbitofrontal cortex (OFC) has been suggested to have an important role in the development of alcohol-abuse disorders and studies from this laboratory demonstrate that OFC-mediated behaviors are impaired in alcohol-dependent animals. However, it is not known whether chronic alcohol (ethanol) exposure alters the fundamental properties of OFC neurons. In this study, mice were exposed to repeated cycles of chronic intermittent ethanol (CIE) exposure to induce dependence and whole-cell patch-clamp electrophysiology was used to examine the effects of CIE treatment on lateral OFC (lOFC) neuron excitability, synaptic transmission, and plasticity. Repeated cycles of CIE exposure and withdrawal enhanced current-evoked action potential (AP) spiking and this was accompanied by a reduction in the after-hyperpolarization and a decrease in the functional activity of SK channels. CIE mice also showed an increase in the AMPA/NMDA ratio, and this was associated with an increase in GluA1/GluA2 AMPA receptor expression and a decrease in GluN2B NMDA receptor subunits. Following CIE treatment, lOFC neurons displayed a persistent long-term potentiation of glutamatergic synaptic transmission following a spike-timing-dependent protocol. Lastly, CIE treatment diminished the inhibitory effect of acute ethanol on AP spiking of lOFC neurons and reduced expression of the GlyT1 transporter. Taken together, these results suggest that chronic exposure to ethanol leads to enhanced intrinsic excitability and glutamatergic synaptic signaling of lOFC neurons. These alterations may contribute to the impairment of OFC-dependent behaviors in alcohol-dependent individuals. PMID:26286839

Fluoxetine regulates mTOR signalling in a region-dependent manner in depression-like mice.

PubMed

Liu, Xiao-Long; Luo, Liu; Mu, Rong-Hao; Liu, Bin-Bin; Geng, Di; Liu, Qing; Yi, Li-Tao

2015-11-02

Previous studies have demonstrated that the mammalian target of rapamycin (mTOR) signaling pathway has an important role in ketamine-induced, rapid antidepressant effects despite the acute administration of fluoxetine not affecting mTOR phosphorylation in the brain. However, the effects of long-term fluoxetine treatment on mTOR modulation have not been assessed to date. In the present study, we examined whether fluoxetine, a type of commonly used antidepressant agent, alters mTOR signaling following chronic administration in different brain regions, including the frontal cortex, hippocampus, amygdala and hypothalamus. We also investigated whether fluoxetine enhanced synaptic protein levels in these regions via the activation of the mTOR signaling pathway and its downstream regulators, p70S6K and 4E-BP-1. The results indicated that chronic fluoxetine treatment attenuated the chronic, unpredictable, mild stress (CUMS)-induced mTOR phosphorylation reduction in the hippocampus and amygdala of mice but not in the frontal cortex or the hypothalamus. Moreover, the CUMS-decreased PSD-95 and synapsin I levels were reversed by fluoxetine, and these effects were blocked by rapamycin only in the hippocampus. In conclusion, our findings suggest that chronic treatment with fluoxetine can induce synaptic protein expression by activating the mTOR signaling pathway in a region-dependent manner and mainly in the hippocampus.

Activity-dependent regulation of synaptic strength by PSD-95 in CA1 neurons.

PubMed

Zhang, Peng; Lisman, John E

2012-02-01

CaMKII and PSD-95 are the two most abundant postsynaptic proteins in the postsynaptic density (PSD). Overexpression of either can dramatically increase synaptic strength and saturate long-term potentiation (LTP). To do so, CaMKII must be activated, but the same is not true for PSD-95; expressing wild-type PSD-95 is sufficient. This raises the question of whether PSD-95's effects are simply an equilibrium process [increasing the number of AMPA receptor (AMPAR) slots] or whether activity is somehow involved. To examine this question, we blocked activity in cultured hippocampal slices with TTX and found that the effects of PSD-95 overexpression were greatly reduced. We next studied the type of receptors involved. The effects of PSD-95 were prevented by antagonists of group I metabotropic glutamate receptors (mGluRs) but not by antagonists of ionotropic glutamate receptors. The inhibition of PSD-95-induced strengthening was not simply a result of inhibition of PSD-95 synthesis. To understand the mechanisms involved, we tested the role of CaMKII. Overexpression of a CaMKII inhibitor, CN19, greatly reduced the effect of PSD-95. We conclude that PSD-95 cannot itself increase synaptic strength simply by increasing the number of AMPAR slots; rather, PSD-95's effects on synaptic strength require an activity-dependent process involving mGluR and CaMKII.

Inflammation Subverts Hippocampal Synaptic Plasticity in Experimental Multiple Sclerosis

PubMed Central

Mandolesi, Georgia; Piccinin, Sonia; Berretta, Nicola; Pignatelli, Marco; Feligioni, Marco; Musella, Alessandra; Gentile, Antonietta; Mori, Francesco; Bernardi, Giorgio; Nicoletti, Ferdinando; Mercuri, Nicola B.; Centonze, Diego

2013-01-01

Abnormal use-dependent synaptic plasticity is universally accepted as the main physiological correlate of memory deficits in neurodegenerative disorders. It is unclear whether synaptic plasticity deficits take place during neuroinflammatory diseases, such as multiple sclerosis (MS) and its mouse model, experimental autoimmune encephalomyelitis (EAE). In EAE mice, we found significant alterations of synaptic plasticity rules in the hippocampus. When compared to control mice, in fact, hippocampal long-term potentiation (LTP) induction was favored over long-term depression (LTD) in EAE, as shown by a significant rightward shift in the frequency–synaptic response function. Notably, LTP induction was also enhanced in hippocampal slices from control mice following interleukin-1β (IL-1β) perfusion, and both EAE and IL-1β inhibited GABAergic spontaneous inhibitory postsynaptic currents (sIPSC) without affecting glutamatergic transmission and AMPA/NMDA ratio. EAE was also associated with selective loss of GABAergic interneurons and with reduced gamma-frequency oscillations in the CA1 region of the hippocampus. Finally, we provided evidence that microglial activation in the EAE hippocampus was associated with IL-1β expression, and hippocampal slices from control mice incubated with activated microglia displayed alterations of GABAergic transmission similar to those seen in EAE brains, through a mechanism dependent on enhanced IL-1β signaling. These data may yield novel insights into the basis of cognitive deficits in EAE and possibly of MS. PMID:23355887

Multiple effects of β-amyloid on single excitatory synaptic connections in the PFC.

PubMed

Wang, Yun; Zhou, Thomas H; Zhi, Zhina; Barakat, Amey; Hlatky, Lynn; Querfurth, Henry

2013-01-01

Prefrontal cortex (PFC) is recognized as an AD-vulnerable region responsible for defects in cognitive functioning. Pyramidal cell (PC) connections are typically facilitating (F) or depressing (D) in PFC. Excitatory post-synaptic potentials (EPSPs) were recorded using patch-clamp from single connections in PFC slices of rats and ferrets in the presence of β-amyloid (Aβ). Synaptic transmission was significantly enhanced or reduced depending on their intrinsic type (facilitating or depressing), Aβ species (Aβ 40 or Aβ 42) and concentration (1-200 nM vs. 0.3-1 μ M). Nanomolar Aβ 40 and Aβ 42 had opposite effects on F-connections, resulting in fewer or increased EPSP failure rates, strengthening or weakening EPSPs and enhancing or inhibiting short-term potentiation [STP: synaptic augmentation (SA) and post-tetanic potentiation (PTP)], respectively. High Aβ 40 concentrations induced inhibition regardless of synaptic type. D-connections were inhibited regardless of Aβ species or concentration. The inhibition induced with bath application was hard to recover by washout, but a complete recovery was obtained with brief local application and prompt washout. Our data suggests that Aβ 40 acts on the prefrontal neuronal network by modulating facilitating and depressing synapses. At higher levels, both Aβ 40 and Aβ 42 inhibit synaptic activity and cause irreversible toxicity once diffusely accumulated in the synaptic environment.

What happens to your brain on the way to Mars.

PubMed

Parihar, Vipan K; Allen, Barrett; Tran, Katherine K; Macaraeg, Trisha G; Chu, Esther M; Kwok, Stephanie F; Chmielewski, Nicole N; Craver, Brianna M; Baulch, Janet E; Acharya, Munjal M; Cucinotta, Francis A; Limoli, Charles L

2015-05-01

As NASA prepares for the first manned spaceflight to Mars, questions have surfaced concerning the potential for increased risks associated with exposure to the spectrum of highly energetic nuclei that comprise galactic cosmic rays. Animal models have revealed an unexpected sensitivity of mature neurons in the brain to charged particles found in space. Astronaut autonomy during long-term space travel is particularly critical as is the need to properly manage planned and unanticipated events, activities that could be compromised by accumulating particle traversals through the brain. Using mice subjected to space-relevant fluences of charged particles, we show significant cortical- and hippocampal-based performance decrements 6 weeks after acute exposure. Animals manifesting cognitive decrements exhibited marked and persistent radiation-induced reductions in dendritic complexity and spine density along medial prefrontal cortical neurons known to mediate neurotransmission specifically interrogated by our behavioral tasks. Significant increases in postsynaptic density protein 95 (PSD-95) revealed major radiation-induced alterations in synaptic integrity. Impaired behavioral performance of individual animals correlated significantly with reduced spine density and trended with increased synaptic puncta, thereby providing quantitative measures of risk for developing cognitive decrements. Our data indicate an unexpected and unique susceptibility of the central nervous system to space radiation exposure, and argue that the underlying radiation sensitivity of delicate neuronal structure may well predispose astronauts to unintended mission-critical performance decrements and/or longer-term neurocognitive sequelae.

