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Sample records for motoneuron synaptic plasticity

  1. Intrinsic and synaptic homeostatic plasticity in motoneurons from mice with glycine receptor mutations

    PubMed Central

    Tadros, M. A.; Farrell, K. E.; Schofield, P. R.; Brichta, A. M.; Graham, B. A.; Fuglevand, A. J.

    2014-01-01

    Inhibitory synaptic inputs to hypoglossal motoneurons (HMs) are important for modulating excitability in brainstem circuits. Here we ask whether reduced inhibition, as occurs in three murine mutants with distinct naturally occurring mutations in the glycine receptor (GlyR), leads to intrinsic and/or synaptic homeostatic plasticity. Whole cell recordings were obtained from HMs in transverse brainstem slices from wild-type (wt), spasmodic (spd), spastic (spa), and oscillator (ot) mice (C57Bl/6, approximately postnatal day 21). Passive and action potential (AP) properties in spd and ot HMs were similar to wt. In contrast, spa HMs had lower input resistances, more depolarized resting membrane potentials, higher rheobase currents, smaller AP amplitudes, and slower afterhyperpolarization current decay times. The excitability of HMs, assessed by “gain” in injected current/firing-frequency plots, was similar in all strains whereas the incidence of rebound spiking was increased in spd. The difference between recruitment and derecruitment current (i.e., ΔI) for AP discharge during ramp current injection was more negative in spa and ot. GABAA miniature inhibitory postsynaptic current (mIPSC) amplitude was increased in spa and ot but not spd, suggesting diminished glycinergic drive leads to compensatory adjustments in the other major fast inhibitory synaptic transmitter system in these mutants. Overall, our data suggest long-term reduction in glycinergic drive to HMs results in changes in intrinsic and synaptic properties that are consistent with homeostatic plasticity in spa and ot but not in spd. We propose such plasticity is an attempt to stabilize HM output, which succeeds in spa but fails in ot. PMID:24401707

  2. Synaptic Control of Motoneuronal Excitability

    PubMed Central

    Rekling, Jens C.; Funk, Gregory D.; Bayliss, Douglas A.; Dong, Xiao-Wei; Feldman, Jack L.

    2016-01-01

    Movement, the fundamental component of behavior and the principal extrinsic action of the brain, is produced when skeletal muscles contract and relax in response to patterns of action potentials generated by motoneurons. The processes that determine the firing behavior of motoneurons are therefore important in understanding the transformation of neural activity to motor behavior. Here, we review recent studies on the control of motoneuronal excitability, focusing on synaptic and cellular properties. We first present a background description of motoneurons: their development, anatomical organization, and membrane properties, both passive and active. We then describe the general anatomical organization of synaptic input to motoneurons, followed by a description of the major transmitter systems that affect motoneuronal excitability, including ligands, receptor distribution, pre- and postsynaptic actions, signal transduction, and functional role. Glutamate is the main excitatory, and GABA and glycine are the main inhibitory transmitters acting through ionotropic receptors. These amino acids signal the principal motor commands from peripheral, spinal, and supraspinal structures. Amines, such as serotonin and norepinephrine, and neuropeptides, as well as the glutamate and GABA acting at metabotropic receptors, modulate motoneuronal excitability through pre- and postsynaptic actions. Acting principally via second messenger systems, their actions converge on common effectors, e.g., leak K+ current, cationic inward current, hyperpolarization-activated inward current, Ca2+ channels, or presynaptic release processes. Together, these numerous inputs mediate and modify incoming motor commands, ultimately generating the coordinated firing patterns that underlie muscle contractions during motor behavior. PMID:10747207

  3. Spinal motoneuron synaptic plasticity during the course of an animal model of multiple sclerosis.

    PubMed

    Marques, K B; Santos, L M B; Oliveira, A L R

    2006-12-01

    During the course of experimental autoimmune encephalomyelitis, a massive loss of motor and sensitive function occurs, which has been classically attributed to the demyelination process. In rats, the clinical signs disappear within 5 days following complete tetraplegia, indicating that demyelination might not be the only cause for the rapid evolution of the disease. The present work investigated the occurrence of experimental autoimmune encephalomyelitis-induced changes of the synaptic covering of spinal motoneurons during exacerbation and after remission. The terminals were typed with transmission electron microscopy as C-, F- and S-type. Immunohistochemical analysis of synaptophysin, glial fibrillary acidic protein and the microglia/macrophage marker F4/80 were also used in order to draw a correlation between the synaptic changes and the glial reaction. The ultrastructural analysis showed that, during exacerbation, there was a strong retraction of both F- and S-type terminals. In this sense, both the covering as well as the length of the remaining terminals suffered great reductions. However, the retracted terminals rapidly returned to apposition, although the mean length remained shorter. A certain level of sprouting may have occurred as, after remission, the number of F-terminals was greater than in the control group. The immunohistochemical analysis showed that the peak of synaptic loss was coincident with an increased macro- and microglial reaction. Our results suggest that the major changes occurring in the spinal cord network during the time course of the disease may contribute significantly to the origin of the clinical signs as well as help to explain their rapid recovery.

  4. Delaying the onset of treadmill exercise following peripheral nerve injury has different effects on axon regeneration and motoneuron synaptic plasticity

    PubMed Central

    Brandt, Jaclyn; Evans, Jonathan T.; Mildenhall, Taylor; Mulligan, Amanda; Konieczny, Aimee; Rose, Samuel J.

    2015-01-01

    Transection of a peripheral nerve results in withdrawal of synapses from motoneurons. Some of the withdrawn synapses are restored spontaneously, but those containing the vesicular glutamate transporter 1 (VGLUT1), and arising mainly from primary afferent neurons, are withdrawn permanently. If animals are exercised immediately after nerve injury, regeneration of the damaged axons is enhanced and no withdrawal of synapses from injured motoneurons can be detected. We investigated whether delaying the onset of exercise until after synapse withdrawal had occurred would yield similar results. In Lewis rats, the right sciatic nerve was cut and repaired. Reinnervation of the soleus muscle was monitored until a direct muscle (M) response was observed to stimulation of the tibial nerve. At that time, rats began 2 wk of daily treadmill exercise using an interval training protocol. Both M responses and electrically-evoked H reflexes were monitored weekly for an additional seven wk. Contacts made by structures containing VGLUT1 or glutamic acid decarboxylase (GAD67) with motoneurons were studied from confocal images of retrogradely labeled cells. Timing of full muscle reinnervation was similar in both delayed and immediately exercised rats. H reflex amplitude in delayed exercised rats was only half that found in immediately exercised animals. Unlike immediately exercised animals, motoneuron contacts containing VGLUT1 in delayed exercised rats were reduced significantly, relative to intact rats. The therapeutic window for application of exercise as a treatment to promote restoration of synaptic inputs onto motoneurons following peripheral nerve injury is different from that for promoting axon regeneration in the periphery. PMID:25632080

  5. Delaying the onset of treadmill exercise following peripheral nerve injury has different effects on axon regeneration and motoneuron synaptic plasticity.

    PubMed

    Brandt, Jaclyn; Evans, Jonathan T; Mildenhall, Taylor; Mulligan, Amanda; Konieczny, Aimee; Rose, Samuel J; English, Arthur W

    2015-04-01

    Transection of a peripheral nerve results in withdrawal of synapses from motoneurons. Some of the withdrawn synapses are restored spontaneously, but those containing the vesicular glutamate transporter 1 (VGLUT1), and arising mainly from primary afferent neurons, are withdrawn permanently. If animals are exercised immediately after nerve injury, regeneration of the damaged axons is enhanced and no withdrawal of synapses from injured motoneurons can be detected. We investigated whether delaying the onset of exercise until after synapse withdrawal had occurred would yield similar results. In Lewis rats, the right sciatic nerve was cut and repaired. Reinnervation of the soleus muscle was monitored until a direct muscle (M) response was observed to stimulation of the tibial nerve. At that time, rats began 2 wk of daily treadmill exercise using an interval training protocol. Both M responses and electrically-evoked H reflexes were monitored weekly for an additional seven wk. Contacts made by structures containing VGLUT1 or glutamic acid decarboxylase (GAD67) with motoneurons were studied from confocal images of retrogradely labeled cells. Timing of full muscle reinnervation was similar in both delayed and immediately exercised rats. H reflex amplitude in delayed exercised rats was only half that found in immediately exercised animals. Unlike immediately exercised animals, motoneuron contacts containing VGLUT1 in delayed exercised rats were reduced significantly, relative to intact rats. The therapeutic window for application of exercise as a treatment to promote restoration of synaptic inputs onto motoneurons following peripheral nerve injury is different from that for promoting axon regeneration in the periphery. Copyright © 2015 the American Physiological Society.

  6. Distribution of vestibulospinal synaptic input to cat triceps surae motoneurons.

    PubMed

    Westcott, S L; Powers, R K; Robinson, F R; Binder, M D

    1995-01-01

    We applied supramaximal, repetitive stimulation to the lateral vestibular nucleus (Deiters' nucleus, DN) at 200 Hz to evoke stead-state synaptic potentials in ipsilateral triceps surae motoneurons of the cat. The effective synaptic currents underlying these potentials were measured using a modified voltage-clamp technique. The steady-state effective synaptic currents evoked by activating DN were generally small and depolarizing (mean 2.5 +/- 2.6 nA). DN stimulation generated hyperpolarizing synaptic currents in 2 of the 34 triceps motoneurons studied. The effective synaptic currents from DN tended to be larger in putative type F motoneurons than in putative type S cells (type F mean 3.0 +/- 3.1 nA; type S mean 1.8 +/- 1.0 nA). There was a statistically significant difference between the inputs to putative type FF and putative type S motoneurons (mean difference 2.8 nA, t = 2.87, P < 0.01). The synaptic input from DN to medial gastrocnemius motoneurons had approximately the same amplitude as that from homonymous Ia afferent fibers. However, the distribution of DN input with respect to putative motor unit type was the opposite of that previously reported for Ia afferent input. Thus, the synaptic input from DN might act to compress the range of recruitment thresholds within the motoneuron pool and thereby increase the gain of its input-output function.

  7. Voltage-dependent amplification of synaptic inputs in respiratory motoneurones

    PubMed Central

    Enríquez Denton, M; Wienecke, J; Zhang, M; Hultborn, H; Kirkwood, P A

    2012-01-01

    The role of persistent inward currents (PICs) in cat respiratory motoneurones (phrenic inspiratory and thoracic expiratory) was investigated by studying the voltage-dependent amplification of central respiratory drive potentials (CRDPs), recorded intracellularly, with action potentials blocked with the local anaesthetic derivative, QX-314. Decerebrate unanaesthetized or barbiturate-anaesthetized preparations were used. In expiratory motoneurones, plateau potentials were observed in the decerebrates, but not under anaesthesia. For phrenic motoneurones, no plateau potentials were observed in either state (except in one motoneurone after the abolition of the respiratory drive by means of a medullary lesion), but all motoneurones showed voltage-dependent amplification of the CRDPs, over a wide range of membrane potentials, too wide to result mainly from PIC activation. The measurements of the amplification were restricted to the phase of excitation, thus excluding the inhibitory phase. Amplification was found to be greatest for the smallest CRDPs in the lowest resistance motoneurones and was reduced or abolished following intracellular injection of the NMDA channel blocker, MK-801. Plateau potentials were readily evoked in non-phrenic cervical motoneurones in the same (decerebrate) preparations. We conclude that the voltage-dependent amplification of synaptic excitation in phrenic motoneurones is mainly the result of NMDA channel modulation rather than the activation of Ca2+ channel mediated PICs, despite phrenic motoneurones being strongly immunohistochemically labelled for CaV1.3 channels. The differential PIC activation in different motoneurones, all of which are CaV1.3 positive, leads us to postulate that the descending modulation of PICs is more selective than has hitherto been believed. PMID:22495582

  8. Sleep, Clocks and Synaptic Plasticity

    PubMed Central

    2014-01-01

    Sleep is widely believed to play an essential role in synaptic plasticity. However, the precise mechanisms governing this presumptive function are largely unknown. There is also evidence for independent circadian oscillations in synaptic strength and morphology. Therefore, synaptic changes observed after sleep reflect interactions between state-dependent (e.g. wake vs. sleep) and state-independent (circadian) processes. In this article we review how sleep and biological clocks influence synaptic plasticity. We discuss these findings in the context of current plasticity-based theories of sleep function and propose a new model that integrates circadian and brain state influences on synaptic plasticity. PMID:25087980

  9. Sleep, clocks, and synaptic plasticity.

    PubMed

    Frank, Marcos G; Cantera, Rafael

    2014-09-01

    Sleep is widely believed to play an essential role in synaptic plasticity. However, the precise mechanisms governing this presumptive function are largely unknown. There is also evidence for independent circadian oscillations in synaptic strength and morphology. Therefore, synaptic changes observed after sleep reflect interactions between state-dependent (e.g., wake versus sleep) and state-independent (circadian) processes. In this review we consider how sleep and biological clocks influence synaptic plasticity. We discuss these findings in the context of current plasticity-based theories of sleep function and propose a new model that integrates circadian and brain-state influences on synaptic plasticity. Copyright © 2014 Elsevier Ltd. All rights reserved.

  10. Optogenetics and synaptic plasticity.

    PubMed

    Xie, Yu-feng; Jackson, Michael F; Macdonald, John F

    2013-11-01

    The intricate and complex interaction between different populations of neurons in the brain has imposed limits on our ability to gain detailed understanding of synaptic transmission and its integration when employing classical electrophysiological approaches. Indeed, electrical field stimulation delivered via traditional microelectrodes does not permit the targeted, precise and selective control of neuronal activity amongst a varied population of neurons and their inputs (eg, cholinergic, dopaminergic or glutamatergic neurons). Recently established optogenetic techniques overcome these limitations allowing precise control of the target neuron populations, which is essential for the elucidation of the neural substrates underlying complex animal behaviors. Indeed, by introducing light-activated channels (ie, microbial opsin genes) into specific neuronal populations, optogenetics enables non-invasive optical control of specific neurons with milliseconds precision. These approaches can readily be applied to freely behaving live animals. Recently there is increased interests in utilizing optogenetics tools to understand synaptic plasticity and learning/memory. Here, we summarize recent progress in applying optogenetics in in the study of synaptic plasticity.

  11. Optogenetics and synaptic plasticity

    PubMed Central

    Xie, Yu-feng; Jackson, Michael F; MacDonald, John F

    2013-01-01

    The intricate and complex interaction between different populations of neurons in the brain has imposed limits on our ability to gain detailed understanding of synaptic transmission and its integration when employing classical electrophysiological approaches. Indeed, electrical field stimulation delivered via traditional microelectrodes does not permit the targeted, precise and selective control of neuronal activity amongst a varied population of neurons and their inputs (eg, cholinergic, dopaminergic or glutamatergic neurons). Recently established optogenetic techniques overcome these limitations allowing precise control of the target neuron populations, which is essential for the elucidation of the neural substrates underlying complex animal behaviors. Indeed, by introducing light-activated channels (ie, microbial opsin genes) into specific neuronal populations, optogenetics enables non-invasive optical control of specific neurons with milliseconds precision. These approaches can readily be applied to freely behaving live animals. Recently there is increased interests in utilizing optogenetics tools to understand synaptic plasticity and learning/memory. Here, we summarize recent progress in applying optogenetics in in the study of synaptic plasticity. PMID:24162508

  12. [Memory and synaptic plasticity].