The interplay between neuronal activity and actin dynamics mimic the setting of an LTD synaptic tag

PubMed Central

Szabó, Eszter C.; Manguinhas, Rita; Fonseca, Rosalina

2016-01-01

Persistent forms of plasticity, such as long-term depression (LTD), are dependent on the interplay between activity-dependent synaptic tags and the capture of plasticity-related proteins. We propose that the synaptic tag represents a structural alteration that turns synapses permissive to change. We found that modulation of actin dynamics has different roles in the induction and maintenance of LTD. Inhibition of either actin depolymerisation or polymerization blocks LTD induction whereas only the inhibition of actin depolymerisation blocks LTD maintenance. Interestingly, we found that actin depolymerisation and CaMKII activation are involved in LTD synaptic-tagging and capture. Moreover, inhibition of actin polymerisation mimics the setting of a synaptic tag, in an activity-dependent manner, allowing the expression of LTD in non-stimulated synapses. Suspending synaptic activation also restricts the time window of synaptic capture, which can be restored by inhibiting actin polymerization. Our results support our hypothesis that modulation of the actin cytoskeleton provides an input-specific signal for synaptic protein capture. PMID:27650071

Corticostriatal circuit defects in Hoxb8 mutant mice

PubMed Central

Nagarajan, Naveen; Jones, Bryan W.; West, Peter J.; Marc, Robert; Capecchi, Mario R.

2018-01-01

Hoxb8 mutant mice exhibit compulsive grooming and hair removal dysfunction similar to humans with the OCD-spectrum disorder, trichotillomania. Since, in the mouse brain, the only detectable cells that label with Hoxb8 cell lineage appear to be microglia, we suggested that defective microglia cause the neuropsychiatric disorder. Does the Hoxb8 mutation in microglia lead to neural circuit dysfunctions? We demonstrate that Hoxb8 mutants contain corticostriatal circuit defects. Golgi staining, ultra-structural, and electrophysiological studies of mutants reveal excess dendritic spines, pre- and post-synaptic structural defects, long-term potentiation and miniature postsynaptic current defects. Hoxb8 mutants also exhibit hyperanxiety and social behavioral deficits similar to mice with neuronal mutations in Sapap3, Slitrk5 and Shank3, reported models of OCD and autism spectrum disorders (ASD’s). Long-term treatment of Hoxb8 mutants with fluoxetine, a serotonin reuptake inhibitor (SSRI), reduces excessive grooming, hyperanxiety and social behavioral impairments. These studies provide linkage between the neuronal defects induced by defective Hoxb8-microglia, and neuronal dysfunctions directly generated by mutations in synaptic components that result in mice that display similar pathological grooming, hyperanxiety and social impairment deficits. Our results shed light on Hoxb8 microglia driven circuit-specific defects and therapeutic approaches that will become essential to developing novel therapies for neuropsychiatric diseases such as OCD and ASD’s with Hoxb8-microglia being the central target. PMID:28948967

Limb segment vibration modulates spinal reflex excitability and muscle mRNA expression after spinal cord injury

PubMed Central

Chang, Shuo-Hsiu; Tseng, Shih-Chiao; McHenry, Colleen L.; Littmann, Andrew E.; Suneja, Manish; Shields, Richard K.

2012-01-01

Objective We investigated the effect of various doses of vertical oscillation (vibration) on soleus H-reflex amplitude and post-activation depression in individuals with and without SCI. We also explored the acute effect of short-term limb vibration on skeletal muscle mRNA expression of genes associated with spinal plasticity. Methods Six healthy adults and five chronic complete SCI subjects received vibratory stimulation of their tibia over three different gravitational accelerations (0.3g, 0.6g, and 1.2g) at a fixed frequency (30 Hz). Soleus H-reflexes were measured before, during, and after vibration. Two additional chronic complete SCI subjects had soleus muscle biopsies 3 h following a single bout of vibration. Results H-reflex amplitude was depressed over 83% in both groups during vibration. This vibratory-induced inhibition lasted over 2 min in the control group, but not in the SCI group. Post-activation depression was modulated during the long-lasting vibratory inhibition. A single bout of mechanical oscillation altered mRNA expression from selected genes associated with synaptic plasticity. Conclusions Vibration of the lower leg inhibits the H-reflex amplitude, influences post-activation depression, and alters skeletal muscle mRNA expression of genes associated with synaptic plasticity. Significance Limb segment vibration may offer a long term method to reduce spinal reflex excitability after SCI. PMID:21963319

Fructose consumption reduces hippocampal synaptic plasticity underlying cognitive performance

PubMed Central

Cisternas, Pedro; Salazar, Paulina; Serrano, Felipe G.; Montecinos-Oliva, Carla; Arredondo, Sebastián B.; Varela-Nallar, Lorena; Barja, Salesa; Vio, Carlos P.; Gomez-Pinilla, Fernando; Inestrosa, Nibaldo C.

2017-01-01

Metabolic syndrome (MetS) is a global epidemic, which involves a spectrum of metabolic disorders comprising diabetes and obesity. The impact of MetS on the brain is becoming to be a concern, however, the poor understanding of mechanisms involved has limited the development of therapeutic strategies. We induced a MetS-like condition by exposing mice to fructose feeding for 7 weeks. There was a dramatic deterioration in the capacity of the hippocampus to sustain synaptic plasticity in the forms of long-term potentiation (LTP) and long-term depression (LTD). Mice exposed to fructose showed a reduction in the number of contact zones and the size of postsynaptic densities (PSDs) in the hippocampus, as well as a decrease in hippocampal neurogenesis. There was an increase in lipid peroxidation likely associated with a deficiency in plasma membrane excitability. Consistent with an overall hippocampal dysfunction, there was a subsequent decrease in hippocampal dependent learning and memory performance, i.e., spatial learning and episodic memory. Most of the pathological sequel of MetS in the brain was reversed three month after discontinue fructose feeding. These results are novel to show that MetS triggers a cascade of molecular events, which disrupt hippocampal functional plasticity, and specific aspects of learning and memory function. The overall information raises concerns about the risk imposed by excessive fructose consumption on the pathology of neurological disorders. PMID:26300486

Cortical Auditory Deafferentation Induces Long-Term Plasticity in the Inferior Colliculus of Adult Rats: Microarray and qPCR Analysis

PubMed Central

Clarkson, Cheryl; Herrero-Turrión, M. Javier; Merchán, Miguel A.

2012-01-01

The cortico-collicular pathway is a bilateral excitatory projection from the cortex to the inferior colliculus (IC). It is asymmetric and predominantly ipsilateral. Using microarrays and RT-qPCR we analyzed changes in gene expression in the IC after unilateral lesions of the auditory cortex, comparing the ICs ipsi- and contralateral to the lesioned side. At 15 days after surgery there were mainly changes in gene expression in the IC ipsilateral to the lesion. Regulation primarily involved inflammatory cascade genes, suggesting a direct effect of degeneration rather than a neuronal plastic reorganization. Ninety days after the cortical lesion the ipsilateral IC showed a significant up-regulation of genes involved in apoptosis and axonal regeneration combined with a down-regulation of genes involved in neurotransmission, synaptic growth, and gap junction assembly. In contrast, the contralateral IC at 90 days post-lesion showed an up-regulation in genes primarily related to neurotransmission, cell proliferation, and synaptic growth. There was also a down-regulation in autophagy and neuroprotection genes. These findings suggest that the reorganization in the IC after descending pathway deafferentation is a long-term process involving extensive changes in gene expression regulation. Regulated genes are involved in many different neuronal functions, and the number and gene rearrangement profile seems to depend on the density of loss of the auditory cortical inputs. PMID:23233834

Bacopa monnieri ameliorates memory deficits in olfactory bulbectomized mice: possible involvement of glutamatergic and cholinergic systems.