    PubMed

    Maitre, M

    1996-01-01

    Short term memory traces are probably induced by a sustained and specific functional activation of some sensory and/or motor circuits in brain. These modifications, which could concern a large proportion of the brain but especially the limbic areas, are constituted primarily by ionic mechanisms and second messengers cascades induced by the activation of glutamatergic receptors (namely NMDA). In the invertebrate (Drosophilia melanogaster, aplysia), the role of serotonergic receptors seems to be more important. The activated cAMP-dependent and calcium dependent protein kinases target several proteins which are reversibly phosphorylated modifying the synaptic functions which in turn induce potentiated (PLT) or depressed (DLT) post-synaptic responses. These phenomena are at the basis of specific protein neosynthesis which is initiated by several early genes or trancription factor (cfos, zif 268, jun, CREB). Specific mRNA migrate to the potentiated synapse or dendritic spine where activated polyribosomes synthesize trophic factor, adhesion molecules and synaptic constituents. The building of new synaptic contacts and/or the plastic evolution of existing synapses could explain long-term LTP and long-term memory traces.

  13. Emerging Roles of Filopodia and Dendritic Spines in Motoneuron Plasticity during Development and Disease

    PubMed Central

    Kanjhan, Refik; Noakes, Peter G.; Bellingham, Mark C.

    2016-01-01

    Motoneurons develop extensive dendritic trees for receiving excitatory and inhibitory synaptic inputs to perform a variety of complex motor tasks. At birth, the somatodendritic domains of mouse hypoglossal and lumbar motoneurons have dense filopodia and spines. Consistent with Vaughn's synaptotropic hypothesis, we propose a developmental unified-hybrid model implicating filopodia in motoneuron spinogenesis/synaptogenesis and dendritic growth and branching critical for circuit formation and synaptic plasticity at embryonic/prenatal/neonatal period. Filopodia density decreases and spine density initially increases until postnatal day 15 (P15) and then decreases by P30. Spine distribution shifts towards the distal dendrites, and spines become shorter (stubby), coinciding with decreases in frequency and increases in amplitude of excitatory postsynaptic currents with maturation. In transgenic mice, either overexpressing the mutated human Cu/Zn-superoxide dismutase (hSOD1G93A) gene or deficient in GABAergic/glycinergic synaptic transmission (gephyrin, GAD-67, or VGAT gene knockout), hypoglossal motoneurons develop excitatory glutamatergic synaptic hyperactivity. Functional synaptic hyperactivity is associated with increased dendritic growth, branching, and increased spine and filopodia density, involving actin-based cytoskeletal and structural remodelling. Energy-dependent ionic pumps that maintain intracellular sodium/calcium homeostasis are chronically challenged by activity and selectively overwhelmed by hyperactivity which eventually causes sustained membrane depolarization leading to excitotoxicity, activating microglia to phagocytose degenerating neurons under neuropathological conditions. PMID:26843990

  14. Signaling for Vesicle Mobilization and Synaptic Plasticity

    PubMed Central

    Levitan, Edwin S.

    2008-01-01

    The hypothesis that release of classical neurotransmitters and neuropeptides is facilitated by increasing the mobility of small synaptic vesicles (SSVs) and dense core vesicles (DCVs) could not be tested until the advent of methods for visualizing these secretory vesicles in living nerve terminals. In fact, fluorescence imaging studies have only since 2005 established that activity increases secretory vesicle mobility in motoneuron terminals and chromaffin cells. Mobilization of DCVs and SSVs appears to be due to liberation of hindered vesicles to promote quicker diffusion. However, F-actin and synapsin, which have been featured in mobilization models, are not required for activity-dependent increases in the mobility of DCVs or SSVs. Most recently, the signaling required for sustained mobilization has been identified for Drosophila motoneuron DCVs and shown to increase synaptic transmission. Specifically, presynaptic endoplasmic reticulum ryanodine receptor (RyR)-mediated Ca2+ release activates Ca2+/calmodulin-dependent kinase II (CamKII) to mobilize DCVs and induce post-tetanic potentiation (PTP) of neuropeptide release in the Drosophila neuromuscular junction. The shared signaling for increasing vesicle mobility and PTP links vesicle mobilization and synaptic plasticity. PMID:18446451

  15. Circadian Regulation of Synaptic Plasticity

    PubMed Central

    Frank, Marcos G.

    2016-01-01

    Circadian rhythms refer to oscillations in biological processes with a period of approximately 24 h. In addition to the sleep/wake cycle, there are circadian rhythms in metabolism, body temperature, hormone output, organ function and gene expression. There is also evidence of circadian rhythms in synaptic plasticity, in some cases driven by a master central clock and in other cases by peripheral clocks. In this article, I review the evidence for circadian influences on synaptic plasticity. I also discuss ways to disentangle the effects of brain state and rhythms on synaptic plasticity. PMID:27420105

  16. Circadian Regulation of Synaptic Plasticity.

    PubMed

    Frank, Marcos G

    2016-07-13

    Circadian rhythms refer to oscillations in biological processes with a period of approximately 24 h. In addition to the sleep/wake cycle, there are circadian rhythms in metabolism, body temperature, hormone output, organ function and gene expression. There is also evidence of circadian rhythms in synaptic plasticity, in some cases driven by a master central clock and in other cases by peripheral clocks. In this article, I review the evidence for circadian influences on synaptic plasticity. I also discuss ways to disentangle the effects of brain state and rhythms on synaptic plasticity.

  17. Ethanol Modulation of Synaptic Plasticity

    PubMed Central

    McCool, Brian A.

    2011-01-01

    Synaptic plasticity in the most general terms represents the flexibility of neurotransmission in response to neuronal activity. Synaptic plasticity is essential both for the moment-by-moment modulation of neural activity in response to dynamic environmental cues and for long-term learning and memory formation. These temporal characteristics are served by an array of pre- and post-synaptic mechanisms that are frequently modulated by ethanol exposure. This modulation likely makes significant contributions to both alcohol abuse and dependence. In this review, I discuss the modulation of both short-term and long-term synaptic plasticity in the context of specific ethanol-sensitive cellular substrates. A general discussion of the available preclinical, animal-model based neurophysiology literature provides a comparison between results from in vitro and in vivo studies. Finally, in the context of alcohol abuse and dependence, the review proposes potential behavioral contributions by ethanol modulation of plasticity. PMID:21195719

  18. Synaptic Plasticity and Translation Initiation

    ERIC Educational Resources Information Center

    Klann, Eric; Antion, Marcia D.; Banko, Jessica L.; Hou, Lingfei

    2004-01-01

    It is widely accepted that protein synthesis, including local protein synthesis at synapses, is required for several forms of synaptic plasticity. Local protein synthesis enables synapses to control synaptic strength independent of the cell body via rapid protein production from pre-existing mRNA. Therefore, regulation of translation initiation is…

  19. Synaptic Plasticity and Translation Initiation

    ERIC Educational Resources Information Center

    Klann, Eric; Antion, Marcia D.; Banko, Jessica L.; Hou, Lingfei

    2004-01-01

    It is widely accepted that protein synthesis, including local protein synthesis at synapses, is required for several forms of synaptic plasticity. Local protein synthesis enables synapses to control synaptic strength independent of the cell body via rapid protein production from pre-existing mRNA. Therefore, regulation of translation initiation is…

  20. Noradrenergic Modulation of Intrinsic and Synaptic Properties of Lumbar Motoneurons in the Neonatal Rat Spinal Cord

    PubMed Central

    Tartas, Maylis; Morin, France; Barrière, Grégory; Goillandeau, Michel; Lacaille, Jean-Claude; Cazalets, Jean-René; Bertrand, Sandrine S.

    2009-01-01

    Although it is known that noradrenaline (NA) powerfully controls spinal motor networks, few data are available regarding the noradrenergic (NAergic) modulation of intrinsic and synaptic properties of neurons in motor networks. Our work explores the cellular basis of NAergic modulation in the rat motor spinal cord. We first show that lumbar motoneurons express the three classes of adrenergic receptors at birth. Using patch-clamp recordings in the newborn rat spinal cord preparation, we characterized the effects of NA and of specific agonists of the three classes of adrenoreceptors on motoneuron membrane properties. NA increases the motoneuron excitability partly via the inhibition of a KIR like current. Methoxamine (α1), clonidine (α2) and isoproterenol (β) differentially modulate the motoneuron membrane potential but also increase motoneuron excitability, these effects being respectively inhibited by the antagonists prazosin (α1), yohimbine (α2) and propranolol (β). We show that the glutamatergic synaptic drive arising from the T13-L2 network is enhanced in motoneurons by NA, methoxamine and isoproterenol. On the other hand, NA, isoproterenol and clonidine inhibit both the frequency and amplitude of miniature glutamatergic EPSCs while methoxamine increases their frequency. The T13-L2 synaptic drive is thereby differentially modulated from the other glutamatergic synapses converging onto motoneurons and enhanced by presynaptic α1 and β receptor activation. Our data thus show that the NAergic system exerts a powerful and complex neuromodulation of lumbar motor networks in the neonatal rat spinal cord. PMID:20300468

  1. Mitochondria, synaptic plasticity, and schizophrenia.

    PubMed

    Ben-Shachar, Dorit; Laifenfeld, Daphna

    2004-01-01

    The conceptualization of schizophrenia as a disorder of connectivity, i.e., of neuronal?synaptic plasticity, suggests abnormal synaptic modeling and neuronal signaling, possibly as a consequence of flawed interactions with the environment, as at least a secondary mechanism underlying the pathophysiology of this disorder. Indeed, deficits in episodic memory and malfunction of hippocampal circuitry, as well as anomalies of axonal sprouting and synapse formation, are all suggestive of diminished neuronal plasticity in schizophrenia. Evidence supports a dysfunction of mitochondria in schizophrenia, including mitochondrial hypoplasia, and a dysfunction of the oxidative phosphorylation system, as well as altered mitochondrial-related gene expression. Mitochondrial dysfunction leads to alterations in ATP production and cytoplasmatic calcium concentrations, as well as reactive oxygen species and nitric oxide production. All of the latter processes have been well established as leading to altered synaptic strength or plasticity. Moreover, mitochondria have been shown to play a role in plasticity of neuronal polarity, and studies in the visual cortex show an association between mitochondria and synaptogenesis. Finally, mitochondrial gene upregulation has been observed following synaptic and neuronal activity. This review proposes that mitochondrial dysfunction in schizophrenia could cause, or arise from, anomalies in processes of plasticity in this disorder.

  2. Pharmacological characterization of the rhythmic synaptic drive onto lumbosacral motoneurons in the chick embryo spinal cord.

    PubMed

    Sernagor, E; Chub, N; Ritter, A; O'Donovan, M J

    1995-11-01

    The isolated spinal cord of the chick embryo generates episodes of rhythmic bursting in which sartorius (hip flexor) and femorotibialis (knee extensor) motoneurons exhibit characteristic patterns of activity. At the beginning of each cycle both sets of motoneurons discharge synchronously. Following this brief synchronous activation sartorius motoneurons stop firing at the time of peak femorotibialis activity, producing a period of alternation between the two sets of motoneurons. Intracellular recording from motoneurons has suggested that the pause is mediated by a synaptically induced shunt conductance. However, the pharmacological basis for this shunt and the nature of the excitatory drive to motoneurons is unknown. To address these questions we have investigated the pharmacology of the rhythmic, synaptic drive to lumbosacral motoneurons using local and bath application of several excitatory and inhibitory antagonists, and documenting their effects on motor output in E10-E12 chick embryos. Local application of bicuculline or picrotoxin over sartorius motoneurons abolished the pause in firing recorded from the sartorius muscle nerve. As a consequence, the pattern of sartorius and femorotibialis activity was similar and the motoneurons were coactive. The pause in sartorius firing was shortened following local application of the glycine antagonist strychnine the nicotinic, cholinergic antagonists mecamylamine, and dihydro-beta-erythroidine and several excitatory amino acid antagonists. Application of the GABA uptake inhibitor nipecotic acid depressed the slow potentials and discharge recorded from the sartorius muscle nerve. These findings suggest that the pause is determined primarily by synaptic inputs acting at motoneuron GABAA receptors with contributions from glycinergic, cholinergic, and glutamatergic inputs. The actions of locally applied GABA onto spinal neurons are consistent with these findings because the neurotransmitter depolarizes spinal neurons and

  3. Treadmill training induced lumbar motoneuron dendritic plasticity and behavior recovery in adult rats after a thoracic contusive spinal cord injury.

    PubMed

    Wang, Hongxing; Liu, Nai-Kui; Zhang, Yi Ping; Deng, Lingxiao; Lu, Qing-Bo; Shields, Christopher B; Walker, Melissa J; Li, Jianan; Xu, Xiao-Ming

    2015-09-01

    Spinal cord injury (SCI) is devastating, causing sensorimotor impairments and paralysis. Persisting functional limitations on physical activity negatively affect overall health in individuals with SCI. Physical training may improve motor function by affecting cellular and molecular responses of motor pathways in the central nervous system (CNS) after SCI. Although motoneurons form the final common path for motor output from the CNS, little is known concerning the effect of exercise training on spared motoneurons below the level of injury. Here we examined the effect of treadmill training on morphological, trophic, and synaptic changes in the lumbar motoneuron pool and on behavior recovery after a moderate contusive SCI inflicted at the 9th thoracic vertebral level (T9) using an Infinite Horizon (IH, 200 kDyne) impactor. We found that treadmill training significantly improved locomotor function, assessed by Basso-Beattie-Bresnahan (BBB) locomotor rating scale, and reduced foot drops, assessed by grid walking performance, as compared with non-training. Additionally, treadmill training significantly increased the total neurite length per lumbar motoneuron innervating the soleus and tibialis anterior muscles of the hindlimbs as compared to non-training. Moreover, treadmill training significantly increased the expression of a neurotrophin brain-derived neurotrophic factor (BDNF) in the lumbar motoneurons as compared to non-training. Finally, treadmill training significantly increased synaptic density, identified by synaptophysin immunoreactivity, in the lumbar motoneuron pool as compared to non-training. However, the density of serotonergic terminals in the same regions did not show a significant difference between treadmill training and non-training. Thus, our study provides a biological basis for exercise training as an effective medical practice to improve recovery after SCI. Such an effect may be mediated by synaptic plasticity, and neurotrophic modification in the

  4. Synaptic Connectivity between Renshaw Cells and Motoneurons in the Recurrent Inhibitory Circuit of the Spinal Cord

    PubMed Central

    Moore, Niall J.; Bhumbra, Gardave S.; Foster, Joshua D.

    2015-01-01

    Renshaw cells represent a fundamental component of one of the first discovered neuronal circuits, but their function in motor control has not been established. They are the only central neurons that receive collateral projections from motor outputs, yet the efficacy of the excitatory synapses from single and converging motoneurons remains unknown. Here we present the results of dual whole-cell recordings from identified, synaptically connected Renshaw cell-motoneuron pairs in the mouse lumbar spinal cord. The responses from single Renshaw cells demonstrate that motoneuron synapses elicit large excitatory conductances with few or no failures. We show that the strong excitatory input from motoneurons results from a high probability of neurotransmitter release onto multiple postsynaptic contacts. Dual current-clamp recordings confirm that single motoneuron inputs were sufficient to depolarize the Renshaw cell beyond threshold for firing. Reciprocal connectivity was observed in approximately one-third of the paired recordings tested. Ventral root stimulation was used to evoke currents from Renshaw cells or motoneurons to characterize responses of single neurons to the activation of their corresponding presynaptic cell populations. Excitatory or inhibitory synaptic inputs in the recurrent inhibitory loop induced substantial effects on the excitability of respective postsynaptic cells. Quantal analysis estimates showed a large number of converging inputs from presynaptic motoneuron and Renshaw cell populations. The combination of considerable synaptic efficacy and extensive connectivity within the recurrent circuitry indicates a role of Renshaw cells in modulating motor outputs that may be considerably more important than has been previously supposed. SIGNIFICANCE STATEMENT We have recently shown that Renshaw cells mediate powerful shunt inhibition on motoneuron excitability. Here we complete a quantitative description of the recurrent circuit using recordings of

  5. Neuronal BDNF Signaling Is Necessary for the Effects of Treadmill Exercise on Synaptic Stripping of Axotomized Motoneurons

    PubMed Central

    Krakowiak, Joey; Liu, Caiyue; Papudesu, Chandana; Ward, P. Jillian; Wilhelm, Jennifer C.; English, Arthur W.

    2015-01-01

    The withdrawal of synaptic inputs from the somata and proximal dendrites of spinal motoneurons following peripheral nerve injury could contribute to poor functional recovery. Decreased availability of neurotrophins to afferent terminals on axotomized motoneurons has been implicated as one cause of the withdrawal. No reduction in contacts made by synaptic inputs immunoreactive to the vesicular glutamate transporter 1 and glutamic acid decarboxylase 67 is noted on axotomized motoneurons if modest treadmill exercise, which stimulates the production of neurotrophins by spinal motoneurons, is applied after nerve injury. In conditional, neuron-specific brain-derived neurotrophic factor (BDNF) knockout mice, a reduction in synaptic contacts onto motoneurons was noted in intact animals which was similar in magnitude to that observed after nerve transection in wild-type controls. No further reduction in coverage was found if nerves were cut in knockout mice. Two weeks of moderate daily treadmill exercise following nerve injury in these BDNF knockout mice did not affect synaptic inputs onto motoneurons. Treadmill exercise has a profound effect on synaptic inputs to motoneurons after peripheral nerve injury which requires BDNF production by those postsynaptic cells. PMID:25918648

  6. The Spacing Effect for Structural Synaptic Plasticity Provides Specificity and Precision in Plastic Changes.

    PubMed

    San Martin, Alvaro; Rela, Lorena; Gelb, Bruce; Pagani, Mario Rafael

    2017-05-10

    In contrast to trials of training without intervals (massed training), training trials spaced over time (spaced training) induce a more persistent memory identified as long-term memory (LTM). This phenomenon, known as the spacing effect for memory, is poorly understood. LTM is supported by structural synaptic plasticity; however, how synapses integrate spaced stimuli remains elusive. Here, we analyzed events of structural synaptic plasticity at the single-synapse level after distinct patterns of stimulation in motoneurons of Drosophila We found that the spacing effect is a phenomenon detected at synaptic level, which determines the specificity and the precision in structural synaptic plasticity. Whereas a single pulse of stimulation (massed) induced structural synaptic plasticity, the same amount of stimulation divided in three spaced stimuli completely prevented it. This inhibitory effect was determined by the length of the interstimulus intervals. The inhibitory effect of the spacing was lost by suppressing the activity of Ras or mitogen-activated protein kinase, whereas the overexpression of Ras-WT enhanced it. Moreover, dividing the same total time of stimulation into five or more stimuli produced a higher precision in the number of events of plasticity. Ras mutations associated with intellectual disability abolished the spacing effect and led neurons to decode distinct stimulation patterns as massed stimulation. This evidence suggests that the spacing effect for memory may result from the effect of the spacing in synaptic plasticity, which appears to be a property not limited to neurons involved in learning and memory. We propose a model of spacing-dependent structural synaptic plasticity.SIGNIFICANCE STATEMENT Long-term memory (LTM) induced by repeated trials spaced over time is known as the spacing effect, a common property in the animal kingdom. Altered mechanisms in the spacing effect have been found in animal models of disorders with intellectual

  7. Membrane-Derived Phospholipids Control Synaptic Neurotransmission and Plasticity

    PubMed Central

    García-Morales, Victoria; Montero, Fernando; González-Forero, David; Rodríguez-Bey, Guillermo; Gómez-Pérez, Laura; Medialdea-Wandossell, María Jesús; Domínguez-Vías, Germán; García-Verdugo, José Manuel; Moreno-López, Bernardo

    2015-01-01

    Synaptic communication is a dynamic process that is key to the regulation of neuronal excitability and information processing in the brain. To date, however, the molecular signals controlling synaptic dynamics have been poorly understood. Membrane-derived bioactive phospholipids are potential candidates to control short-term tuning of synaptic signaling, a plastic event essential for information processing at both the cellular and neuronal network levels in the brain. Here, we showed that phospholipids affect excitatory and inhibitory neurotransmission by different degrees, loci, and mechanisms of action. Signaling triggered by lysophosphatidic acid (LPA) evoked rapid and reversible depression of excitatory and inhibitory postsynaptic currents. At excitatory synapses, LPA-induced depression depended on LPA1/Gαi/o-protein/phospholipase C/myosin light chain kinase cascade at the presynaptic site. LPA increased myosin light chain phosphorylation, which is known to trigger actomyosin contraction, and reduced the number of synaptic vesicles docked to active zones in excitatory boutons. At inhibitory synapses, postsynaptic LPA signaling led to dephosphorylation, and internalization of the GABAAγ2 subunit through the LPA1/Gα12/13-protein/RhoA/Rho kinase/calcineurin pathway. However, LPA-induced depression of GABAergic transmission was correlated with an endocytosis-independent reduction of GABAA receptors, possibly by GABAAγ2 dephosphorylation and subsequent increased lateral diffusion. Furthermore, endogenous LPA signaling, mainly via LPA1, mediated activity-dependent inhibitory depression in a model of experimental synaptic plasticity. Finally, LPA signaling, most likely restraining the excitatory drive incoming to motoneurons, regulated performance of motor output commands, a basic brain processing task. We propose that lysophospholipids serve as potential local messengers that tune synaptic strength to precedent activity of the neuron. PMID:25996636

  8. Regulation and Restoration of Motoneuronal Synaptic Transmission During Neuromuscular Regeneration in the Pulmonate Snail Helisoma trivolvis

    PubMed Central

    Turner, M. B.; Szabo-Maas, T. M.; Poyer, J. C.; Zoran, M. J.

    2015-01-01

    Regeneration of motor systems involves reestablishment of central control networks, reinnervation of muscle targets by motoneurons, and reconnection of neuromodulatory circuits. Still, how these processes are integrated as motor function is restored during regeneration remains ill defined. Here, we examined the mechanisms underlying motoneuronal regeneration of neuromuscular synapses related to feeding movements in the pulmonate snail Helisoma trivolvis. Neurons B19 and B110, although activated during different phases of the feeding pattern, innervate similar sets of muscles. However, the percentage of muscle fibers innervated, the efficacy of excitatory junction potentials, and the strength of muscle contractions were different for each cell’s specific connections. After peripheral nerve crush, a sequence of transient electrical and chemical connections formed centrally within the buccal ganglia. Neuromuscular synapse regeneration involved a three-phase process: the emergence of spontaneous synaptic transmission (P1), the acquisition of evoked potentials of weak efficacy (P2), and the establishment of functional reinnervation (P3). Differential synaptic efficacy at muscle contacts was recapitulated in cell culture. Differences in motoneuronal presynaptic properties (i.e., quantal content) were the basis of disparate neuromuscular synapse function, suggesting a role for retrograde target influences. We propose a homeostatic model of molluscan motor system regeneration. This model has three restoration events: (1) transient central synaptogenesis during axonal outgrowth, (2) intermotoneuronal inhibitory synaptogenesis during initial neuromuscular synapse formation, and (3) target-dependent regulation of neuromuscular junction formation. PMID:21876114

  9. Distinct and developmentally regulated activity-dependent plasticity at descending glutamatergic synapses on flexor and extensor motoneurons

    PubMed Central

    Lenschow, Constanze; Cazalets, Jean-René; Bertrand, Sandrine S.

    2016-01-01

    Activity-dependent synaptic plasticity (ADSP) is paramount to synaptic processing and maturation. However, identifying the ADSP capabilities of the numerous synapses converging onto spinal motoneurons (MNs) remain elusive. Using spinal cord slices from mice at two developmental stages, 1–4 and 8–12 postnatal days (P1–P4; P8–P12), we found that high-frequency stimulation of presumed reticulospinal neuron axons in the ventrolateral funiculus (VLF) induced either an NMDA receptor-dependent-long-term depression (LTD), a short-term depression (STD) or no synaptic modulation in limb MNs. Our study shows that P1–P4 cervical MNs expressed the same plasticity profiles as P8–P12 lumbar MNs rather than P1–P4 lumbar MNs indicating that ADSP expression at VLF-MN synapses is linked to the rostrocaudal development of spinal motor circuitry. Interestingly, we observed that the ADSP expressed at VLF-MN was related to the functional flexor or extensor MN subtype. Moreover, heterosynaptic plasticity was triggered in MNs by VLF axon tetanisation at neighbouring synapses not directly involved in the plasticity induction. ADSP at VLF-MN synapses specify differential integrative synaptic processing by flexor and extensor MNs and could contribute to the maturation of spinal motor circuits and developmental acquisition of weight-bearing locomotion. PMID:27329279

  10. Neuronal cytoskeleton in synaptic plasticity and regeneration.

    PubMed

    Gordon-Weeks, Phillip R; Fournier, Alyson E

    2014-04-01

    During development, dynamic changes in the axonal growth cone and dendrite are necessary for exploratory movements underlying initial axo-dendritic contact and ultimately the formation of a functional synapse. In the adult central nervous system, an impressive degree of plasticity is retained through morphological and molecular rearrangements in the pre- and post-synaptic compartments that underlie the strengthening or weakening of synaptic pathways. Plasticity is regulated by the interplay of permissive and inhibitory extracellular cues, which signal through receptors at the synapse to regulate the closure of critical periods of developmental plasticity as well as by acute changes in plasticity in response to experience and activity in the adult. The molecular underpinnings of synaptic plasticity are actively studied and it is clear that the cytoskeleton is a key substrate for many cues that affect plasticity. Many of the cues that restrict synaptic plasticity exhibit residual activity in the injured adult CNS and restrict regenerative growth by targeting the cytoskeleton. Here, we review some of the latest insights into how cytoskeletal remodeling affects neuronal plasticity and discuss how the cytoskeleton is being targeted in an effort to promote plasticity and repair following traumatic injury in the central nervous system. © 2013 International Society for Neurochemistry.

  11. Network response synchronization enhanced by synaptic plasticity

    NASA Astrophysics Data System (ADS)

    Lobov, S.; Simonov, A.; Kastalskiy, I.; Kazantsev, V.

    2016-02-01

    Synchronization of neural network response on spatially localized periodic stimulation was studied. The network consisted of synaptically coupled spiking neurons with spike-timing-dependent synaptic plasticity (STDP). Network connectivity was defined by time evolving matrix of synaptic weights. We found that the steady-state spatial pattern of the weights could be rearranged due to locally applied external periodic stimulation. A method for visualization of synaptic weights as vector field was introduced to monitor the evolving connectivity matrix. We demonstrated that changes in the vector field and associated weight rearrangements underlay an enhancement of synchronization range.

  12. Neuroimmune regulation of homeostatic synaptic plasticity.

    PubMed

    Pribiag, Horia; Stellwagen, David

    2014-03-01

    Homeostatic synaptic plasticity refers to a set of negative-feedback mechanisms that are used by neurons to maintain activity within a functional range. While it is becoming increasingly clear that homeostatic regulation of synapse function is a key principle in the nervous system, the molecular details of this regulation are only beginning to be uncovered. Recent evidence implicates molecules classically associated with the peripheral immune system in the modulation of homeostatic synaptic plasticity. In particular, the pro-inflammatory cytokine TNFα, class I major histocompatibility complex, and neuronal pentraxin 2 are essential in the regulation of the compensatory synaptic response that occurs in response to prolonged neuronal inactivity. This review will present and discuss current evidence implicating neuroimmune molecules in the homeostatic regulation of synapse function. This article is part of the Special Issue entitled 'Homeostatic Synaptic Plasticity'.

  13. Influence of stretch-evoked synaptic potentials on firing probability of cat spinal motoneurones.

    PubMed

    Gustafsson, B; McCrea, D

    1984-02-01

    Shapes of post-synaptic potentials (p.s.p.s) in cat motoneurones were compared with the time course of correlated changes in firing probability during repetitive firing. Excitatory and inhibitory post-synaptic potentials (e.p.s.p.s. and i.p.s.p.s) were evoked by brief triangular stretches of the triceps surae-plantaris muscles. Depolarizing current was injected through the recording micro-electrode to evoke repetitive firing and the post-stimulus time histogram of motoneurone spikes was obtained. E.p.s.p.s (n = 80) of different sizes (30-1040 microV) and rise times (1.1-8.2 ms) were investigated in fifty-nine motoneurones. The majority of the e.p.s.p.s were recorded in triceps surae-plantaris motoneurones with high levels of synaptic noise (estimated peak-to-peak fluctuations of 1.5-3.5 mV). This noise was generated by keeping the triceps surae-plantaris muscles stretched to a near maximal degree. The remaining e.p.s.p.s were recorded in motoneurones to other hind-limb muscles with a low level of synaptic noise. The height of the primary peak of the correlogram with respect to base-line firing rate increased in proportion to both amplitude and rising slope of the e.p.s.p.s. Using normalization procedures or using e.p.s.p.s of constant amplitude but different slopes and vice versa, the relative peak height increased with e.p.s.p. peak derivative with a slope of around 6/mV per millisecond and with e.p.s.p peak amplitude with a slope of about 1/mV. The shape of the correlogram (peak and trough) seemed well described by a linear combination of the shape of the e.p.s.p. derivative and that of the e.p.s.p. itself. The relative e.p.s.p. contribution (e.p.s.p.:e.p.s.p. derivative ratio) varied with e.p.s.p. amplitude and noise level, being largest (mostly 0.25-1.0) for small e.p.s.p.s (100-300 microV) in high levels of synaptic noise and smaller (0-0.25) for larger e.p.s.p.s and for e.p.s.p.s in a low noise background. In conformity with the above finding, a leaky

  14. Motor activity in the isolated spinal cord of the chick embryo: synaptic drive and firing pattern of single motoneurons.

    PubMed

    O'Donovan, M J

    1989-03-01

    The cellular mechanisms underlying embryonic motility were investigated using intracellular recording from motoneurons and electrotonic recording from muscle nerves during motor activity generated by an isolated spinal cord preparation of 12- to 15-d-old chick embryos. DC-coupled recordings from sartorius (a flexor) and femorotibialis (an extensor) muscle nerves revealed that both sets of motoneurons were depolarized at the same time in each cycle even when the motoneurons fired out of phase. Sartorius motoneurons fired briefly on the rising phase of the depolarization and then stopped firing before discharging a second burst of spikes as the depolarization decayed. By contrast, femorotibialis motoneurons fired at the peak of their depolarization, which was coincident with the interruption in sartorius activity. Intracellular recordings from antidromically identified motoneurons confirmed that flexor and extensor motoneurons were depolarized at the same time during each cycle of activity. The discharge of femorotibialis motoneurons, and others presumed to be extensors, followed changes in membrane potential so that maximal firing occurred during peak depolarization. The relationship between discharge and membrane potential was different in sartorius motoneurons (and in others presumed to be flexors) because they fired briefly on the rising phase of the depolarization and then stopped firing during peak depolarization. In some of these cells firing resumed as the membrane potential decayed back to rest. Intracellular injection of depolarizing current into sartorius motoneurons during motor activity reversed the direction of the membrane potential change from depolarizing to hyperpolarizing during the pause in sartorius discharge. In addition, the discharge evoked by the depolarizing current was blocked during the reversed part of the synaptic potential revealing its inhibitory nature. The occurrence of the IPSP was accompanied by a large reduction in motoneuronal

  15. Loss of the Coffin-Lowry syndrome-associated gene RSK2 alters ERK activity, synaptic function and axonal transport in Drosophila motoneurons.