PubMed

Le, Xoan Thi; Pham, Hang Thi Nguyet; Do, Phuong Thi; Fujiwara, Hironori; Tanaka, Ken; Li, Feng; Van Nguyen, Tai; Nguyen, Khoi Minh; Matsumoto, Kinzo

2013-10-01

This study investigated the effects of alcoholic extract of Bacopa monnieri (L.) Wettst. (BM) on cognitive deficits using olfactory bulbectomized (OBX) mice and the underlying molecular mechanisms of its action. OBX mice were treated daily with BM (50 mg/kg, p.o.) or a reference drug, tacrine (2.5 mg/kg, i.p.), 1 week before and continuously 3 days after OBX. Cognitive performance of the animals was analyzed by the novel object recognition test, modified Y maze test, and fear conditioning test. Brain tissues of OBX animals were used for neurochemical and immunohistochemical studies. OBX impaired non-spatial short-term memory, spatial working memory, and long-term fair memory. BM administration ameliorated these memory disturbances. The effect of BM on short-term memory deficits was abolished by a muscarinic receptor antagonist, scopolamine. OBX downregulated phosphorylation of synaptic plasticity-related signaling proteins: NR1 subunit of N-methyl-D-aspartate receptor, glutamate receptor 1 (GluR1), and calmodulin-dependent kinase II but not cyclic AMP-responsive element binding protein (CREB), and reduced brain-derived neurotrophic factor (BDNF) mRNA in the hippocampus. OBX also reduced choline acetyltransferase in the hippocampus and cholinergic neurons in the medial septum, and enlarged the size of lateral ventricle. BM administration reversed these OBX-induced neurochemical and histological alterations, except the decrease of GluR1 phosphorylation, and enhanced CREB phosphorylation. Moreover, BM treatment inhibited ex vivo activity of acetylcholinesterase in the brain. These results indicate that BM treatment ameliorates OBX-induced cognition dysfunction via a mechanism involving enhancement of synaptic plasticity-related signaling and BDNF transcription and protection of cholinergic systems from OBX-induced neuronal damage.

Neurotrophin-3 Enhances the Synaptic Organizing Function of TrkC-Protein Tyrosine Phosphatase σ in Rat Hippocampal Neurons.

PubMed

Ammendrup-Johnsen, Ina; Naito, Yusuke; Craig, Ann Marie; Takahashi, Hideto

2015-09-09

Neurotrophin-3 (NT-3) and its high-affinity receptor TrkC play crucial trophic roles in neuronal differentiation, axon outgrowth, and synapse development and plasticity in the nervous system. We demonstrated previously that postsynaptic TrkC functions as a glutamatergic synapse-inducing (synaptogenic) cell adhesion molecule trans-interacting with presynaptic protein tyrosine phosphatase σ (PTPσ). Given that NT-3 and PTPσ bind distinct domains of the TrkC extracellular region, here we tested the hypothesis that NT-3 modulates TrkC/PTPσ binding and synaptogenic activity. NT-3 enhanced PTPσ binding to cell surface-expressed TrkC and facilitated the presynapse-inducing activity of TrkC in rat hippocampal neurons. Imaging of recycling presynaptic vesicles combined with TrkC knockdown and rescue approaches demonstrated that NT-3 rapidly potentiates presynaptic function via binding endogenous postsynaptic TrkC in a tyrosine kinase-independent manner. Thus, NT-3 positively modulates the TrkC-PTPσ complex for glutamatergic presynaptic assembly and function independently from TrkC kinase activation. Our findings provide new insight into synaptic roles of neurotrophin signaling and mechanisms controlling synaptic organizing complexes. Significance statement: Although many synaptogenic adhesion complexes have been identified in recent years, little is known about modulatory mechanisms. Here, we demonstrate a novel role of neurotrophin-3 in synaptic assembly and function as a positive modulator of the TrkC-protein tyrosine phosphatase σ complex. This study provides new insight into the involvement of neurotrophin signaling in synapse development and plasticity, presenting a molecular mechanism that may underlie previous observations of short- and long-term enhancement of presynaptic function by neurotrophin. Given the links of synaptogenic adhesion molecules to autism and schizophrenia, this study might also contribute to a better understanding of the pathogenesis of these disorders and provide a new direction for ameliorating imbalances in synaptic signaling networks. Copyright © 2015 the authors 0270-6474/15/3512425-07$15.00/0.

Resolving TRPV1 and TNF-α Mediated Spinal Cord Synaptic Plasticity and Inflammatory Pain with Neuroprotectin D1

PubMed Central

Park, Chul-Kyu; Lü, Ning; Xu, Zhen-Zhong; Liu, Tong; Serhan, Charles N.; Ji, Ru-Rong

2011-01-01

Mechanisms of inflammatory pain are not fully understood. We investigated the role of TRPV1 and TNF-α, two critical mediators for inflammatory pain, in regulating spinal cord synaptic transmission. We found in mice lacking Trpv1 the frequency but not the amplitude of spontaneous EPSCs (sEPSCs) in lamina II neurons of spinal cord slices is reduced. Further, C-fiber-induced spinal long-term potentiation (LTP) in vivo is abolished in Trpv1 knockout mice. TNF-α also increases sEPSC frequency but not amplitude in spinal lamina IIo neurons, and this increase is abolished in Trpv1 knockout mice. Single-cell PCR analysis revealed that TNF-α-responding neurons in lamina IIo are exclusively excitatory (vGluT2+) neurons. Notably, neuroprotectin-1 (NPD1), an anti-inflammatory lipid mediator derived from omega-3 polyunsaturated fatty acid (docosahexaenoic acid) blocks TNF-α- and capsaicin-evoked sEPSC frequency increases but has no effect on basal synaptic transmission. Strikingly, NPD1 potently inhibits capsaicin-induced TRPV1 current (IC50=0.4 nM) in dissociated dorsal root ganglion neurons, and this IC50 is ≈ 500 times lower than that of AMG9810, a commonly used TRPV1 antagonist. NPD1 inhibition of TRPV1 is mediated by GPCRs, since the effects were blocked by pertussis toxin. In contrast, NPD1 had not effect on mustard oil-induced TRPA1 currents. Spinal injection of NPD1, at very low doses (0.1–10 ng), blocks spinal LTP and reduces TRPV1-dependent inflammatory pain, without affecting baseline pain. NPD1 also reduces TRPV1-independent but TNF-α-dependent pain hypersensitivity. Our findings demonstrate a novel role of NPD1 in regulating TRPV1/TNF-α-mediated spinal synaptic plasticity and identify NPD1 as a novel analgesic for treating inflammatory pain. PMID:22016541

Restoration of Long-Term Potentiation in Middle-Aged Hippocampus After Induction of Brain-Derived Neurotrophic Factor

PubMed Central

Rex, Christopher S.; Lauterborn, Julie C.; Lin, Ching-Yi; Kramár, Eniko A.; Rogers, Gary A.; Gall, Christine M.; Lynch, Gary

2006-01-01

Rex, Christopher S., Julie C. Lauterborn, Ching-Yi Lin, Eniko A. Kramár, Gary A. Rogers, Christine M. Gall, and Gary Lynch. Restoration of long-term potentiation in middle-aged hippocampus after induction of brain-derived neurotrophic factor. J Neurophysiol 96: 677-685, 2006. First published May 17, 2006; doi:10.1152/jn.00336.2006. Restoration of neuronal viability and synaptic plasticity through increased trophic support is widely regarded as a potential therapy for the cognitive declines that characterize aging. Previous studies have shown that in the hippocampal CA1 basal dendritic field deficits in the stabilization of long-term potentiation (LTP) are evident by middle age. The present study tested whether increasing endogenous brain-derived neurotrophic factor (BDNF) could reverse this age-related change. We report here that in middle-aged (8- to 10-mo-old) rats, in vivo treatments with a positive AMPA-type glutamate receptor modulator both increase BDNF protein levels in the cortical telencephalon and restore stabilization of basal dendritic LTP as assessed in acute hippocampal slices 18 h after the last drug treatment. These effects were not attributed to enhanced synaptic transmission or to facilitation of burst responses used to induce LTP. Increasing extracellular levels of BDNF by exogenous application to slices of middle-aged rats was also sufficient to rescue the stabilization of basal dendritic LTP. Finally, otherwise stable LTP in ampakine-treated middle-aged rats can be eliminated by infusion of the extracellular BDNF scavenger TrkB-Fc. Together these results indicate that increases in endogenous BDNF signaling can offset deficits in the postinduction processes that stabilize LTP. PMID:16707719

Beneficial effects of postnatal choline supplementation on long-Term neurocognitive deficit resulting from fetal-Neonatal iron deficiency.

PubMed

Kennedy, Bruce C; Tran, Phu V; Kohli, Maulika; Maertens, Jamie J; Gewirtz, Jonathan C; Georgieff, Michael K

2018-01-15

Early-life iron deficiency is a common nutrient condition worldwide and can result in cognitive impairment in adulthood despite iron treatment. In rodents, prenatal choline supplementation can diminish long-term hippocampal gene dysregulation and neurocognitive deficits caused by iron deficiency. Since fetal iron status is generally unknown in humans, we determined whether postnatal choline supplementation exerts similar beneficial effects. Male rat pups were made iron deficient (ID) by providing pregnant and nursing dams an ID diet (3-6ppm Fe) from gestational day (G) 3 through postnatal day (P) 7, and an iron-sufficient (IS) diet (200ppm Fe) thereafter. Control pups were provided IS diet throughout. Choline (5ppm) was given to half the nursing dams and weanlings in each group from P11-P30. P65 rat cognitive performance was assessed by novel object recognition (NOR). Real-time PCR was performed to validate expression levels of synaptic plasticity genes known to be dysregulated by early-life iron deficiency. Postnatal choline supplementation prevented impairment of NOR memory in formerly iron-deficient (FID) adult rats but impaired NOR memory in IS controls. Gene expression analysis revealed a recovery of 4 out of 10 dysregulated genes compared to 8 of the same 10 genes that we previously demonstrated to recover following prenatal choline supplementation. Recognition memory deficits induced by early-life iron deficiency can be prevented by postnatal choline supplementation and disrupted expression of a subset of synaptic plasticity genes can be ameliorated. The positive response to postnatal choline represents a potential adjunctive therapeutic supplement to treat iron-deficient anemic children in order to spare long-term neurodevelopmental deficits. Copyright © 2017. Published by Elsevier B.V.