    PubMed

    Beck, Katherina; Ehmann, Nadine; Andlauer, Till F M; Ljaschenko, Dmitrij; Strecker, Katrin; Fischer, Matthias; Kittel, Robert J; Raabe, Thomas

    2015-11-01

    Plastic changes in synaptic properties are considered as fundamental for adaptive behaviors. Extracellular-signal-regulated kinase (ERK)-mediated signaling has been implicated in regulation of synaptic plasticity. Ribosomal S6 kinase 2 (RSK2) acts as a regulator and downstream effector of ERK. In the brain, RSK2 is predominantly expressed in regions required for learning and memory. Loss-of-function mutations in human RSK2 cause Coffin-Lowry syndrome, which is characterized by severe mental retardation and low IQ scores in affected males. Knockout of RSK2 in mice or the RSK ortholog in Drosophila results in a variety of learning and memory defects. However, overall brain structure in these animals is not affected, leaving open the question of the pathophysiological consequences. Using the fly neuromuscular system as a model for excitatory glutamatergic synapses, we show that removal of RSK function causes distinct defects in motoneurons and at the neuromuscular junction. Based on histochemical and electrophysiological analyses, we conclude that RSK is required for normal synaptic morphology and function. Furthermore, loss of RSK function interferes with ERK signaling at different levels. Elevated ERK activity was evident in the somata of motoneurons, whereas decreased ERK activity was observed in axons and the presynapse. In addition, we uncovered a novel function of RSK in anterograde axonal transport. Our results emphasize the importance of fine-tuning ERK activity in neuronal processes underlying higher brain functions. In this context, RSK acts as a modulator of ERK signaling.

  16. Loss of the Coffin-Lowry syndrome-associated gene RSK2 alters ERK activity, synaptic function and axonal transport in Drosophila motoneurons

    PubMed Central

    Beck, Katherina; Ehmann, Nadine; Andlauer, Till F. M.; Ljaschenko, Dmitrij; Strecker, Katrin; Fischer, Matthias; Kittel, Robert J.; Raabe, Thomas

    2015-01-01

    ABSTRACT Plastic changes in synaptic properties are considered as fundamental for adaptive behaviors. Extracellular-signal-regulated kinase (ERK)-mediated signaling has been implicated in regulation of synaptic plasticity. Ribosomal S6 kinase 2 (RSK2) acts as a regulator and downstream effector of ERK. In the brain, RSK2 is predominantly expressed in regions required for learning and memory. Loss-of-function mutations in human RSK2 cause Coffin-Lowry syndrome, which is characterized by severe mental retardation and low IQ scores in affected males. Knockout of RSK2 in mice or the RSK ortholog in Drosophila results in a variety of learning and memory defects. However, overall brain structure in these animals is not affected, leaving open the question of the pathophysiological consequences. Using the fly neuromuscular system as a model for excitatory glutamatergic synapses, we show that removal of RSK function causes distinct defects in motoneurons and at the neuromuscular junction. Based on histochemical and electrophysiological analyses, we conclude that RSK is required for normal synaptic morphology and function. Furthermore, loss of RSK function interferes with ERK signaling at different levels. Elevated ERK activity was evident in the somata of motoneurons, whereas decreased ERK activity was observed in axons and the presynapse. In addition, we uncovered a novel function of RSK in anterograde axonal transport. Our results emphasize the importance of fine-tuning ERK activity in neuronal processes underlying higher brain functions. In this context, RSK acts as a modulator of ERK signaling. PMID:26398944

  17. Synaptic Vesicle Proteins and Active Zone Plasticity

    PubMed Central

    Kittel, Robert J.; Heckmann, Manfred

    2016-01-01

    Neurotransmitter is released from synaptic vesicles at the highly specialized presynaptic active zone (AZ). The complex molecular architecture of AZs mediates the speed, precision and plasticity of synaptic transmission. Importantly, structural and functional properties of AZs vary significantly, even for a given connection. Thus, there appear to be distinct AZ states, which fundamentally influence neuronal communication by controlling the positioning and release of synaptic vesicles. Vice versa, recent evidence has revealed that synaptic vesicle components also modulate organizational states of the AZ. The protein-rich cytomatrix at the active zone (CAZ) provides a structural platform for molecular interactions guiding vesicle exocytosis. Studies in Drosophila have now demonstrated that the vesicle proteins Synaptotagmin-1 (Syt1) and Rab3 also regulate glutamate release by shaping differentiation of the CAZ ultrastructure. We review these unexpected findings and discuss mechanistic interpretations of the reciprocal relationship between synaptic vesicles and AZ states, which has heretofore received little attention. PMID:27148040

  18. Intramuscular AAV delivery of NT-3 alters synaptic transmission to motoneurons in adult rats

    PubMed Central

    Petruska, Jeffrey C.; Kitay, Brandon; Boyce, Vanessa S.; Kaspar, Brian; Pearse, Damien; Gage, Fred H.; Mendell, Lorne M.

    2010-01-01

    We examined whether elevating levels of neurotrophin-3 (NT-3) in the spinal cord and dorsal root ganglion (DRG) would alter connections made by muscle spindle afferent fibers on motoneurons. Adeno-associated virus (AAV) serotypes AAV1, AAV2 and AAV5, selected for their tropism profile, were engineered with the NT-3 gene and administered to the medial gastrocnemius muscle in adult rats. ELISA studies in muscle, DRG and spinal cord revealed that NT-3 concentration in all tissues peaked about 3 months after a single viral injection; after 6 months NT-3 concentration returned to normal values. Intracellular recording in triceps surae motoneurons revealed complex electrophysiological changes. Moderate elevation in cord NT-3 resulted in diminished segmental excitatory postsynaptic potential (EPSP) amplitude, perhaps as a result of the observed decrease in motoneuron input resistance. With further elevation in NT-3 expression, the decline in EPSP amplitude was reversed indicating that NT-3 at higher concentration could increase EPSP amplitude. No correlation was observed between EPSP amplitude and NT-3 concentration in the DRG. Treatment with control viruses could elevate NT-3 levels minimally resulting in measurable electrophysiological effects, perhaps as a result of inflammation associated with injection. EPSPs elicited by stimulation of the ventrolateral funiculus underwent a consistent decline in amplitude independent of NT-3 level. These novel correlations between modified NT-3 expression and single-cell electrophysiological parameters indicate that intramuscular administration of AAV(NT-3) can exert long lasting effects on synaptic transmission to motoneurons. This approach to neurotrophin delivery could be useful in modifying spinal function after injury. PMID:20849530

  19. Inhibitory synaptic drive patterns motoneuronal activity in rhythmic preparations of isolated thoracic ganglia in the stick insect.

    PubMed

    Büschges, A

    1998-02-09

    During active leg movements of an insect leg, the activity of the motoneuron pools of each individual leg joint is generated by the interaction between signals from central rhythm generating sources, peripheral signals as well as coordinating signals from other leg joints and legs. The nature of the synaptic drive from the central rhythm generators onto the motoneuron pools of the individual leg joints during rhythmic motor activity of the stick insect (Carausius morosus) middle leg has been investigated. In the isolated mesothoracic ganglion central rhythm generators were activated pharmacologically by topical application of the muscarinic agonist pilocarpine. Motoneurons supplying the femur-tibia (FT) joint were investigated in detail. Recordings from neuropil processes of these motoneurons revealed that patterning of their rhythmic activity is based on cyclic hyperpolarizing synaptic inputs. These inputs are in clear antiphase for extensor and flexor motoneurons. DCC (discontinuous current clamp) and dSEVC (discontinuous single electrode voltage clamp) recordings showed reversal potentials of the inhibitory inputs between -80 to -85 mV (FETi, N=7; Flex MN, N=3). After intracellular injection of TEA rhythmic inhibition in FETi was decreased by about 84% (N=4). Both findings indicate that the cyclic inhibition is mediated by potassium ions. Thus, it appears that central rhythm generators pattern motor activity in antagonistic tibial motoneuron pools by cyclic alternating inhibition.

  20. The role of synaptic ion channels in synaptic plasticity

    PubMed Central

    Voglis, Giannis; Tavernarakis, Nektarios

    2006-01-01

    The nervous system receives a large amount of information about the environment through elaborate sensory routes. Processing and integration of these wide-ranging inputs often results in long-term behavioural alterations as a result of past experiences. These relatively permanent changes in behaviour are manifestations of the capacity of the nervous system for learning and memory. At the cellular level, synaptic plasticity is one of the mechanisms underlying this process. Repeated neural activity generates physiological changes in the nervous system that ultimately modulate neuronal communication through synaptic transmission. Recent studies implicate both presynaptic and postsynaptic ion channels in the process of synapse strength modulation. Here, we review the role of synaptic ion channels in learning and memory, and discuss the implications and significance of these findings towards deciphering the molecular biology of learning and memory. PMID:17077866

  1. Glial responses to synaptic damage and plasticity.

    PubMed

    Aldskogius, H; Liu, L; Svensson, M

    1999-10-01

    We review three principally different forms of injury-induced synaptic alterations. (1) Displacement of presynaptic terminals from perikarya and dendrites of axotomized neurons, (2) central changes in primary afferent terminals of peripherally axotomized sensory ganglion cells, and (3) anterograde Wallerian-type degeneration following interruption of central axonal pathways. All these instances rapidly activate astrocytes and microglia in the vicinity of the affected synaptic terminals. The evidence suggests that activated astrocytes play important and direct roles in synapse elimination and in the processes mediating collateral reinnervation. The roles of microglia are enigmatic. They undergo activation close to axotomized motoneuron perikarya, where synapse displacement occurs, but not adjacent to axotomized intrinsic central nervous system neurons, where synapse displacement also occurs. Microglia are also rapidly activated around central primary sensory terminals of peripherally axotomized sensory ganglion cells. Occasional phagocytosis of degenerating axon terminals by microglia occur in the latter situation. However, the role of microglia may be more oriented toward the general tissue conditions rather than specifically toward synaptic terminals.

  2. Synaptic Plasticity and Memory Formation

    DTIC Science & Technology

    1994-05-31

    The name " Ampakines " has been used to describe this family; when more is known about structure-activity relationships, it should be possible to...regarding the physiological effects of the drugs. Excised patch studies have shown that Ampakines prolong the duration of AMPA receptor-mediated...also revealed that Ampakines produce the expected facilitation and prolongation of synaptic responses in situ; these drugs are thus the first compounds

  3. Permanent central synaptic disconnection of proprioceptors after nerve injury and regeneration. II. Loss of functional connectivity with motoneurons.

    PubMed

    Bullinger, Katie L; Nardelli, Paul; Pinter, Martin J; Alvarez, Francisco J; Cope, Timothy C

    2011-11-01

    Regeneration of a cut muscle nerve fails to restore the stretch reflex, and the companion paper to this article [Alvarez FJ, Titus-Mitchell HE, Bullinger KL, Kraszpulski M, Nardelli P, Cope TC. J Neurophysiol (August 10, 2011). doi:10.1152/jn.01095.2010] suggests an important central contribution from substantial and persistent disassembly of synapses between regenerated primary afferents and motoneurons. In the present study we tested for physiological correlates of synaptic disruption. Anesthetized adult rats were studied 6 mo or more after a muscle nerve was severed and surgically rejoined. We recorded action potentials (spikes) from individual muscle afferents classified as IA like (*IA) by several criteria and tested for their capacity to produce excitatory postsynaptic potentials (EPSPs) in homonymous motoneurons, using spike-triggered averaging (STA). Nearly every paired recording from a *IA afferent and homonymous motoneuron (93%) produced a STA EPSP in normal rats, but that percentage was only 17% in rats with regenerated nerves. In addition, the number of motoneurons that produced aggregate excitatory stretch synaptic potentials (eSSPs) in response to stretch of the reinnervated muscle was reduced from 100% normally to 60% after nerve regeneration. The decline in functional connectivity was not attributable to synaptic depression, which returned to its normally low level after regeneration. From these findings and those in the companion paper, we put forward a model in which synaptic excitation of motoneurons by muscle stretch is reduced not only by misguided axon regeneration that reconnects afferents to the wrong receptor type but also by retraction of synapses with motoneurons by spindle afferents that successfully reconnect with spindle receptors in the periphery.

  4. Synaptic plasticity with discrete state synapses

    NASA Astrophysics Data System (ADS)

    Abarbanel, Henry D. I.; Talathi, Sachin S.; Gibb, Leif; Rabinovich, M. I.

    2005-09-01

    Experimental observations on synaptic plasticity at individual glutamatergic synapses from the CA3 Shaffer collateral pathway onto CA1 pyramidal cells in the hippocampus suggest that the transitions in synaptic strength occur among discrete levels at individual synapses [C. C. H. Petersen , Proc. Natl. Acad. Sci. USA 85, 4732 (1998); O’Connor, Wittenberg, and Wang, D. H. O’Connor , Proc. Natl. Acad. Sci. USA (to be published); J. M. Montgomery and D. V. Madison, Trends Neurosci. 27, 744 (2004)]. This happens for both long term potentiation (LTP) and long term depression (LTD) induction protocols. O’Connor, Wittenberg, and Wang have argued that three states would account for their observations on individual synapses in the CA3-CA1 pathway. We develop a quantitative model of this three-state system with transitions among the states determined by a competition between kinases and phosphatases shown by D. H. O’Connor , to be determinant of LTP and LTD, respectively. Specific predictions for various plasticity protocols are given by coupling this description of discrete synaptic α -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor ligand gated ion channel conductance changes to a model of postsynaptic membrane potential and associated intracellular calcium fluxes to yield the transition rates among the states. We then present various LTP and LTD induction protocols to the model system and report the resulting whole cell changes in AMPA conductance. We also examine the effect of our discrete state synaptic plasticity model on the synchronization of realistic oscillating neurons. We show that one-to-one synchronization is enhanced by the plasticity we discuss here and the presynaptic and postsynaptic oscillations are in phase. Synaptic strength saturates naturally in this model and does not require artificial upper or lower cutoffs, in contrast to earlier models of plasticity.

  5. GABAergic synaptic scaling in embryonic motoneurons is mediated by a shift in the chloride reversal potential

    PubMed Central

    Gonzalez-Islas, Carlos; Chub, Nikolai; Garcia-Bereguiain, Miguel Angel; Wenner, Peter

    2010-01-01

    Homeostatic synaptic plasticity ensures that networks maintain specific levels of activity by regulating synaptic strength in a compensatory manner. When spontaneous network activity (SNA) was blocked in vivo in the embryonic spinal cord, compensatory increases in excitatory GABAergic synaptic inputs were observed. This homeostatic synaptic strengthening was observed as an increase in the amplitude of GABAergic miniature postsynaptic currents (mPSCs). We find that this process is mediated by an increase in chloride accumulation which produces a depolarizing shift in the GABAergic reversal potential (EGABA). The findings demonstrate a previously unrecognized mechanism underlying homeostatic synaptic scaling. Similar shifts in EGABA have been described following various forms of neuronal injury, introducing the possibility that these shifts in EGABA represent a homeostatic response. PMID:20881119

  6. Diacylglycerol Kinases in the Coordination of Synaptic Plasticity

    PubMed Central

    Lee, Dongwon; Kim, Eunjoon; Tanaka-Yamamoto, Keiko

    2016-01-01

    Synaptic plasticity is activity-dependent modification of the efficacy of synaptic transmission. Although, detailed mechanisms underlying synaptic plasticity are diverse and vary at different types of synapses, diacylglycerol (DAG)-associated signaling has been considered as an important regulator of many forms of synaptic plasticity, including long-term potentiation (LTP) and long-term depression (LTD). Recent evidences indicate that DAG kinases (DGKs), which phosphorylate DAG to phosphatidic acid to terminate DAG signaling, are important regulators of LTP and LTD, as supported by the results from mice lacking specific DGK isoforms. This review will summarize these studies and discuss how specific DGK isoforms distinctly regulate different forms of synaptic plasticity at pre- and postsynaptic sites. In addition, we propose a general role of DGKs as coordinators of synaptic plasticity that make local synaptic environments more permissive for synaptic plasticity by regulating DAG concentration and interacting with other synaptic proteins. PMID:27630986

  7. Nanoscale analysis of structural synaptic plasticity

    PubMed Central

    Bourne, Jennifer N.; Harris, Kristen M.

    2011-01-01

    In the 1950’s, transmission electron microscopy was first used to reveal the diversity in synaptic structure and composition in the central nervous system [1;2]. Since then, visualization and reconstruction of serial thin sections have provided three-dimensional contexts in which to understand how synapses are modified with plasticity, learning, and sensory input [3–17]. Three-dimensional reconstruction from serial section electron microscopy (ssEM) has proven invaluable for the comprehensive analysis of structural synaptic plasticity. It has provided the needed nanometer resolution to localize and measure key subcellular structures, such as the postsynaptic density (PSD) and presynaptic vesicles which define a synapse, polyribosomes as sites of local protein synthesis, smooth endoplasmic reticulum (SER) for local regulation of calcium and trafficking of membrane proteins, endosomes for recycling, and fine astroglial processes at the perimeter of some synapses. Thus, ssEM is an essential tool for nanoscale analysis of the cell biological and anatomical modifications that underlie changes in synaptic strength. Here we discuss several important issues associated with interpreting the functional significance of structural synaptic plasticity, especially during long-term potentiation, a widely studied cellular model of learning and memory. PMID:22088391

  8. Reduced synaptic activity precedes synaptic stripping in vagal motoneurons after axotomy.

    PubMed

    Yamada, Jun; Hayashi, Yoshinori; Jinno, Shozo; Wu, Zhou; Inoue, Kazuhide; Kohsaka, Shinichi; Nakanishi, Hiroshi

    2008-10-01

    Activated microglia, which spread on the motor neurons following nerve injury, engage in the displacement of detached afferent synaptic boutons from the surface of regenerating motor neurons. This phenomenon is known as "synaptic stripping." The present study attempted to examine whether changes in the synaptic inputs after motor nerve injury correlated with the microglial attachment to the dorsal motor neurons of the vagus (DMV). DMV neurons in Wistar rats could survive after nerve injury, whereas most of injured DMV neurons in the C57BL/6 mice died. At 2 days after nerve injury, a significant decrease was observed in the frequencies of both spontaneous and miniature EPSCs and IPSCs recorded from DMV neurons in the slice preparation but not from the mechanically dissociated neurons in the Wistar rats. At this stage, no direct apposition of microglia on the injured neurons was observed. High-K(+) stimulation restored their frequencies to control levels. Furthermore, PPADS and DPCPX, antagonists of P2 and adenosine receptors, respectively, also stimulated the recovery of their frequencies. In contrast, no significant change was detected in the spontaneous EPSCs frequency recorded from the severely injured DMV neurons in the slice preparation of the C57BL/6 mice. These observations strongly suggest that presynaptic inhibition through glia-derived ATP and adenosine, thus precedes synaptic stripping in regenerating DMV neurons following nerve injury.

  9. Synaptic Plasticity as a Cortical Coding Scheme

    PubMed Central

    Froemke, Robert C.; Schreiner, Christoph E.

    2015-01-01

    Processing of auditory information requires constant adjustment due to alterations of the environment and changing conditions in the nervous system with age, health, and experience. Consequently, patterns of activity in cortical networks have complex dynamics over a wide range of timescales, from milliseconds to days and longer. In the primary auditory cortex (AI), multiple forms of adaptation and plasticity shape synaptic input and action potential output. However, the variance of neuronal responses has made it difficult to characterize AI receptive fields and to determine the function of AI in processing auditory information such as vocalizations. Here we describe recent studies on the temporal modulation of cortical responses and consider the relation of synaptic plasticity to neural coding. PMID:26497430

  10. Theoretical models of synaptic short term plasticity

    PubMed Central

    Hennig, Matthias H.

    2013-01-01

    Short term plasticity is a highly abundant form of rapid, activity-dependent modulation of synaptic efficacy. A shared set of mechanisms can cause both depression and enhancement of the postsynaptic response at different synapses, with important consequences for information processing. Mathematical models have been extensively used to study the mechanisms and roles of short term plasticity. This review provides an overview of existing models and their biological basis, and of their main properties. Special attention will be given to slow processes such as calcium channel inactivation and the effect of activation of presynaptic autoreceptors. PMID:23626536

  11. CDK5 downregulation enhances synaptic plasticity.

    PubMed

    Posada-Duque, Rafael Andrés; Ramirez, Omar; Härtel, Steffen; Inestrosa, Nibaldo C; Bodaleo, Felipe; González-Billault, Christian; Kirkwood, Alfredo; Cardona-Gómez, Gloria Patricia

    2017-01-01

    CDK5 is a serine/threonine kinase that is involved in the normal function of the adult brain and plays a role in neurotransmission and synaptic plasticity. However, its over-regulation has been associated with Tau hyperphosphorylation and cognitive deficits. Our previous studies have demonstrated that CDK5 targeting using shRNA-miR provides neuroprotection and prevents cognitive deficits. Dendritic spine morphogenesis and forms of long-term synaptic plasticity-such as long-term potentiation (LTP)-have been proposed as essential processes of neuroplasticity. However, whether CDK5 participates in these processes remains controversial and depends on the experimental model. Using wild-type mice that received injections of CDK5 shRNA-miR in CA1 showed an increased LTP and recovered the PPF in deficient LTP of APPswe/PS1Δ9 transgenic mice. On mature hippocampal neurons CDK5, shRNA-miR for 12 days induced increased dendritic protrusion morphogenesis, which was dependent on Rac activity. In addition, silencing of CDK5 increased BDNF expression, temporarily increased phosphorylation of CaMKII, ERK, and CREB; and facilitated calcium signaling in neurites. Together, our data suggest that CDK5 downregulation induces synaptic plasticity in mature neurons involving Ca(2+) signaling and BDNF/CREB activation.

  12. The developmental stages of synaptic plasticity

    PubMed Central

    Lohmann, Christian; Kessels, Helmut W

    2014-01-01

    Abstract The brain is programmed to drive behaviour by precisely wiring the appropriate neuronal circuits. Wiring and rewiring of neuronal circuits largely depends on the orchestrated changes in the strengths of synaptic contacts. Here, we review how the rules of synaptic plasticity change during development of the brain, from birth to independence. We focus on the changes that occur at the postsynaptic side of excitatory glutamatergic synapses in the rodent hippocampus and neocortex. First we summarize the current data on the structure of synapses and the developmental expression patterns of the key molecular players of synaptic plasticity, N-methyl-d-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, as well as pivotal kinases (Ca2+/calmodulin-dependent protein kinase II, protein kinase A, protein kinase C) and phosphatases (PP1, PP2A, PP2B). In the second part we relate these findings to important characteristics of the emerging network. We argue that the concerted and gradual shifts in the usage of plasticity molecules comply with the changing need for (re)wiring neuronal circuits. PMID:24144877

  13. Synaptic Plasticity, Dementia and Alzheimer Disease.

    PubMed

    Skaper, Stephen D; Facci, Laura; Zusso, Morena; Giusti, Pietro

    2017-01-13

    Neuroplasticity is not only shaped by learning and memory but is also a mediator of responses to neuron attrition and injury (compensatory plasticity). As an ongoing process it reacts to neuronal cell activity and injury, death, and genesis, which encompasses the modulation of structural and functional processes of axons, dendrites, and synapses. The range of structural elements that comprise plasticity includes long-term potentiation (a cellular correlate of learning and memory), synaptic efficacy and remodelling, synaptogenesis, axonal sprouting and dendritic remodelling, and neurogenesis and recruitment. Degenerative diseases of the human brain continue to pose one of biomedicine's most intractable problems. Research on human neurodegeneration is now moving from descriptive to mechanistic analyses. At the same time, it is increasing apparent that morphological lesions traditionally used by neuropathologists to confirm post-mortem clinical diagnosis might furnish us with an experimentally tractable handle to understand causative pathways. Consider the aging-dependent neurodegenerative disorder Alzheimer's disease (AD) which is characterised at the neuropathological level by deposits of insoluble amyloid b-peptide (Ab) in extracellular plaques and aggregated tau protein, which is found largely in the intracellular neurofibrillary tangles. We now appreciate that mild cognitive impairment in early AD may be due to synaptic dysfunction caused by accumulation of non-fibrillar, oligomeric Ab, occurring well in advance of evident widespread synaptic loss and neurodegeneration. Soluble Ab oligomers can adversely affect synaptic structure and plasticity at extremely low concentrations, although the molecular substrates by which synaptic memory mechanisms are disrupted remain to be fully elucidated. The dendritic spine constitutes a primary locus of excitatory synaptic transmission in the mammalian central nervous system. These structures protruding from dendritic shafts

  14. Selective Requirement for Maintenance of Synaptic Contacts onto Motoneurons by Target-Derived trkB Receptors.

    PubMed

    Zhu, Xiya; Ward, Patricia J; English, Arthur W

    2016-01-01

    Synaptic contacts onto motoneurons were studied in mice in which the gene for the trkB neurotrophin receptor was knocked out selectively in a subset of spinal motoneurons. The extent of contacts by structures immunoreactive for either of two different vesicular glutamate transporters (VGLUT1 and VGLUT2), the vesicular GABA transporter, or glutamic acid decarboxylase 67 (GAD67) with the somata of motoneurons, was studied in wild type and trkB knockout cells in tamoxifen treated male and female SLICK-trkB(-/-) mice. Selective knockout of the trkB gene resulted in a marked reduction in contacts made by VGLUT2- and GAD67-immunoreactive structures in both sexes and a significant reduction in contacts containing only glycine in male mice. No reduction was found for glycinergic contacts in female mice or for VGLUT1 immunoreactive contacts in either sex. Signaling through postsynaptic trkB receptors is considered to be an essential part of a cellular mechanism for maintaining the contacts of some, but not all, synaptic contacts onto motoneurons.

  15. Selective Requirement for Maintenance of Synaptic Contacts onto Motoneurons by Target-Derived trkB Receptors

    PubMed Central

    2016-01-01

    Synaptic contacts onto motoneurons were studied in mice in which the gene for the trkB neurotrophin receptor was knocked out selectively in a subset of spinal motoneurons. The extent of contacts by structures immunoreactive for either of two different vesicular glutamate transporters (VGLUT1 and VGLUT2), the vesicular GABA transporter, or glutamic acid decarboxylase 67 (GAD67) with the somata of motoneurons, was studied in wild type and trkB knockout cells in tamoxifen treated male and female SLICK-trkB−/− mice. Selective knockout of the trkB gene resulted in a marked reduction in contacts made by VGLUT2- and GAD67-immunoreactive structures in both sexes and a significant reduction in contacts containing only glycine in male mice. No reduction was found for glycinergic contacts in female mice or for VGLUT1 immunoreactive contacts in either sex. Signaling through postsynaptic trkB receptors is considered to be an essential part of a cellular mechanism for maintaining the contacts of some, but not all, synaptic contacts onto motoneurons. PMID:27433358

  16. The synaptic current evoked in cat spinal motoneurones by impulses in single group 1a axons.

    PubMed Central

    Finkel, A S; Redman, S J

    1983-01-01

    Excitatory post-synaptic potentials (e.p.s.p.s) were evoked in motoneurones of anaesthetized cats by impulses in single group 1 a axons. E.p.s.p.s with a time course which indicated a somatic site of origin were voltage-clamped using a single micro-electrode clamp. Excitatory post-synaptic currents (e.p.s.c.s) were found to peak in less than 0.2 ms, and to decay with an exponential time course. The time constant of decay was usually in the range 0.3-0.4 ms (at 37 degrees C). At the resting membrane potential, an e.p.s.p. with a peak of 100 microV was generated by an average peak e.p.s.c. of 330 pA. This corresponded to an average peak conductance increase of 5 nS. The e.p.s.c. decreased with membrane depolarization, and reversed to become an outward current at a null potential of +4.6 +/- 2 mV (+/- S.E. of mean; n = 7). Membrane hyperpolarization caused the peak e.p.s.c. to increase and the time constant of decay of the e.p.s.c. to decrease. The total charge in the synaptic current did not increase with hyperpolarization. This observation can explain earlier observations which showed that the peak amplitude of the e.p.s.p. did not increase with hyperpolarization. The number of ion channels opened by transmitter release at a single somatic bouton was estimated to be in the range 40-240. PMID:6313911

  17. Permanent central synaptic disconnection of proprioceptors after nerve injury and regeneration. I. Loss of VGLUT1/IA synapses on motoneurons.

    PubMed

    Alvarez, Francisco J; Titus-Mitchell, Haley E; Bullinger, Katie L; Kraszpulski, Michal; Nardelli, Paul; Cope, Timothy C

    2011-11-01

    Motor and sensory proprioceptive axons reinnervate muscles after peripheral nerve transections followed by microsurgical reattachment; nevertheless, motor coordination remains abnormal and stretch reflexes absent. We analyzed the possibility that permanent losses of central IA afferent synapses, as a consequence of peripheral nerve injury, are responsible for this deficit. VGLUT1 was used as a marker of proprioceptive synapses on rat motoneurons. After nerve injuries synapses are stripped from motoneurons, but while other excitatory and inhibitory inputs eventually recover, VGLUT1 synapses are permanently lost on the cell body (75-95% synaptic losses) and on the proximal 100 μm of dendrite (50% loss). Lost VGLUT1 synapses did not recover, even many months after muscle reinnervation. Interestingly, VGLUT1 density in more distal dendrites did not change. To investigate whether losses are due to VGLUT1 downregulation in injured IA afferents or to complete synaptic disassembly and regression of IA ventral projections, we studied the central trajectories and synaptic varicosities of axon collaterals from control and regenerated afferents with IA-like responses to stretch that were intracellularly filled with neurobiotin. VGLUT1 was present in all synaptic varicosities, identified with the synaptic marker SV2, of control and regenerated afferents. However, regenerated afferents lacked axon collaterals and synapses in lamina IX. In conjunction with the companion electrophysiological study [Bullinger KL, Nardelli P, Pinter MJ, Alvarez FJ, Cope TC. J Neurophysiol (August 10, 2011). doi:10.1152/jn.01097.2010], we conclude that peripheral nerve injuries cause a permanent retraction of IA afferent synaptic varicosities from lamina IX and disconnection with motoneurons that is not recovered after peripheral regeneration and reinnervation of muscle by sensory and motor axons.