N-Acetylcysteine Reverses Cocaine Induced Metaplasticity

PubMed Central

Moussawi, Khaled; Pacchioni, Alejandra; Moran, Megan; Olive, M. Foster; Gass, Justin T.; Lavin, Antonieta; Kalivas, Peter W

2009-01-01

Cocaine addiction is characterized by an impaired ability to develop adaptive behaviors that can compete with cocaine seeking, implying a deficit in the ability to induce plasticity in cortico-accumbens circuitry critical for regulating motivated behavior. RWe found that rats withdrawn from cocaine self-administration had a marked in vivo deficit in the ability to develop long-term potentation (LTP) and depression (LTD) in the nucleus accumbens core subregion following stimulation of prefrontal cortex. N-acetylcysteine treatment prevents relapse in animal models and craving in humans by activating cystine-glutamate exchange and thereby stimulating extrasynaptic metabotropic glutamate receptors (mGluR). N-acetylcysteine treatment restored the ability to induce LTP and LTD by indirectly stimulating mGluR2/3 and mGluR5, respectively. Cocaine self-administration induces metaplasticity that inhibits the further induction of synaptic plasticity, and this impairment can be reversed by N-acetylcysteine, a drug that also prevents relapse. PMID:19136971

DNA methylation regulates neurophysiological spatial representation in memory formation

PubMed Central

Roth, Eric D.; Roth, Tania L.; Money, Kelli M.; SenGupta, Sonda; Eason, Dawn E.; Sweatt, J. David

2015-01-01

Epigenetic mechanisms including altered DNA methylation are critical for altered gene transcription subserving synaptic plasticity and the retention of learned behavior. Here we tested the idea that one role for activity-dependent altered DNA methylation is stabilization of cognition-associated hippocampal place cell firing in response to novel place learning. We observed that a behavioral protocol (spatial exploration of a novel environment) known to induce hippocampal place cell remapping resulted in alterations of hippocampal Bdnf DNA methylation. Further studies using neurophysiological in vivo single unit recordings revealed that pharmacological manipulations of DNA methylation decreased long-term but not short-term place field stability. Together our data highlight a role for DNA methylation in regulating neurophysiological spatial representation and memory formation. PMID:25960947

Long-term Ameliorative Effects of the Antidepressant Fluoxetine Exposure on Cognitive Deficits in 3 × TgAD Mice.

PubMed

Jin, Li; Gao, Li-Feng; Sun, Dong-Sheng; Wu, Hao; Wang, Qun; Ke, Dan; Lei, Hao; Wang, Jian-Zhi; Liu, Gong-Ping

2017-08-01

Fluoxetine, a selective serotonin reuptake inhibitor, is neuroprotective; therefore, it has been applied to treat some neurodegenerative disorders. For instance, chronic fluoxetine exposure has short-term effects on Alzheimer's disease (AD). However, the long-term ameliorative effects of fluoxetine exposure on AD have not been reported. In the present study, 6-month-old 3 × TgAD mice were treated with fluoxetine for 15 days, and then the influence of fluoxetine was detected at 20 days after the drug withdrawal. We found that chronic fluoxetine treatment ameliorated cognitive deficits of 3 × TgAD mice and increased the volume of the hippocampal CA1 and dentate gyrus (DG) with increased neuron number and dendritic spine density. Meanwhile, fluoxetine exposure also stimulated the long-term potentiation (LTP) in hippocampal DG. The synaptic-related protein expression increased via activation of the cyclic AMP response element binding (CREB) protein/brain-derived neurotrophic factor (BDNF) signaling pathway induced by fluoxetine exposure. Lastly, we found that fluoxetine treatment decreased beta-amyloid (Aβ) levels. These results further certified that fluoxetine may be a potent effective drug for AD.

Non-ionotropic signaling by the NMDA receptor: controversy and opportunity.

PubMed

Gray, John A; Zito, Karen; Hell, Johannes W

2016-01-01

Provocative emerging evidence suggests that the N-methyl-d-aspartate (NMDA) receptor can signal in the absence of ion flux through the receptor. This non-ionotropic signaling is thought to be due to agonist-induced conformational changes in the receptor, independently of channel opening. Non-ionotropic NMDA receptor signaling has been proposed to be sufficient to induce synaptic long-term depression (LTD), directly challenging the decades-old model that prolonged low-level calcium influx is required to induce LTD. Here, we briefly review these recent findings, focusing primarily on the potential role of non-ionotropic signaling in NMDA receptor-mediated LTD. Further reports concerning additional roles of non-ionotropic NMDA receptor signaling are also discussed. If validated, this new view of NMDA receptor-mediated signaling will usher in an exciting new era of exploring synapse function and dysfunction.

Non-ionotropic signaling by the NMDA receptor: controversy and opportunity

PubMed Central

Gray, John A.; Zito, Karen; Hell, Johannes W.

2016-01-01

Provocative emerging evidence suggests that the N-methyl-d-aspartate (NMDA) receptor can signal in the absence of ion flux through the receptor. This non-ionotropic signaling is thought to be due to agonist-induced conformational changes in the receptor, independently of channel opening. Non-ionotropic NMDA receptor signaling has been proposed to be sufficient to induce synaptic long-term depression (LTD), directly challenging the decades-old model that prolonged low-level calcium influx is required to induce LTD. Here, we briefly review these recent findings, focusing primarily on the potential role of non-ionotropic signaling in NMDA receptor-mediated LTD. Further reports concerning additional roles of non-ionotropic NMDA receptor signaling are also discussed. If validated, this new view of NMDA receptor-mediated signaling will usher in an exciting new era of exploring synapse function and dysfunction. PMID:27303637

Defective synaptic transmission and structure in the dentate gyrus and selective fear memory impairment in the Rsk2 mutant mouse model of Coffin-Lowry syndrome.

PubMed

Morice, Elise; Farley, Séverine; Poirier, Roseline; Dallerac, Glenn; Chagneau, Carine; Pannetier, Solange; Hanauer, André; Davis, Sabrina; Vaillend, Cyrille; Laroche, Serge

2013-10-01

The Coffin-Lowry syndrome (CLS) is a syndromic form of intellectual disability caused by loss-of-function of the RSK2 serine/threonine kinase encoded by the rsk2 gene. Rsk2 knockout mice, a murine model of CLS, exhibit spatial learning and memory impairments, yet the underlying neural mechanisms are unknown. In the current study, we examined the performance of Rsk2 knockout mice in cued, trace and contextual fear memory paradigms and identified selective deficits in the consolidation and reconsolidation of hippocampal-dependent fear memories as task difficulty and hippocampal demand increase. Electrophysiological, biochemical and electron microscopy analyses were carried out in the dentate gyrus of the hippocampus to explore potential alterations in neuronal functions and structure. In vivo and in vitro electrophysiology revealed impaired synaptic transmission, decreased network excitability and reduced AMPA and NMDA conductance in Rsk2 knockout mice. In the absence of RSK2, standard measures of short-term and long-term potentiation (LTP) were normal, however LTP-induced CREB phosphorylation and expression of the transcription factors EGR1/ZIF268 were reduced and that of the scaffolding protein SHANK3 was blocked, indicating impaired activity-dependent gene regulation. At the structural level, the density of perforated and non-perforated synapses and of multiple spine boutons was not altered, however, a clear enlargement of spine neck width and post-synaptic densities indicates altered synapse ultrastructure. These findings show that RSK2 loss-of-function is associated in the dentate gyrus with multi-level alterations that encompass modifications of glutamate receptor channel properties, synaptic transmission, plasticity-associated gene expression and spine morphology, providing novel insights into the mechanisms contributing to cognitive impairments in CLS. Copyright © 2013 Elsevier Inc. All rights reserved.

Synaptic Scaling in Combination with Many Generic Plasticity Mechanisms Stabilizes Circuit Connectivity

PubMed Central

Tetzlaff, Christian; Kolodziejski, Christoph; Timme, Marc; Wörgötter, Florentin

2011-01-01

Synaptic scaling is a slow process that modifies synapses, keeping the firing rate of neural circuits in specific regimes. Together with other processes, such as conventional synaptic plasticity in the form of long term depression and potentiation, synaptic scaling changes the synaptic patterns in a network, ensuring diverse, functionally relevant, stable, and input-dependent connectivity. How synaptic patterns are generated and stabilized, however, is largely unknown. Here we formally describe and analyze synaptic scaling based on results from experimental studies and demonstrate that the combination of different conventional plasticity mechanisms and synaptic scaling provides a powerful general framework for regulating network connectivity. In addition, we design several simple models that reproduce experimentally observed synaptic distributions as well as the observed synaptic modifications during sustained activity changes. These models predict that the combination of plasticity with scaling generates globally stable, input-controlled synaptic patterns, also in recurrent networks. Thus, in combination with other forms of plasticity, synaptic scaling can robustly yield neuronal circuits with high synaptic diversity, which potentially enables robust dynamic storage of complex activation patterns. This mechanism is even more pronounced when considering networks with a realistic degree of inhibition. Synaptic scaling combined with plasticity could thus be the basis for learning structured behavior even in initially random networks. PMID:22203799

High sucrose consumption induces memory impairment in rats associated with electrophysiological modifications but not with metabolic changes in the hippocampus.