  18. Myelination: an overlooked mechanism of synaptic plasticity?

    PubMed

    Fields, R Douglas

    2005-12-01

    Myelination of the brain continues through childhood into adolescence and early adulthood--the question is, Why? Two new articles provide intriguing evidence that myelination may be an underappreciated mechanism of activity-dependent nervous system plasticity: one study reported increased myelination associated with extensive piano playing, another indicated that rats have increased myelination of the corpus callosum when raised in environments providing increased social interaction and cognitive stimulation. These articles make it clear that activity-dependent effects on myelination cannot be considered strictly a developmental event. They raise the question of whether myelination is an overlooked mechanism of activity-dependent plasticity, extending in humans until at least age 30. It has been argued that regulating the speed of conduction across long fiber tracts would have a major influence on synaptic response, by coordinating the timing of afferent input to maximize temporal summation. The increase in synaptic amplitude could be as large as neurotransmitter-based mechanisms of plasticity, such as LTP. These new findings raise a larger question: How did the oligodendrocytes know they were practicing the piano or that their environment was socially complex?

  19. Synaptic and nonsynaptic plasticity approximating probabilistic inference

    PubMed Central

    Tully, Philip J.; Hennig, Matthias H.; Lansner, Anders

    2014-01-01

    Learning and memory operations in neural circuits are believed to involve molecular cascades of synaptic and nonsynaptic changes that lead to a diverse repertoire of dynamical phenomena at higher levels of processing. Hebbian and homeostatic plasticity, neuromodulation, and intrinsic excitability all conspire to form and maintain memories. But it is still unclear how these seemingly redundant mechanisms could jointly orchestrate learning in a more unified system. To this end, a Hebbian learning rule for spiking neurons inspired by Bayesian statistics is proposed. In this model, synaptic weights and intrinsic currents are adapted on-line upon arrival of single spikes, which initiate a cascade of temporally interacting memory traces that locally estimate probabilities associated with relative neuronal activation levels. Trace dynamics enable synaptic learning to readily demonstrate a spike-timing dependence, stably return to a set-point over long time scales, and remain competitive despite this stability. Beyond unsupervised learning, linking the traces with an external plasticity-modulating signal enables spike-based reinforcement learning. At the postsynaptic neuron, the traces are represented by an activity-dependent ion channel that is shown to regulate the input received by a postsynaptic cell and generate intrinsic graded persistent firing levels. We show how spike-based Hebbian-Bayesian learning can be performed in a simulated inference task using integrate-and-fire (IAF) neurons that are Poisson-firing and background-driven, similar to the preferred regime of cortical neurons. Our results support the view that neurons can represent information in the form of probability distributions, and that probabilistic inference could be a functional by-product of coupled synaptic and nonsynaptic mechanisms operating over several timescales. The model provides a biophysical realization of Bayesian computation by reconciling several observed neural phenomena whose

  20. [Effect of calcium deficiency and addition of calcium antagonists on motoneuron synaptic potentials of isolated Emys orbicularis turtle spinal cord].

    PubMed

    Batueva, I V

    1980-01-01

    In experiments carried out on the isolated spinal cord of the tortoise Emys orbicularis postsynaptic potentials produced in spinal motoneurons by stimulation of the descending tracts and dorsal roots were investigated by means of the intracellular recording technique. Postsynaptic potentials were completely and reversibly blocked in Ca2+-free solutions containing 5.0 mM Mg2+ or 2.0 mM Mn2+. The amplitude and frequency of spontaneous synaptic potentials were also reduced under these conditions. The effect of Ca2+-free medium indicates that the synaptic transmission in these synapses is mediated by chemical mechanism.

  1. Endocannabinoids in Synaptic Plasticity and Neuroprotection

    PubMed Central

    Xu, Jian-Yi; Chen, Chu

    2014-01-01

    Endocannabinoids (eCBs) are endogenous lipid mediators involved in a variety of physiological, pharmacological, and pathological processes. While activation of the eCB system primarily induces inhibitory effects on both GABAergic and glutamatergic synaptic transmission and plasticity through acting on presynaptically-expressed CB1 receptors in the brain, accumulated information suggests that eCB signaling is also capable of facilitating or potentiating excitatory synaptic transmission in the hippocampus. Recent studies show that a long-lasting potentiation of excitatory synaptic transmission at Schaffer collateral (SC)-CA1 synapses is induced by spatiotemporally primed inputs, accompanying with a long-term depression of inhibitory synaptic transmission (I-LTD) in hippocampal CA1 pyramidal neurons. This input-timing-dependent long-lasting synaptic potentiation at SC-CA1 synapses is mediated by 2-arachidonoylglycerol (2-AG) signaling triggered by activation of postsynaptic NMDA receptors, group I metabotropic glutamate receptors (mGluRs), and a concurrent rise in intracellular Ca2+. Emerging evidence now also indicates that 2-AG is an important signaling mediator keeping brain homeostasis by exerting its anti-inflammatory and neuroprotective effects in response to harmful insults through CB1/2 receptor-dependent and/or independent mechanisms. Activation of the nuclear receptor protein peroxisome proliferator-activated receptor-γ (PPARγ) apparently is one of the important mechanisms in resolving neuroinflammation and protecting neurons produced by 2-AG signaling. Thus, the information summarized in this review suggests that the role of eCB signaling in maintaining integrity of brain function is greater than what we thought previously. PMID:24571856

  2. Active dendrites, potassium channels and synaptic plasticity.

    PubMed Central

    Johnston, Daniel; Christie, Brian R; Frick, Andreas; Gray, Richard; Hoffman, Dax A; Schexnayder, Lalania K; Watanabe, Shigeo; Yuan, Li-Lian

    2003-01-01

    The dendrites of CA1 pyramidal neurons in the hippocampus express numerous types of voltage-gated ion channel, but the distributions or densities of many of these channels are very non-uniform. Sodium channels in the dendrites are responsible for action potential (AP) propagation from the axon into the dendrites (back-propagation); calcium channels are responsible for local changes in dendritic calcium concentrations following back-propagating APs and synaptic potentials; and potassium channels help regulate overall dendritic excitability. Several lines of evidence are presented here to suggest that back-propagating APs, when coincident with excitatory synaptic input, can lead to the induction of either long-term depression (LTD) or long-term potentiation (LTP). The induction of LTD or LTP is correlated with the magnitude of the rise in intracellular calcium. When brief bursts of synaptic potentials are paired with postsynaptic APs in a theta-burst pairing paradigm, the induction of LTP is dependent on the invasion of the AP into the dendritic tree. The amplitude of the AP in the dendrites is dependent, in part, on the activity of a transient, A-type potassium channel that is expressed at high density in the dendrites and correlates with the induction of the LTP. Furthermore, during the expression phase of the LTP, there are local changes in dendritic excitability that may result from modulation of the functioning of this transient potassium channel. The results support the view that the active properties of dendrites play important roles in synaptic integration and synaptic plasticity of these neurons. PMID:12740112

  3. Genetic differences in hippocampal synaptic plasticity.

    PubMed

    Prakash, S; Ambrosio, E; Alguacil, L F; Del Olmo, N

    2009-06-30

    Synaptic plasticity is considered a physiological substrate for learning and memory [Lynch MA (2004) Long-term potentiation and memory. Physiol Rev 84:87-136] that contributes to maladaptive learning in drug addiction [Schoenbaum G, Roesch MR, Stalnaker TA (2006) Orbitofrontal cortex, decision-making and drug addiction. Trends Neurosci 29:116-124]. Many studies have revealed that drug addiction has a strong hereditary component [Kosten TA, Ambrosio E (2002) HPA axis function and drug addictive behaviors: insights from studies with Lewis and Fischer 344 inbred rats. Psychoneuroendocrinology 27:35-69; Uhl GR (2004) Molecular genetic underpinnings of human substance abuse vulnerability: likely contributions to understanding addiction as a mnemonic process. Neuropharmacology 47 (Suppl 1):140-147], however the contribution of the genetic background to drug-induced changes in synaptic plasticity has been scarcely studied. The present study reports on an analysis of long-term potentiation (LTP) and depotentiation in Lewis (LEW) and Fischer-344 (F344) rats, two inbred rat strains that show different proneness to drugs of abuse and are considered an experimental model of genetic vulnerability to addiction [Kosten TA, Ambrosio E (2002) HPA axis function and drug addictive behaviors: insights from studies with Lewis and Fischer 344 inbred rats. Psychoneuroendocrinology 27:35-69]. The induction of saturated-LTP was similar in LEW and F344 rats treated with saline or cocaine. However, only slices from LEW saline-treated rats showed the reversal of LTP; thus, the depotentiation of saturated-LTP was not observed in cocaine-injected LEW rats and in F344 animals (treated either with cocaine or saline). These results suggest significant differences in hippocampal synaptic plasticity between Lewis and Fischer 344 rats.

  4. Epigenetic Basis of Neuronal and Synaptic Plasticity.

    PubMed

    Karpova, Nina N; Sales, Amanda J; Joca, Samia R

    2017-01-01

    Neuronal network and plasticity change as a function of experience. Altered neural connectivity leads to distinct transcriptional programs of neuronal plasticity-related genes. The environmental challenges throughout life may promote long-lasting reprogramming of gene expression and the development of brain disorders. The modifications in neuronal epigenome mediate gene-environmental interactions and are required for activity-dependent regulation of neuronal differentiation, maturation and plasticity. Here, we highlight the latest advances in understanding the role of the main players of epigenetic machinery (DNA methylation and demethylation, histone modifications, chromatin-remodeling enzymes, transposons, and non-coding RNAs) in activity-dependent and long- term neural and synaptic plasticity. The review focuses on both the transcriptional and post-transcriptional regulation of gene expression levels, including the processes of promoter activation, alternative splicing, regulation of stability of gene transcripts by natural antisense RNAs, and alternative polyadenylation. Further, we discuss the epigenetic aspects of impaired neuronal plasticity and the pathogenesis of neurodevelopmental (Rett syndrome, Fragile X Syndrome, genomic imprinting disorders, schizophrenia, and others), stressrelated (mood disorders) and neurodegenerative Alzheimer's, Parkinson's and Huntington's disorders. The review also highlights the pharmacological compounds that modulate epigenetic programming of gene expression, the potential treatment strategies of discussed brain disorders, and the questions that should be addressed during the development of effective and safe approaches for the treatment of brain disorders.

  5. Computational Neuroscience: Modeling the Systems Biology of Synaptic Plasticity

    PubMed Central

    Kotaleski, Jeanette Hellgren; Blackwell, Kim T.

    2016-01-01

    Preface Synaptic plasticity is a mechanism proposed to underlie learning and memory. The complexity of the interactions between ion channels, enzymes, and genes involved in synaptic plasticity impedes a deep understanding of this phenomenon. Computer modeling is an approach to investigate the information processing that is performed by signaling pathways underlying synaptic plasticity. In the past few years, new software developments that blend computational neuroscience techniques with systems biology techniques have allowed large-scale, quantitative modeling of synaptic plasticity in neurons. We highlight significant advancements produced by these modeling efforts and introduce promising approaches that utilize advancements in live cell imaging. PMID:20300102

  6. Involvement of brain-derived neurotrophic factor and sonic hedgehog in the spinal cord plasticity after neurotoxic partial removal of lumbar motoneurons.

    PubMed

    Gulino, Rosario; Gulisano, Massimo

    2012-07-01

    Adult mammals could spontaneously achieve a partial sensory-motor recovery after spinal cord injury, by mechanisms including synaptic plasticity. We previously showed that this recovery is associated to the expression of synapsin-I, and that sonic hedgehog and Notch-1 could be also involved in plasticity. The role of brain-derived neurotrophic factor and glutamate receptors in regulating synaptic efficacy has been explored in the last decade but, although these mechanisms are now well-defined in the brain, the molecular mechanisms underlying the so called "spinal learning" are still less clear. Here, we measured the expression levels of choline acetyltransferase, synapsin-I, sonic hedgehog, Notch-1, glutamate receptor subunits (GluR1, GluR2, GluR4, NMDAR1) and brain-derived neurotrophic factor, in a motoneuron-depleted mouse spinal lesion model obtained by intramuscular injection of cholera toxin-B saporin. The lesion caused the down-regulation of the majority of analysed proteins. Moreover, we found that in lesioned but not in control spinal tissue, synapsin-I expression is associated to that of both brain-derived neurotrophic factor and sonic hedgehog, whereas GluR2 expression is linked to that of Shh. These results suggest that brain-derived neurotrophic factor and sonic hedgehog could collaborate in modulating synaptic plasticity after the removal of motoneurons, by a mechanism involving both pre- and post-synaptic processes. Interestingly, the involvement of sonic hedgehog showed here is novel, and offers new routes to address spinal cord plasticity and repair.

  7. Caffeine, adenosine receptors, and synaptic plasticity.

    PubMed

    Costenla, Ana Rita; Cunha, Rodrigo A; de Mendonça, Alexandre

    2010-01-01

    Few studies to date have looked at the effects of caffeine on synaptic plasticity, and those that did used very high concentrations of caffeine, whereas the brain concentrations attained by regular coffee consumption in humans should be in the low micromolar range, where caffeine exerts pharmacological actions mainly by antagonizing adenosine receptors. Accordingly, rats drinking caffeine (1 g/L) for 3 weeks, displayed a concentration of caffeine of circa 22 microM in the hippocampus. It is known that selective adenosine A1 receptor antagonists facilitate, whereas selective adenosine A2A receptor antagonists attenuate, long term potentiation (LTP) in the hippocampus. Although caffeine is a non-selective antagonist of adenosine receptors, it attenuates frequency-induced LTP in hippocampal slices in a manner similar to selective adenosine A2A receptor antagonists. These effects of low micromolar concentration of caffeine (30 microM) are maintained in aged animals, which is important when a possible beneficial effect for caffeine in age-related cognitive decline is proposed. Future studies will still be required to confirm and detail the involvement of A1 and A2A receptors in the effects of caffeine on hippocampal synaptic plasticity, using both pharmacological and genetic approaches.

  8. Population synaptic potentials evoked in lumbar motoneurons following stimulation of the nucleus reticularis gigantocellularis during carbachol-induced atonia.

    PubMed

    Yamuy, J; Jiménez, I; Morales, F; Rudomin, P; Chase, M

    1994-03-14

    The effect of electrical stimulation of the medullary nucleus reticularis gigantocellularis (NRGc) on lumbar spinal cord motoneurons was studied in the decerebrate cat using sucrose-gap recordings from ventral roots. The NRGc was stimulated ipsi- and contralaterally before and during atonia elicited by the microinjection of carbachol into the pontine reticular formation. Prior to carbachol administration, the NRGc-induced response recorded from the sucrose-gap consisted of two consecutive excitatory population synaptic potentials followed by a long-lasting, small amplitude inhibitory population synaptic potential. Following carbachol injection, the same NRGc stimulus evoked a distinct, large amplitude inhibitory population synaptic potential, whereas the excitatory population synaptic potentials decreased in amplitude. In addition, after carbachol administration, the amplitude of the monosynaptic excitatory population synaptic potential, which was evoked by stimulation of group Ia afferents in hindlimb nerves, was reduced by 18 to 43%. When evoked at the peak of the NRGc-induced inhibitory response, this potential was further decreased in amplitude. Systemic strychnine administration (0.07-0.1 mg/kg, i.v.) blocked the NRGc-induced inhibitory population synaptic potential and promoted an increase in the amplitude of the excitatory population synaptic potentials induced by stimulation of the NRGc and group Ia afferents. These data indicate that during the state of carbachol-induced atonia, the NRGc effects on ipsi- and contralateral spinal cord motoneurons are predominantly inhibitory and that glycine is likely to be involved in this inhibitory process. These results support the hypothesis that the nucleus reticularis gigantocellularis is part of the system responsible for state-dependent somatomotor inhibition that occurs during active sleep.