PubMed

Lemos, C; Rial, D; Gonçalves, F Q; Pires, J; Silva, H B; Matheus, F C; da Silva, A C; Marques, J M; Rodrigues, R J; Jarak, I; Prediger, R D; Reis, F; Carvalho, R A; Pereira, F C; Cunha, R A

2016-02-19

High sugar consumption is a risk factor for metabolic disturbances leading to memory impairment. Thus, rats subject to high sucrose intake (HSu) develop a metabolic syndrome and display memory deficits. We now investigated if these HSu-induced memory deficits were associated with metabolic and electrophysiological alterations in the hippocampus. Male Wistar rats were submitted for 9 weeks to a sucrose-rich diet (35% sucrose solution) and subsequently to a battery of behavioral tests; after sacrifice, their hippocampi were collected for ex vivo high-resolution magic angle spinning (HRMAS) metabolic characterization and electrophysiological extracellular recordings in slices. HSu rats displayed a decreased memory performance (object displacement and novel object recognition tasks) and helpless behavior (forced swimming test), without altered locomotion (open field). HRMAS analysis indicated a similar hippocampal metabolic profile of HSu and control rats. HSu rats also displayed no change of synaptic transmission and plasticity (long-term potentiation) in hippocampal Schaffer fibers-CA1 pyramid synapses, but had decreased amplitude of long-term depression in the temporoammonic (TA) pathway. Furthermore, HSu rats had an increased density of inhibitory adenosine A1 receptors (A1R), that translated into a greater potency of A1R in Schaffer fiber synapses, but not in the TA pathway, whereas the endogenous activation of A1R in HSu rats was preserved in the TA pathway but abolished in Schaffer fiber synapses. These results suggest that HSu triggers a hippocampal-dependent memory impairment that is not associated with altered hippocampal metabolism but is probably related to modified synaptic plasticity in hippocampal TA synapses. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

Amyloid-β₂₅₋₃₅ induces impairment of cognitive function and long-term potentiation through phosphorylation of collapsin response mediator protein 2.

PubMed

Isono, Toshinari; Yamashita, Naoya; Obara, Masami; Araki, Tomomi; Nakamura, Fumio; Kamiya, Yoshinori; Alkam, Tursun; Nitta, Atsumi; Nabeshima, Toshitaka; Mikoshiba, Katsuhiko; Ohshima, Toshio; Goshima, Yoshio

2013-11-01

Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) protein and tau deposition in the brain. Numerous studies have reported a central role of Aβ in the development of AD, but the pathogenesis is not well understood. Collapsin response mediator protein 2 (CRMP2), an intracellular protein mediating a repulsive axon guidance molecule, Semaphorin3A, is also accumulated in neurofibrillary tangles in AD brains. To gain insight into the role of CRMP2 phosphorylation in AD pathogenesis, we investigated the effects of Aβ neurotoxicity in CRMP2 phosphorylation-deficient knock-in (crmp2(ki/ki)) mice, in which the serine residue at 522 was replaced with alanine. Intracerebroventricular (i.c.v.) injection of Aβ₂₅₋₃₅ peptide, a neurotoxic fragment of Aβ protein, to wild-type (wt) mice increased hippocampal phosphorylation of CRMP2. Behavioral assessment revealed that i.c.v. injection of Aβ₂₅₋₃₅ peptide caused impairment of novel object recognition in wt mice, while the same peptide did not in crmp2(ki/ki) mice. In electrophysiological recording, wt and crmp2(ki/ki) mice have similar input-output basal synaptic transmission and paired-pulse ratios. However, long-term potentiation was impaired in hippocampal slices of Aβ₂₅₋₃₅ peptide-treated wt but not those of crmp2(ki/ki). Our findings indicate that CRMP2 phosphorylation is required for Aβ-induced impairment of cognitive memory and synaptic plasticity. Copyright © 2013 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

Input- and subunit-specific AMPA receptor trafficking underlying long-term potentiation at hippocampal CA3 synapses.

PubMed

Kakegawa, Wataru; Tsuzuki, Keisuke; Yoshida, Yukari; Kameyama, Kimihiko; Ozawa, Seiji

2004-07-01

Hippocampal CA3 pyramidal neurons receive synaptic inputs from both mossy fibres (MFs) and associational fibres (AFs). Long-term potentiation (LTP) at these synapses differs in its induction sites and N-methyl-D-aspartate receptor (NMDAR) dependence. Most evidence favours the presynaptic and postsynaptic mechanisms for induction of MF LTP and AF LTP, respectively. This implies that molecular and functional properties differ between MF and AF synapses at both presynaptic and postsynaptic sites. In this study, we focused on the difference in the postsynaptic trafficking of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) between these synapses. To trace the subunit-specific trafficking of AMPARs at each synapse, GluR1 and GluR2 subunits were introduced into CA3 pyramidal neurons in hippocampal organotypic cultures using the Sindbis viral expression system. The electrophysiologically-tagged GluR2 AMPARs, produced by the viral-mediated transfer of the unedited form of GluR2 (GluR2Q), were inserted into both MF and AF postsynaptic sites in a neuronal activity-independent manner. Endogenous Ca(2+)-impermeable AMPARs at these synapses were replaced with exogenous Ca(2+)-permeable receptors, and Ca(2+) influx via the newly expressed postsynaptic AMPARs induced NMDAR-independent LTP at AF synapses. In contrast, no GluR1 AMPAR produced by the gene transfer was constitutively incorporated into AF postsynaptic sites, and only a small amount into MF postsynaptic sites. The synaptic trafficking of GluR1 AMPARs was triggered by the activity of Ca(2+)/calmodulin-dependent kinase II or high-frequency stimulation to induce LTP at AF synapses, but not at MF synapses. These results indicate that MF and AF postsynaptic sites possess distinct properties for AMPAR trafficking in CA3 pyramidal neurons.

Calcium signaling, excitability, and synaptic plasticity defects in a mouse model of Alzheimer's disease.

PubMed

Zhang, Hua; Liu, Jie; Sun, Suya; Pchitskaya, Ekaterina; Popugaeva, Elena; Bezprozvanny, Ilya

2015-01-01

Alzheimer's disease (AD) and aging result in impaired ability to store memories, but the cellular mechanisms responsible for these defects are poorly understood. Presenilin 1 (PS1) mutations are responsible for many early-onset familial AD (FAD) cases. The phenomenon of hippocampal long-term potentiation (LTP) is widely used in studies of memory formation and storage. Recent data revealed long-term LTP maintenance (L-LTP) is impaired in PS1-M146V knock-in (KI) FAD mice. To understand the basis for this phenomenon, in the present study we analyzed structural synaptic plasticity in hippocampal cultures from wild type (WT) and KI mice. We discovered that exposure to picrotoxin induces formation of mushroom spines in both WT and KI cultures, but the maintenance of mushroom spines is impaired in KI neurons. This maintenance defect can be explained by an abnormal firing pattern during the consolidation phase of structural plasticity in KI neurons. Reduced frequency of neuronal firing in KI neurons is caused by enhanced calcium-induced calcium release (CICR), enhanced activity of calcium-activated potassium channels, and increased afterhyperpolarization. As a result, "consolidation" pattern of neuronal activity converted to "depotentiation" pattern of neuronal activity in KI neurons. Consistent with this model, we demonstrated that pharmacological inhibitors of CICR (dantrolene), of calcium-activated potassium channels (apamin), and of calcium-dependent phosphatase calcineurin (FK506) are able to rescue structural plasticity defects in KI neurons. Furthermore, we demonstrate that incubation with dantrolene or apamin also rescued L-LTP defects in KI hippocampal slices, suggesting a role for a similar mechanism. This proposed mechanism may be responsible for memory defects in AD but also for age-related memory decline.

TLR3 deficiency impairs spinal cord synaptic transmission, central sensitization, and pruritus in mice

PubMed Central

Liu, Tong; Berta, Temugin; Xu, Zhen-Zhong; Park, Chul-Kyu; Zhang, Ling; Lü, Ning; Liu, Qin; Liu, Yang; Gao, Yong-Jing; Liu, Yen-Chin; Ma, Qiufu; Dong, Xinzhong; Ji, Ru-Rong

2012-01-01

Itch, also known as pruritus, is a common, intractable symptom of several skin diseases, such as atopic dermatitis and xerosis. TLRs mediate innate immunity and regulate neuropathic pain, but their roles in pruritus are elusive. Here, we report that scratching behaviors induced by histamine-dependent and -independent pruritogens are markedly reduced in mice lacking the Tlr3 gene. TLR3 is expressed mainly by small-sized primary sensory neurons in dorsal root ganglions (DRGs) that coexpress the itch signaling pathway components transient receptor potential subtype V1 and gastrin-releasing peptide. Notably, we found that treatment with a TLR3 agonist induces inward currents and action potentials in DRG neurons and elicited scratching in WT mice but not Tlr3–/– mice. Furthermore, excitatory synaptic transmission in spinal cord slices and long-term potentiation in the intact spinal cord were impaired in Tlr3–/– mice but not Tlr7–/– mice. Consequently, central sensitization–driven pain hypersensitivity, but not acute pain, was impaired in Tlr3–/– mice. In addition, TLR3 knockdown in DRGs also attenuated pruritus in WT mice. Finally, chronic itch in a dry skin condition was substantially reduced in Tlr3–/– mice. Our findings demonstrate a critical role of TLR3 in regulating sensory neuronal excitability, spinal cord synaptic transmission, and central sensitization. TLR3 may serve as a new target for developing anti-itch treatment. PMID:22565312

Role of ASIC1a in Aβ-induced synaptic alterations in the hippocampus.

PubMed

Mango, D; Nisticò, R

2018-05-01

Acid-sensing ion channels (ASICs) are widely expressed in the mammalian central nervous system where they play a key role in synaptic transmission and in specific forms of memory. On the other hand, ASICs can be persistently active under pathological conditions contributing to neuronal damage in ischemic stroke, brain trauma, epilepsy and Parkinson's disease. However, to date no experimental evidence has linked ASICs to Alzheimer's disease (AD). Aim of the present work was to investigate, in CA1 pyramidal neurons, the possible involvement of ASIC1a in the Aβ-mediated effect on metabotropic glutamate (mGlu) receptor dependent transmission. We found that, in slices pretreated with Aβ, the pharmacological blockade of ASIC1a restored the increased intrinsic excitability following group I mGlu receptor activation. This suggests that, under certain conditions, ASIC1a might further contribute to the Aβ-related depolarizing response. We have recently demonstrated that ASIC1a is also involved long-term depression (LTD) induced either by low-frequency stimulation or by application of the group I mGlu receptor agonist DHPG. Here, we have shown that psalmotoxin-1, a selective blocker of ASIC1a, rescued the DHPG-LTD facilitation associated with genetic and non-genetic models of AD. Overall, these results suggest that a functional coupling between ASIC1a and mGlu receptors occurs and might contribute to the synaptic alterations associated with AD. Copyright © 2018 Elsevier Ltd. All rights reserved.

Alteration of synaptic plasticity in rat dorsal striatum induced by chronic ethanol intake and withdrawal via ERK pathway.

PubMed

Cui, Sheng-zhong; Wang, Shen-jun; Li, Jing; Xie, Gui-qin; Zhou, Rong; Chen, Ling; Yuan, Xiao-ru

2011-02-01

The dorsal striatum has been proposed to contribute to the formation of drug-seeking behaviors, leading to excessive and compulsive drug usage, such as addiction. The current study aimed to investigate the involvement of extracellular signal-regulated kinase (ERK) pathway in the modification of striatal synaptic plasticity. Ethanol was administered to rats in drinking water at concentration of 6% (v/v) for 30 days. Rats were sacrificed on day 10, 20, or 30 during ethanol intake or on withdrawal day 1, 3, or 7 following 30-d ethanol intake. The striata were removed either for electrophysiological recording or for protein immuno-blot analysis. Extracellular recording technique was used to record population spikes (PS) induced by high-frequency stimulation (HFS) in the dorsolateral striatum (DLS). Corticostriatal long-term depression (LTD) was determined to be dependent upon ERK signaling. Chronic ethanol intake (CEI) attenuated ERK phosphorylation and LTD induction, whereas withdrawal for one day (W1D) potentiated ERK phosphorylation and LTD induction. These results showed that the impact of chronic ethanol intake and withdrawal on corticostriatal synaptic plasticity was associated with ethanol's effect on ERK phosphorylation. In particular, pharmacological inhibition of ERK hyper-phosphorylation by U0126 prevented LTD induction in the DLS and attenuated ethanol withdrawal syndrome as well. In rat DLS, chronic ethanol intake and withdrawal altered LTD induction via ERK signaling pathway. Ethanol withdrawal syndrome is mediated, at least partly, by ERK hyper-phosphorylation in the DLS.

Polygalasaponin XXXII from Polygala tenuifolia root improves hippocampal-dependent learning and memory.

PubMed

Xue, Wei; Hu, Jin-feng; Yuan, Yu-he; Sun, Jian-dong; Li, Bo-yu; Zhang, Dong-ming; Li, Chuang-jun; Chen, Nai-hong

2009-09-01

The aim of this study was to investigate the cognition-enhancing activity and underlying mechanisms of a triterpenoid saponin (polygalasaponin XXXII, PGS32) isolated from the roots of Polygala tenuifolia Willd. The Morris water maze was used to evaluate the spatial learning and memory of mice. To detect the basic properties of synaptic transmission and long-term potentiation (LTP) in the dentate gyrus of rats, electrophysiological recordings were made of evoked potentials. Western blotting analysis and immunofluorescence assays were used to determine the phosphorylation of extracellular signal-regulated kinase (ERK), cAMP response element-binding protein (CREB), synapsin I and the expression of brain derived neurotrophic factor (BDNF). When administered at 0.125, 0.5, or 2 mg/kg, PGS32 could significantly prevent scopolamine-induced cognitive impairments in mice. Intracerebroventricular (icv) administration of PGS32 greatly enhanced basic synaptic transmission in the dentate gyrus of rats and induced LTP. In primary hippocampal neurons, as well as in the hippocampus of maze-trained mice, PGS32 activated the mitogen-activated protein (MAP) kinase cascade by promoting phosphorylation of ERK, CREB and synapsin I. The expression of BDNF was also greatly enhanced in the hippocampus. Our findings suggest that PGS32 can improve hippocampus-dependent learning and memory, possibly through improvement of synaptic transmission, activation of the MAP kinase cascade and enhancement of the level of BDNF. Therefore, PGS32 shows promise as a potential cognition-enhancing therapeutic drug.

Polygalasaponin XXXII from Polygala tenuifolia root improves hippocampal-dependent learning and memory

PubMed Central

Xue, Wei; Hu, Jin-feng; Yuan, Yu-he; Sun, Jian-dong; Li, Bo-yu; Zhang, Dong-ming; Li, Chuang-jun; Chen, Nai-hong

2009-01-01

Aim: The aim of this study was to investigate the cognition-enhancing activity and underlying mechanisms of a triterpenoid saponin (polygalasaponin XXXII, PGS32) isolated from the roots of Polygala tenuifolia Willd. Methods: The Morris water maze was used to evaluate the spatial learning and memory of mice. To detect the basic properties of synaptic transmission and long-term potentiation (LTP) in the dentate gyrus of rats, electrophysiological recordings were made of evoked potentials. Western blotting analysis and immunofluorescence assays were used to determine the phosphorylation of extracellular signal-regulated kinase (ERK), cAMP response element-binding protein (CREB), synapsin I and the expression of brain derived neurotrophic factor (BDNF). Results: When administered at 0.125, 0.5, or 2 mg/kg, PGS32 could significantly prevent scopolamine-induced cognitive impairments in mice. Intracerebroventricular (icv) administration of PGS32 greatly enhanced basic synaptic transmission in the dentate gyrus of rats and induced LTP. In primary hippocampal neurons, as well as in the hippocampus of maze-trained mice, PGS32 activated the mitogen-activated protein (MAP) kinase cascade by promoting phosphorylation of ERK, CREB and synapsin I. The expression of BDNF was also greatly enhanced in the hippocampus. Conclusion: Our findings suggest that PGS32 can improve hippocampus-dependent learning and memory, possibly through improvement of synaptic transmission, activation of the MAP kinase cascade and enhancement of the level of BDNF. Therefore, PGS32 shows promise as a potential cognition-enhancing therapeutic drug. PMID:19684611

Chronic spinal cord stimulation modifies intrinsic cardiac synaptic efficacy in the suppression of atrial fibrillation

PubMed Central

Ardell, Jeffrey L.; Cardinal, René; Beaumont, Eric; Vermeulen, Michel; Smith, Frank M.; Armour, J. Andrew

2014-01-01

We sought to determine whether spinal cord stimulation (SCS) therapy, when applied chronically to canines, imparts long-lasting cardio-protective effects on neurogenic atrial tachyarrhythmia induction and, if so, whether its effects can be attributable to i) changes in intrinsic cardiac (IC) neuronal transmembrane properties vs ii) modification of their interneuronal stochastic interactivity that initiates such pathology. Data derived from canines subjected to long-term SCS [(group 1 studied after 3–4 weeks SCS; n=5) (group 2: studied 5 weeks SCS; n=11)] were compared to data derived from 10 control animals (including 4 sham SCS electrode implantations). During terminal studies conducted under anesthesia, chronotropic and inotropic responses to vagal nerve or stellate ganglion stimulation were similar in all 3 groups. Chronic SCS suppressed atrial tachyarrhythmia induction evoked by mediastinal nerve stimulation. When induced, arrhythmia durations were shortened (controls: median of 27s; SCS 3–4 weeks: median of 16s; SCS 5 weeks: median of 7s). Phasic and accommodating right atrial neuronal somata displayed similar passive and active membrane properties in vitro, whether derived from sham or either chronic SCS groups. Synaptic efficacy was differentially enhanced in accommodating (not phasic) IC neurons by chronic SCS. Taken together these data indicate that chronic SCS therapy modifies IC neuronal stochastic inter-connectivity in atrial fibrillation suppression by altering synaptic function without directly targeting the transmembrane properties of individual IC neuronal somata. PMID:25301713

Cortical afferents onto the nucleus Reticularis thalami promote plasticity of low-threshold excitability through GluN2C-NMDARs.