  9. Calcineurin mediates homeostatic synaptic plasticity by regulating retinoic acid synthesis

    PubMed Central

    Arendt, Kristin L.; Zhang, Zhenjie; Ganesan, Subhashree; Hintze, Maik; Shin, Maggie M.; Tang, Yitai; Cho, Ahryon; Graef, Isabella A.; Chen, Lu

    2015-01-01

    Homeostatic synaptic plasticity is a form of non-Hebbian plasticity that maintains stability of the network and fidelity for information processing in response to prolonged perturbation of network and synaptic activity. Prolonged blockade of synaptic activity decreases resting Ca2+ levels in neurons, thereby inducing retinoic acid (RA) synthesis and RA-dependent homeostatic synaptic plasticity; however, the signal transduction pathway that links reduced Ca2+-levels to RA synthesis remains unknown. Here we identify the Ca2+-dependent protein phosphatase calcineurin (CaN) as a key regulator for RA synthesis and homeostatic synaptic plasticity. Prolonged inhibition of CaN activity promotes RA synthesis in neurons, and leads to increased excitatory and decreased inhibitory synaptic transmission. These effects of CaN inhibitors on synaptic transmission are blocked by pharmacological inhibitors of RA synthesis or acute genetic deletion of the RA receptor RARα. Thus, CaN, acting upstream of RA, plays a critical role in gating RA signaling pathway in response to synaptic activity. Moreover, activity blockade-induced homeostatic synaptic plasticity is absent in CaN knockout neurons, demonstrating the essential role of CaN in RA-dependent homeostatic synaptic plasticity. Interestingly, in GluA1 S831A and S845A knockin mice, CaN inhibitor- and RA-induced regulation of synaptic transmission is intact, suggesting that phosphorylation of GluA1 C-terminal serine residues S831 and S845 is not required for CaN inhibitor- or RA-induced homeostatic synaptic plasticity. Thus, our study uncovers an unforeseen role of CaN in postsynaptic signaling, and defines CaN as the Ca2+-sensing signaling molecule that mediates RA-dependent homeostatic synaptic plasticity. PMID:26443861

  10. Fragile X mental retardation protein and synaptic plasticity.

    PubMed

    Sidorov, Michael S; Auerbach, Benjamin D; Bear, Mark F

    2013-04-08

    Loss of the translational repressor FMRP causes Fragile X syndrome. In healthy neurons, FMRP modulates the local translation of numerous synaptic proteins. Synthesis of these proteins is required for the maintenance and regulation of long-lasting changes in synaptic strength. In this role as a translational inhibitor, FMRP exerts profound effects on synaptic plasticity.

  11. Biochemical mechanisms for translational regulation in synaptic plasticity.

    PubMed

    Klann, Eric; Dever, Thomas E

    2004-12-01

    Changes in gene expression are required for long-lasting synaptic plasticity and long-term memory in both invertebrates and vertebrates. Regulation of local protein synthesis allows synapses to control synaptic strength independently of messenger RNA synthesis in the cell body. Recent reports indicate that several biochemical signalling cascades couple neurotransmitter and neurotrophin receptors to translational regulatory factors in protein synthesis-dependent forms of synaptic plasticity and memory. In this review, we highlight these translational regulatory mechanisms and the signalling pathways that govern the expression of synaptic plasticity in response to specific types of neuronal stimulation.

  12. Role of MicroRNA in Governing Synaptic Plasticity

    PubMed Central

    2016-01-01

    Although synaptic plasticity in neural circuits is orchestrated by an ocean of genes, molecules, and proteins, the underlying mechanisms remain poorly understood. Recently, it is well acknowledged that miRNA exerts widespread regulation over the translation and degradation of target gene in nervous system. Increasing evidence suggests that quite a few specific miRNAs play important roles in various respects of synaptic plasticity including synaptogenesis, synaptic morphology alteration, and synaptic function modification. More importantly, the miRNA-mediated regulation of synaptic plasticity is not only responsible for synapse development and function but also involved in the pathophysiology of plasticity-related diseases. A review is made here on the function of miRNAs in governing synaptic plasticity, emphasizing the emerging regulatory role of individual miRNAs in synaptic morphological and functional plasticity, as well as their implications in neurological disorders. Understanding of the way in which miRNAs contribute to synaptic plasticity provides rational clues in establishing the novel therapeutic strategy for plasticity-related diseases. PMID:27034846

  13. Synaptic Plasticity onto Dopamine Neurons Shapes Fear Learning.

    PubMed

    Pignatelli, Marco; Umanah, George Kwabena Essien; Ribeiro, Sissi Palma; Chen, Rong; Karuppagounder, Senthilkumar Senthil; Yau, Hau-Jie; Eacker, Stephen; Dawson, Valina Lynn; Dawson, Ted Murray; Bonci, Antonello

    2017-01-18

    Fear learning is a fundamental behavioral process that requires dopamine (DA) release. Experience-dependent synaptic plasticity occurs on DA neurons while an organism is engaged in aversive experiences. However, whether synaptic plasticity onto DA neurons is causally involved in aversion learning is unknown. Here, we show that a stress priming procedure enhances fear learning by engaging VTA synaptic plasticity. Moreover, we took advantage of the ability of the ATPase Thorase to regulate the internalization of AMPA receptors (AMPARs) in order to selectively manipulate glutamatergic synaptic plasticity on DA neurons. Genetic ablation of Thorase in DAT(+) neurons produced increased AMPAR surface expression and function that lead to impaired induction of both long-term depression (LTD) and long-term potentiation (LTP). Strikingly, animals lacking Thorase in DAT(+) neurons expressed greater associative learning in a fear conditioning paradigm. In conclusion, our data provide a novel, causal link between synaptic plasticity onto DA neurons and fear learning.

  14. Transient ECM protease activity promotes synaptic plasticity

    PubMed Central

    Magnowska, Marta; Gorkiewicz, Tomasz; Suska, Anna; Wawrzyniak, Marcin; Rutkowska-Wlodarczyk, Izabela; Kaczmarek, Leszek; Wlodarczyk, Jakub

    2016-01-01

    Activity-dependent proteolysis at a synapse has been recognized as a pivotal factor in controlling dynamic changes in dendritic spine shape and function; however, excessive proteolytic activity is detrimental to the cells. The exact mechanism of control of these seemingly contradictory outcomes of protease activity remains unknown. Here, we reveal that dendritic spine maturation is strictly controlled by the proteolytic activity, and its inhibition by the endogenous inhibitor (Tissue inhibitor of matrix metalloproteinases-1 – TIMP-1). Excessive proteolytic activity impairs long-term potentiation of the synaptic efficacy (LTP), and this impairment could be rescued by inhibition of protease activity. Moreover LTP is altered persistently when the ability of TIMP-1 to inhibit protease activity is abrogated, further demonstrating the role of such inhibition in the promotion of synaptic plasticity under well-defined conditions. We also show that dendritic spine maturation involves an intermediate formation of elongated spines, followed by their conversion into mushroom shape. The formation of mushroom-shaped spines is accompanied by increase in AMPA/NMDA ratio of glutamate receptors. Altogether, our results identify inhibition of protease activity as a critical regulatory mechanism for dendritic spines maturation. PMID:27282248

  15. Modulation of synaptic plasticity by stress hormone associates with plastic alteration of synaptic NMDA receptor in the adult hippocampus.

    PubMed

    Tse, Yiu Chung; Bagot, Rosemary C; Hutter, Juliana A; Wong, Alice S; Wong, Tak Pan

    2011-01-01

    Stress exerts a profound impact on learning and memory, in part, through the actions of adrenal corticosterone (CORT) on synaptic plasticity, a cellular model of learning and memory. Increasing findings suggest that CORT exerts its impact on synaptic plasticity by altering the functional properties of glutamate receptors, which include changes in the motility and function of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid subtype of glutamate receptor (AMPAR) that are responsible for the expression of synaptic plasticity. Here we provide evidence that CORT could also regulate synaptic plasticity by modulating the function of synaptic N-methyl-D-aspartate receptors (NMDARs), which mediate the induction of synaptic plasticity. We found that stress level CORT applied to adult rat hippocampal slices potentiated evoked NMDAR-mediated synaptic responses within 30 min. Surprisingly, following this fast-onset change, we observed a slow-onset (>1 hour after termination of CORT exposure) increase in synaptic expression of GluN2A-containing NMDARs. To investigate the consequences of the distinct fast- and slow-onset modulation of NMDARs for synaptic plasticity, we examined the formation of long-term potentiation (LTP) and long-term depression (LTD) within relevant time windows. Paralleling the increased NMDAR function, both LTP and LTD were facilitated during CORT treatment. However, 1-2 hours after CORT treatment when synaptic expression of GluN2A-containing NMDARs is increased, bidirectional plasticity was no longer facilitated. Our findings reveal the remarkable plasticity of NMDARs in the adult hippocampus in response to CORT. CORT-mediated slow-onset increase in GluN2A in hippocampal synapses could be a homeostatic mechanism to normalize synaptic plasticity following fast-onset stress-induced facilitation.

  16. The transformation of synaptic to system plasticity in motor output from the sacral cord of the adult mouse

    PubMed Central

    Elbasiouny, Sherif M.; Collins, William F.; Heckman, C. J.

    2015-01-01

    Synaptic plasticity is fundamental in shaping the output of neural networks. The transformation of synaptic plasticity at the cellular level into plasticity at the system level involves multiple factors, including behavior of local networks of interneurons. Here we investigate the synaptic to system transformation for plasticity in motor output in an in vitro preparation of the adult mouse spinal cord. System plasticity was assessed from compound action potentials (APs) in spinal ventral roots, which were generated simultaneously by the axons of many motoneurons (MNs). Synaptic plasticity was assessed from intracellular recordings of MNs. A computer model of the MN pool was used to identify the middle steps in the transformation from synaptic to system behavior. Two input systems that converge on the same MN pool were studied: one sensory and one descending. The two synaptic input systems generated very different motor outputs, with sensory stimulation consistently evoking short-term depression (STD) whereas descending stimulation had bimodal plasticity: STD at low frequencies but short-term facilitation (STF) at high frequencies. Intracellular and pharmacological studies revealed contributions from monosynaptic excitation and stimulus time-locked inhibition but also considerable asynchronous excitation sustained from local network activity. The computer simulations showed that STD in the monosynaptic excitatory input was the primary driver of the system STD in the sensory input whereas network excitation underlies the bimodal plasticity in the descending system. These results provide insight on the roles of plasticity in the monosynaptic and polysynaptic inputs converging on the same MN pool to overall motor plasticity. PMID:26203107

  17. Common mechanisms of synaptic plasticity in vertebrates and invertebrates

    PubMed Central

    Glanzman, David L.

    2016-01-01

    Until recently, the literature on learning-related synaptic plasticity in invertebrates has been dominated by models assuming plasticity is mediated by presynaptic changes, whereas the vertebrate literature has been dominated by models assuming it is mediated by postsynaptic changes. Here I will argue that this situation does not reflect a biological reality and that, in fact, invertebrate and vertebrate nervous systems share a common set of mechanisms of synaptic plasticity. PMID:20152143

  18. Cellular and molecular bases of memory: synaptic and neuronal plasticity.

    PubMed

    Wang, J H; Ko, G Y; Kelly, P T

    1997-07-01

    Discoveries made during the past decade have greatly improved our understanding of how the nervous system functions. This review article examines the relation between memory and the cellular mechanisms of neuronal and synaptic plasticity in the central nervous system. Evidence indicating that activity-dependent short- and long-term changes in strength of synaptic transmission are important for memory processes is examined. Focus is placed on one model of synaptic plasticity called long-term potentiation, and its similarities with memory processes are illustrated. Recent studies show that the regulation of synaptic strength is bidirectional (e.g., synaptic potentiation or depression). Mechanisms involving intracellular signaling pathways that regulate synaptic strength are described, and the specific roles of calcium, protein kinases, protein phosphatases, and retrograde messengers are emphasized. Evidence suggests that changes in synaptic ultrastructure, dendritic ultrastructure, and neuronal gene expression may also contribute to mechanisms of synaptic plasticity. Also discussed are recent findings about postsynaptic mechanisms that regulate short-term synaptic facilitation and neuronal burst-pattern activity, as well as evidence about the subcellular location (presynaptic or postsynaptic) of mechanisms involved in long-term synaptic plasticity.

  19. Sleep and synaptic plasticity in the developing and adult brain.

    PubMed

    Frank, Marcos G

    2015-01-01

    Sleep is hypothesized to play an integral role in brain plasticity. This has traditionally been investigated using behavioral assays. In the last 10-15 years, studies combining sleep measurements with in vitro and in vivo models of synaptic plasticity have provided exciting new insights into how sleep alters synaptic strength. In addition, new theories have been proposed that integrate older ideas about sleep function and recent discoveries in the field of synaptic plasticity. There remain, however, important challenges and unanswered questions. For example, sleep does not appear to have a single effect on synaptic strength. An unbiased review of the literature indicates that the effects of sleep vary widely depending on ontogenetic stage, the type of waking experience (or stimulation protocols) that precede sleep and the type of neuronal synapse under examination. In this review, I discuss these key findings in the context of current theories that posit different roles for sleep in synaptic plasticity.

  20. Differential synaptic effects on physiological flexor hindlimb motoneurons from cutaneous nerve inputs in spinal cat.

    PubMed

    Leahy, J C; Durkovic, R G

    1991-08-01

    1. We previously demonstrated in the spinal cat that superficial peroneal cutaneous nerve stimulation produced strong reflex contraction in tibialis anterior (TA) and semitendinosus (St) muscles but unexpectedly produced mixed effects in another physiological flexor muscle, extensor digitorum longus (EDL). The goal of the present study was to further characterize the organization of ipsilateral cutaneous reflexes by examining the postsynaptic potentials (PSPs) produced in St, TA, and EDL motoneurons by superficial peroneal and saphenous nerve stimulation in decerebrate, spinal cats. 2. In TA and St motoneurons, low-intensity cutaneous nerve stimulation that activated only large (A alpha) fibers [i.e., approximately 2-3 times threshold (T)], typically produced biphasic PSPs consisting of an initial excitatory phase and subsequent inhibitory phase (EPSP, IPSP). Increasing the stimulus intensity to activate both large (A alpha) and small (A delta) myelinated cutaneous fibers supramaximally (15-45 T) tended to enhance later excitatory components in TA and St motoneurons. 3. In EDL motoneurons, 2-3 T stimulation of the superficial peroneal nerve evoked initial inhibition (of variable magnitude) in 7/10 EDL motoneurons tested, with either excitation (n = 2) or mixed effects (n = 1) observed in the remaining EDL motoneurons. Saphenous nerve stimuli produced excitation either alone, or preceded by an inhibitory phase in EDL. Increasing the stimulus intensity enhanced later inhibitory influences from superficial peroneal and excitatory influences both from superficial peroneal and saphenous nerve inputs in EDL motoneurons. 4. Short-latency (less than 1.8 ms) EPSPs were observed in a few motoneurons in all reflex pathways examined, except for EPSPs in EDL motoneurons evoked by saphenous stimulation. IPSPs with central latencies less than 1.8 ms were also produced by both saphenous (TA, n = 1; EDL, n = 2) and superficial peroneal (EDL, n = 4) nerve stimulation. 5. The results

  1. 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

  2. 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.