PubMed

Fernandez, Laura M J; Pellegrini, Chiara; Vantomme, Gil; Béard, Elidie; Lüthi, Anita; Astori, Simone

2017-09-25

Thalamus and cortex represent a highly integrated processing unit that elaborates sensory representations. Interposed between cortex and thalamus, the nucleus Reticularis thalami (nRt) receives strong cortical glutamatergic input and mediates top-down inhibitory feedback to thalamus. Despite growing appreciation that the nRt is integral for thalamocortical functions from sleep to attentional wakefulness, we still face considerable gaps in the synaptic bases for cortico-nRt communication and plastic regulation. Here, we examined modulation of nRt excitability by cortical synaptic drive in Ntsr1-Cre x ChR2 tg/+ mice expressing Channelrhodopsin2 in layer 6 corticothalamic cells. We found that cortico-nRt synapses express a major portion of NMDA receptors containing the GluN2C subunit (GluN2C-NMDARs). Upon repetitive photoactivation (10 Hz trains), GluN2C-NMDARs induced a long-term increase in nRt excitability involving a potentiated recruitment of T-type Ca 2+ channels. In anaesthetized mice, analogous stimulation of cortical afferents onto nRt produced long-lasting changes in cortical local field potentials (LFPs), with delta oscillations being augmented at the expense of slow oscillations. This shift in LFP spectral composition was sensitive to NMDAR blockade in the nRt. Our data reveal a novel mechanism involving plastic modification of synaptically recruited T-type Ca 2+ channels and nRt bursting and indicate a critical role for GluN2C-NMDARs in thalamocortical rhythmogenesis.

Selective alterations of NMDAR function and plasticity in D1 and D2 medium spiny neurons in the nucleus accumbens shell following chronic intermittent ethanol exposure.

PubMed

Renteria, Rafael; Maier, Esther Y; Buske, Tavanna R; Morrisett, Richard A

2017-01-01

A major mouse model widely adopted in recent years to induce pronounced ethanol intake is the ethanol vapor model known as "CIE" or "Chronic Intermittent Ethanol." One critical question concerning this model is whether the rapid induction of high blood ethanol levels for such short time periods is sufficient to induce alterations in N-methyl-d-aspartate receptor (NMDAR) function which may contribute to excessive ethanol intake. In this study, we determined whether such short term intermittent ethanol exposure modulates NMDAR function as well as other prominent electrophysiological properties and the expression of plasticity in both D1 (D1+) and D2 (D1-) dopamine receptor expressing medium spiny neurons (MSNs) in the nucleus accumbens (NAc) shell. To distinguish between the two subtypes of MSNs in the NAc we treated Drd1a-TdTomato transgenic mice with CIE vapor and electrophysiological recordings were conducted 24 h after the last vapor exposure. To investigate CIE induced alterations in plasticity, long-term depression (LTD) was induced by pairing low frequency stimulation (LFS) with post synaptic depolarization. In ethanol naïve mice, LFS induced synaptic depression (LTD) was apparent exclusively in D1+ MSNs. Whereas in slices prepared from CIE treated mice, LFS induced synaptic potentiation (LTP) in D1+ MSNs. Furthermore, following CIE exposure, LFS now produced LTD in D1- MSNs. We found that CIE exposure induced an increase in excitability in D1+ MSNs with no change in D1- MSNs. After CIE, we found a significant increase in spontaneous EPSCs (sEPSCs) frequency in D1+ but not D1- MSNs suggesting alterations in baseline α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) mediated signaling. CIE induced changes in NMDAR function were measured using the NMDA/AMPA ratio and input-output curves of isolated NMDAR currents. We observed a significant increase in NMDAR function in D1+ MSNs and a decrease in D1- MSNs after ethanol vapor exposure. The reversal of NMDAR function may account for the CIE induced alterations in the expression of plasticity. The cell type specific alterations in excitatory signaling in the NAc shell may constitute an important neuroadaptation necessary for the expression of increased ethanol consumption induced by intermittent ethanol vapor exposure. This article is part of the Special Issue entitled 'Ionotropic glutamate receptors'. Copyright © 2016 Elsevier Ltd. All rights reserved.

Sleep deprivation causes memory deficits by negatively impacting neuronal connectivity in hippocampal area CA1

PubMed Central

Havekes, Robbert; Park, Alan J; Tudor, Jennifer C; Luczak, Vincent G; Hansen, Rolf T; Ferri, Sarah L; Bruinenberg, Vibeke M; Poplawski, Shane G; Day, Jonathan P; Aton, Sara J; Radwańska, Kasia; Meerlo, Peter; Houslay, Miles D; Baillie, George S; Abel, Ted

2016-01-01

Brief periods of sleep loss have long-lasting consequences such as impaired memory consolidation. Structural changes in synaptic connectivity have been proposed as a substrate of memory storage. Here, we examine the impact of brief periods of sleep deprivation on dendritic structure. In mice, we find that five hours of sleep deprivation decreases dendritic spine numbers selectively in hippocampal area CA1 and increased activity of the filamentous actin severing protein cofilin. Recovery sleep normalizes these structural alterations. Suppression of cofilin function prevents spine loss, deficits in hippocampal synaptic plasticity, and impairments in long-term memory caused by sleep deprivation. The elevated cofilin activity is caused by cAMP-degrading phosphodiesterase-4A5 (PDE4A5), which hampers cAMP-PKA-LIMK signaling. Attenuating PDE4A5 function prevents changes in cAMP-PKA-LIMK-cofilin signaling and cognitive deficits associated with sleep deprivation. Our work demonstrates the necessity of an intact cAMP-PDE4-PKA-LIMK-cofilin activation-signaling pathway for sleep deprivation-induced memory disruption and reduction in hippocampal spine density. DOI: http://dx.doi.org/10.7554/eLife.13424.001 PMID:27549340

Lack of Pannexin 1 Alters Synaptic GluN2 Subunit Composition and Spatial Reversal Learning in Mice.

PubMed

Gajardo, Ivana; Salazar, Claudia S; Lopez-Espíndola, Daniela; Estay, Carolina; Flores-Muñoz, Carolina; Elgueta, Claudio; Gonzalez-Jamett, Arlek M; Martínez, Agustín D; Muñoz, Pablo; Ardiles, Álvaro O

2018-01-01

Long-term potentiation (LTP) and long-term depression (LTD) are two forms of synaptic plasticity that have been considered as the cellular substrate of memory formation. Although LTP has received considerable more attention, recent evidences indicate that LTD plays also important roles in the acquisition and storage of novel information in the brain. Pannexin 1 (Panx1) is a membrane protein that forms non-selective channels which have been shown to modulate the induction of hippocampal synaptic plasticity. Animals lacking Panx1 or blockade of Pannexin 1 channels precludes the induction of LTD and facilitates LTP. To evaluate if the absence of Panx1 also affects the acquisition of rapidly changing information we trained Panx1 knockout (KO) mice and wild type (WT) littermates in a visual and hidden version of the Morris water maze (MWM). We found that KO mice find the hidden platform similarly although slightly quicker than WT animals, nonetheless, when the hidden platform was located in the opposite quadrant (OQ) to the previous learned location, KO mice spent significantly more time in the previous quadrant than in the new location indicating that the absence of Panx1 affects the reversion of a previously acquired spatial memory. Consistently, we observed changes in the content of synaptic proteins critical to LTD, such as GluN2 subunits of N-methyl-D-aspartate receptors (NMDARs), which changed their contribution to synaptic plasticity in conditions of Panx1 ablation. Our findings give further support to the role of Panx1 channels on the modulation of synaptic plasticity induction, learning and memory processes.

Neuronal inhibition and synaptic plasticity of basal ganglia neurons in Parkinson's disease

PubMed Central

Milosevic, Luka; Kalia, Suneil K; Hodaie, Mojgan; Lozano, Andres M; Fasano, Alfonso; Popovic, Milos R; Hutchison, William D

2018-01-01

Abstract Deep brain stimulation of the subthalamic nucleus is an effective treatment for Parkinson’s disease symptoms. The therapeutic benefits of deep brain stimulation are frequency-dependent, but the underlying physiological mechanisms remain unclear. To advance deep brain stimulation therapy an understanding of fundamental mechanisms is critical. The objectives of this study were to (i) compare the frequency-dependent effects on cell firing in subthalamic nucleus and substantia nigra pars reticulata; (ii) quantify frequency-dependent effects on short-term plasticity in substantia nigra pars reticulata; and (iii) investigate effects of continuous long-train high frequency stimulation (comparable to conventional deep brain stimulation) on synaptic plasticity. Two closely spaced (600 µm) microelectrodes were advanced into the subthalamic nucleus (n = 27) and substantia nigra pars reticulata (n = 14) of 22 patients undergoing deep brain stimulation surgery for Parkinson’s disease. Cell firing and evoked field potentials were recorded with one microelectrode during stimulation trains from the adjacent microelectrode across a range of frequencies (1–100 Hz, 100 µA, 0.3 ms, 50–60 pulses). Subthalamic firing attenuated with ≥20 Hz (P < 0.01) stimulation (silenced at 100 Hz), while substantia nigra pars reticulata decreased with ≥3 Hz (P < 0.05) (silenced at 50 Hz). Substantia nigra pars reticulata also exhibited a more prominent increase in transient silent period following stimulation. Patients with longer silent periods after 100 Hz stimulation in the subthalamic nucleus tended to have better clinical outcome after deep brain stimulation. At ≥30 Hz the first evoked field potential of the stimulation train in substantia nigra pars reticulata was potentiated (P < 0.05); however, the average amplitude of the subsequent potentials was rapidly attenuated (P < 0.01). This is suggestive of synaptic facilitation followed by rapid depression. Paired pulse ratios calculated at the beginning of the train revealed that 20 Hz (P < 0.05) was the minimum frequency required to induce synaptic depression. Lastly, the average amplitude of evoked field potentials during 1 Hz pulses showed significant inhibitory synaptic potentiation after long-train high frequency stimulation (P < 0.001) and these increases were coupled with increased durations of neuronal inhibition (P < 0.01). The subthalamic nucleus exhibited a higher frequency threshold for stimulation-induced inhibition than the substantia nigra pars reticulata likely due to differing ratios of GABA:glutamate terminals on the soma and/or the nature of their GABAergic inputs (pallidal versus striatal). We suggest that enhancement of inhibitory synaptic plasticity, and frequency-dependent potentiation and depression are putative mechanisms of deep brain stimulation. Furthermore, we foresee that future closed-loop deep brain stimulation systems (with more frequent off stimulation periods) may benefit from inhibitory synaptic potentiation that occurs after high frequency stimulation. PMID:29236966

T-type calcium channels in synaptic plasticity

PubMed Central

Lambert, Régis C.

2017-01-01

ABSTRACT The role of T-type calcium currents is rarely considered in the extensive literature covering the mechanisms of long-term synaptic plasticity. This situation reflects the lack of suitable T-type channel antagonists that till recently has hampered investigations of the functional roles of these channels. However, with the development of new pharmacological and genetic tools, a clear involvement of T-type channels in synaptic plasticity is starting to emerge. Here, we review a number of studies showing that T-type channels participate to numerous homo- and hetero-synaptic plasticity mechanisms that involve different molecular partners and both pre- and post-synaptic modifications. The existence of T-channel dependent and independent plasticity at the same synapse strongly suggests a subcellular localization of these channels and their partners that allows specific interactions. Moreover, we illustrate the functional importance of T-channel dependent synaptic plasticity in neocortex and thalamus. PMID:27653665

Distinct Roles of NMDAR and mGluR5 in Light Exposure Reversal of Feedforward Synaptic Strength in V1 of Juvenile Mice after Binocular Vision Deprivation.

PubMed

Tie, Xiaoxiu; Li, Shuo; Feng, Yilin; Lai, Biqin; Liu, Sheng; Jiang, Bin

2018-06-01

In the visual cortex, sensory deprivation causes global augmentation of the amplitude of AMPA receptor-mediated miniature EPSCs in layer 2/3 pyramidal cells and enhancement of NMDA receptor-dependent long-term potentiation (LTP) in cells activated in layer 4, effects that are both rapidly reversed by light exposure. Layer 2/3 pyramidal cells receive both feedforward input from layer 4 and intra-cortical lateral input from the same layer, LTP is mainly induced by the former input. Whether feedforward excitatory synaptic strength is affected by visual deprivation and light exposure, how this synaptic strength correlates with the magnitude of LTP in this pathway, and the underlying mechanism have not been explored. Here, we showed that in juvenile mice, both dark rearing and dark exposure reduced the feedforward excitatory synaptic strength, and the effects can be reversed completely by 10-12 h and 6-8 h light exposure, respectively. However, inhibition of NMDA receptors by CPP or mGluR5 by MPEP, prevented the effect of light exposure on the mice reared in the dark from birth, while only inhibition of NMDAR prevented the effect of light exposure on dark-exposed mice. These results suggested that the activation of both NMDAR and mGluR5 are essential in the light exposure reversal of feedforward excitatory synaptic strength in the dark reared mice from birth; while in the dark exposed mice, only activation of NMDAR is required. Copyright © 2018. Published by Elsevier Ltd.

Spaceflight induces changes in the synaptic circuitry of the postnatal developing neocortex

NASA Technical Reports Server (NTRS)

DeFelipe, J.; Arellano, J. I.; Merchan-Perez, A.; Gonzalez-Albo, M. C.; Walton, K.; Llinas, R.

2002-01-01

The establishment of the adult pattern of neocortical circuitry depends on various intrinsic and extrinsic factors, whose modification during development can lead to alterations in cortical organization and function. We report the effect of 16 days of spaceflight [Neurolab mission; from postnatal day 14 (P14) to P30] on the neocortical representation of the hindlimb synaptic circuitry in rats. As a result, we show, for the first time, that development in microgravity leads to changes in the number and morphology of cortical synapses in a laminar-specific manner. In the layers II/III and Va, the synaptic cross-sectional lengths were significantly larger in flight animals than in ground control animals. Flight animals also showed significantly lower synaptic densities in layers II/III, IV and Va. The greatest difference was found in layer II/III, where there was a difference of 344 million synapses per mm(3) (15.6% decrease). Furthermore, after a 4 month period of re-adaptation to terrestrial gravity, some changes disappeared (i.e. the alterations were transient), while conversely, some new differences also appeared. For example, significant differences in synaptic density in layers II/III and Va after re-adaptation were no longer observed, whereas in layer IV the density of synapses increased notably in flight animals (a difference of 185 million synapses per mm(3) or 13.4%). In addition, all the changes observed only affected asymmetrical synapses, which are known to be excitatory. These results indicates that terrestrial gravity is a necessary environmental parameter for normal cortical synaptogenesis. These findings are fundamental in planning future long-term spaceflights.

Chronic methamphetamine exposure produces a delayed, long-lasting memory deficit.

PubMed

North, Ashley; Swant, Jarod; Salvatore, Michael F; Gamble-George, Joyonna; Prins, Petra; Butler, Brittany; Mittal, Mukul K; Heltsley, Rebecca; Clark, John T; Khoshbouei, Habibeh

2013-05-01

Methamphetamine (METH) is a highly addictive and neurotoxic psychostimulant. Its use in humans is often associated with neurocognitive impairment. Whether this is due to long-term deficits in short-term memory and/or hippocampal plasticity remains unclear. Recently, we reported that METH increases baseline synaptic transmission and reduces LTP in an ex vivo preparation of the hippocampal CA1 region from young mice. In the current study, we tested the hypothesis that a repeated neurotoxic regimen of METH exposure in adolescent mice decreases hippocampal synaptic plasticity and produces a deficit in short-term memory. Contrary to our prediction, there was no change in the hippocampal plasticity or short-term memory when measured after 14 days of METH exposure. However, we found that at 7, 14, and 21 days of drug abstinence, METH-exposed mice exhibited a deficit in spatial memory, which was accompanied by a decrease in hippocampal plasticity. Our results support the interpretation that the deleterious cognitive consequences of neurotoxic levels of METH exposure may manifest and persist after drug abstinence. Therefore, therapeutic strategies should consider short-term as well as long-term consequences of methamphetamine exposure. Copyright © 2012 Wiley Periodicals, Inc.

Narp Deletion Blocks Extinction of Morphine Place Preference Conditioning

PubMed Central

Crombag, Hans S; Dickson, Mercy; Dinenna, Megan; Johnson, Alexander W; Perin, Mark S; Holland, Peter C; Baraban, Jay M; Reti, Irving M

2008-01-01

As drug abuse can be viewed as a maladaptive form of neuronal plasticity, attention has focused on defining the synaptic plasticity mechanisms that mediate the long-term effects of these drugs. As Narp is secreted at synaptic sites and binds to the extracellular surface of AMPA receptors, it has been implicated in mediating enduring forms of synaptic plasticity. Accordingly, to assess its potential role in the long-lasting behavioral effects of drugs of abuse, we have investigated the impact of Narp deletion on sustained behavioral responses elicited by repeated morphine administration. Narp knockout mice display normal locomotor sensitization and conditioned place preference, but are markedly resistant to extinction of place preference. Thus, these findings indicate that Narp plays a selective role in extinction, possibly by its effects on AMPA receptor trafficking. PMID:18536700