  3. The mean time to express synaptic plasticity in integrate-and-express, stochastic models of synaptic plasticity induction.

    PubMed

    Elliott, Terry

    2011-01-01

    Stochastic models of synaptic plasticity propose that single synapses perform a directed random walk of fixed step sizes in synaptic strength, thereby embracing the view that the mechanisms of synaptic plasticity constitute a stochastic dynamical system. However, fluctuations in synaptic strength present a formidable challenge to such an approach. We have previously proposed that single synapses must interpose an integration and filtering mechanism between the induction of synaptic plasticity and the expression of synaptic plasticity in order to control fluctuations. We analyze a class of three such mechanisms in the presence of possibly non-Markovian plasticity induction processes, deriving expressions for the mean expression time in these models. One of these filtering mechanisms constitutes a discrete low-pass filter that could be implemented on a small collection of molecules at single synapses, such as CaMKII, and we analyze this discrete filter in some detail. After considering Markov induction processes, we examine our own stochastic model of spike-timing-dependent plasticity, for which the probability density functions of the induction of plasticity steps have previously been derived. We determine the dependence of the mean time to express a plasticity step on pre- and postsynaptic firing rates in this model, and we also consider, numerically, the long-term stability against fluctuations of patterns of neuronal connectivity that typically emerge during neuronal development.

  4. The Ubiquitin-Proteasome Pathway and Synaptic Plasticity

    ERIC Educational Resources Information Center

    Hegde, Ashok N.

    2010-01-01

    Proteolysis by the ubiquitin-proteasome pathway (UPP) has emerged as a new molecular mechanism that controls wide-ranging functions in the nervous system, including fine-tuning of synaptic connections during development and synaptic plasticity in the adult organism. In the UPP, attachment of a small protein, ubiquitin, tags the substrates for…

  5. The Ubiquitin-Proteasome Pathway and Synaptic Plasticity

    ERIC Educational Resources Information Center

    Hegde, Ashok N.

    2010-01-01

    Proteolysis by the ubiquitin-proteasome pathway (UPP) has emerged as a new molecular mechanism that controls wide-ranging functions in the nervous system, including fine-tuning of synaptic connections during development and synaptic plasticity in the adult organism. In the UPP, attachment of a small protein, ubiquitin, tags the substrates for…

  6. Synaptic plasticity by antidromic firing during hippocampal network oscillations.

    PubMed

    Bukalo, Olena; Campanac, Emilie; Hoffman, Dax A; Fields, R Douglas

    2013-03-26

    Learning and other cognitive tasks require integrating new experiences into context. In contrast to sensory-evoked synaptic plasticity, comparatively little is known of how synaptic plasticity may be regulated by intrinsic activity in the brain, much of which can involve nonclassical modes of neuronal firing and integration. Coherent high-frequency oscillations of electrical activity in CA1 hippocampal neurons [sharp-wave ripple complexes (SPW-Rs)] functionally couple neurons into transient ensembles. These oscillations occur during slow-wave sleep or at rest. Neurons that participate in SPW-Rs are distinguished from adjacent nonparticipating neurons by firing action potentials that are initiated ectopically in the distal region of axons and propagate antidromically to the cell body. This activity is facilitated by GABA(A)-mediated depolarization of axons and electrotonic coupling. The possible effects of antidromic firing on synaptic strength are unknown. We find that facilitation of spontaneous SPW-Rs in hippocampal slices by increasing gap-junction coupling or by GABA(A)-mediated axon depolarization resulted in a reduction of synaptic strength, and electrical stimulation of axons evoked a widespread, long-lasting synaptic depression. Unlike other forms of synaptic plasticity, this synaptic depression is not dependent upon synaptic input or glutamate receptor activation, but rather requires L-type calcium channel activation and functional gap junctions. Synaptic stimulation delivered after antidromic firing, which was otherwise too weak to induce synaptic potentiation, triggered a long-lasting increase in synaptic strength. Rescaling synaptic weights in subsets of neurons firing antidromically during SPW-Rs might contribute to memory consolidation by sharpening specificity of subsequent synaptic input and promoting incorporation of novel information.

  7. Natural patterns of activity and long-term synaptic plasticity

    PubMed Central

    Paulsen, Ole; Sejnowski, Terrence J

    2010-01-01

    Long-term potentiation (LTP) of synaptic transmission is traditionally elicited by massively synchronous, high-frequency inputs, which rarely occur naturally. Recent in vitro experiments have revealed that both LTP and long-term depression (LTD) can arise by appropriately pairing weak synaptic inputs with action potentials in the postsynaptic cell. This discovery has generated new insights into the conditions under which synaptic modification may occur in pyramidal neurons in vivo. First, it has been shown that the temporal order of the synaptic input and the postsynaptic spike within a narrow temporal window determines whether LTP or LTD is elicited, according to a temporally asymmetric Hebbian learning rule. Second, backpropagating action potentials are able to serve as a global signal for synaptic plasticity in a neuron compared with local associative interactions between synaptic inputs on dendrites. Third, a specific temporal pattern of activity — postsynaptic bursting — accompanies synaptic potentiation in adults. PMID:10753798

  8. Activity blockade and GABAA receptor blockade produce synaptic scaling through chloride accumulation in embryonic spinal motoneurons and interneurons.

    PubMed

    Lindsly, Casie; Gonzalez-Islas, Carlos; Wenner, Peter

    2014-01-01

    Synaptic scaling represents a process whereby the distribution of a cell's synaptic strengths are altered by a multiplicative scaling factor. Scaling is thought to be a compensatory response that homeostatically controls spiking activity levels in the cell or network. Previously, we observed GABAergic synaptic scaling in embryonic spinal motoneurons following in vivo blockade of either spiking activity or GABAA receptors (GABAARs). We had determined that activity blockade triggered upward GABAergic scaling through chloride accumulation, thus increasing the driving force for these currents. To determine whether chloride accumulation also underlies GABAergic scaling following GABAAR blockade we have developed a new technique. We expressed a genetically encoded chloride-indicator, Clomeleon, in the embryonic chick spinal cord, which provides a non-invasive fast measure of intracellular chloride. Using this technique we now show that chloride accumulation underlies GABAergic scaling following blockade of either spiking activity or the GABAAR. The finding that GABAAR blockade and activity blockade trigger scaling via a common mechanism supports our hypothesis that activity blockade reduces GABAAR activation, which triggers synaptic scaling. In addition, Clomeleon imaging demonstrated the time course and widespread nature of GABAergic scaling through chloride accumulation, as it was also observed in spinal interneurons. This suggests that homeostatic scaling via chloride accumulation is a common feature in many neuronal classes within the embryonic spinal cord and opens the possibility that this process may occur throughout the nervous system at early stages of development.

  9. The synaptic connexions to intercostal motoneurones as revealed by the average common excitation potential.

    PubMed

    Kirkwood, P A; Sears, T A

    1978-02-01

    1. The hypothesis is advanced that the joint occurrence of unitary e.p.s.p.s evoked in motoneurones by branches of common stem presynaptic fibres causes, on average, transient depolarization in one motoneurone at the time of discharge in another motoneurone of the same pool. 2. The hypothesis was tested in anaesthetized, paralysed cats by averaging the naturally occurring synpatic noise of thoracic inspiratory motoneurones with an averager triggered by spikes from other inspiratory motoneurones. These spikes were obtained as efferent discharges in nerve filaments supplying the proximal regions of the external intercostal muscles. 3. A transient depolarization centred around the time of the trigger spikes was consistently observed and was designated the average common excitation (a.c.e.) potential. 4. The peak depolarization lay between -1.0 and +4.6 msec (mean +0.7 msec) with respect to the trigger spikes and the rise times of its most prominent component ranged from 4 to 16 msec (mean 8.4 msec). 5. The amplitudes of the a.c.e. potentials ranged from 6 to 104 muV (mean 32 muV) when the trigger spikes were derived from a filament in the same segment as the relevant motoneurones, and from 3 to 42 muV (mean 19 muV) when the filament was two segments rostral to the motoneurone. 6. Cells innervating the proximal region of the intercostal space gave larger a.c.e. potentials than those innervating more distal regions and also showed larger central respiratory drive potentials. 7. A.c.e. potentials were observed for either alpha or gamma spikes as triggers. The potentials were usually smaller for the gamma than for the alpha spikes, the mean ration being about 0.6. The presence of the a.c.e. potentials from the gamma spikes was taken as evidence for alpha-gamma coactivation by common presynaptic axons. 8. A theory is developed which quantitatively accounts for the main features of both the a.c.e. potential and the short term synchrony observed by Sears & Stagg (1976). 9

  10. Experience-dependent homeostatic synaptic plasticity in neocortex

    PubMed Central

    Whitt, Jessica L.; Petrus, Emily; Lee, Hey-Kyoung

    2013-01-01

    The organism’s ability to adapt to the changing sensory environment is due in part to the ability of the nervous system to change with experience. Input and synapse specific Hebbian plasticity, such as long-term potentiation (LTP) and long-term depression (LTD), are critical for sculpting the nervous system to wire its circuit in tune with the environment and for storing memories. However, these synaptic plasticity mechanisms are innately unstable and require another mode of plasticity that maintains homeostasis to allow neurons to function within a desired dynamic range. Several modes of homeostatic adaptation are known, some of which work at the synaptic level. This review will focus on the known mechanisms of experience-induced homeostatic synaptic plasticity in the neocortex and their potential function in sensory cortex plasticity. PMID:23466332

  11. Astrocytes gate Hebbian synaptic plasticity in the striatum

    PubMed Central

    Valtcheva, Silvana; Venance, Laurent

    2016-01-01

    Astrocytes, via excitatory amino-acid transporter type-2 (EAAT2), are the major sink for released glutamate and contribute to set the strength and timing of synaptic inputs. The conditions required for the emergence of Hebbian plasticity from distributed neural activity remain elusive. Here, we investigate the role of EAAT2 in the expression of a major physiologically relevant form of Hebbian learning, spike timing-dependent plasticity (STDP). We find that a transient blockade of EAAT2 disrupts the temporal contingency required for Hebbian synaptic plasticity. Indeed, STDP is replaced by aberrant non-timing-dependent plasticity occurring for uncorrelated events. Conversely, EAAT2 overexpression impairs the detection of correlated activity and precludes STDP expression. Our findings demonstrate that EAAT2 sets the appropriate glutamate dynamics for the optimal temporal contingency between pre- and postsynaptic activity required for STDP emergence, and highlight the role of astrocytes as gatekeepers for Hebbian synaptic plasticity. PMID:27996006

  12. Experience-dependent structural synaptic plasticity in the mammalian brain.

    PubMed

    Holtmaat, Anthony; Svoboda, Karel

    2009-09-01

    Synaptic plasticity in adult neural circuits may involve the strengthening or weakening of existing synapses as well as structural plasticity, including synapse formation and elimination. Indeed, long-term in vivo imaging studies are beginning to reveal the structural dynamics of neocortical neurons in the normal and injured adult brain. Although the overall cell-specific morphology of axons and dendrites, as well as of a subpopulation of small synaptic structures, are remarkably stable, there is increasing evidence that experience-dependent plasticity of specific circuits in the somatosensory and visual cortex involves cell type-specific structural plasticity: some boutons and dendritic spines appear and disappear, accompanied by synapse formation and elimination, respectively. This Review focuses on recent evidence for such structural forms of synaptic plasticity in the mammalian cortex and outlines open questions.

  13. Molecular mechanisms underlying neuronal synaptic plasticity: systems biology meets computational neuroscience in the wilds of synaptic plasticity.

    PubMed

    Blackwell, Kim T; Jedrzejewska-Szmek, Joanna

    2013-01-01

    Interactions among signaling pathways that are activated by transmembrane receptors produce complex networks and emergent dynamical behaviors that are implicated in synaptic plasticity. Temporal dynamics and spatial aspects are critical determinants of cell responses such as synaptic plasticity, although the mapping between spatiotemporal activity pattern and direction of synaptic plasticity is not completely understood. Computational modeling of neuronal signaling pathways has significantly contributed to understanding signaling pathways underlying synaptic plasticity. Spatial models of signaling pathways in hippocampal neurons have revealed mechanisms underlying the spatial distribution of extracellular signal-related kinase (ERK) activation in hippocampal neurons. Other spatial models have demonstrated that the major role of anchoring proteins in striatal and hippocampal synaptic plasticity is to place molecules near their activators. Simulations of yet other models have revealed that the spatial distribution of synaptic plasticity may differ for potentiation versus depression. In general, the most significant advances have been made by interactive modeling and experiments; thus, an interdisciplinary approach should be applied to investigate critical issues in neuronal signaling pathways. These issues include identifying which transmembrane receptors are key for activating ERK in neurons, and the crucial targets of kinases that produce long-lasting synaptic plasticity. Although the number of computer programs for computationally efficient simulation of large reaction-diffusion networks is increasing, parameter estimation and sensitivity analysis in these spatial models remain more difficult than in single compartment models. Advances in live cell imaging coupled with further software development will continue to accelerate the development of spatial models of synaptic plasticity. Copyright © 2013 Wiley Periodicals, Inc.

  14. The Extent of Synaptic Stripping of Motoneurons after Axotomy Is Not Correlated to Activation of Surrounding Glia or Downregulation of Postsynaptic Adhesion Molecules

    PubMed Central

    Berg, Alexander; Zelano, Johan; Thams, Sebastian; Cullheim, Staffan

    2013-01-01

    Synapse elimination in the adult central nervous system can be modelled by axotomy of spinal motoneurons which triggers removal of synapses from the cell surface of lesioned motoneurons by processes that remain elusive. Proposed candidate mechanisms are removal of synapses by reactive microglia and astrocytes, based on the remarkable activation of these cell types in the vicinity of motoneurons following axon lesion, and/or decreased expression of synaptic adhesion molecules in lesioned motoneurons. In the present study, we investigated glia activation and adhesion molecule expression in motoneurons in two mouse strains with deviant patterns of synapse elimination following axotomy. Mice deficient in complement protein C3 display a markedly reduced loss of synapses from axotomized motoneurons, whereas mice with impaired function of major histocompatibility complex (MHC) class Ia display an augmented degree of stripping after axotomy. Activation of microglia and astrocytes was assessed by semiquantative immunohistochemistry for Iba 1 (microglia) and GFAP (astrocytes), while expression of synaptic adhesion molecules was determined by in situ hybridization. In spite of the fact that the two mouse strains display very different degrees of synapse elimination, no differences in terms of glial activation or in the downregulation of the studied adhesion molecules (SynCAM1, neuroligin-2,-3 and netrin G-2 ligand) could be detected. We conclude that neither glia activation nor downregulation of synaptic adhesion molecules are correlated to the different extent of the synaptic stripping in the two studied strains. Instead the magnitude of the stripping event is most likely a consequence of a precise molecular signaling, which at least in part is mediated by immune molecules. PMID:23527240

  15. Berberine chloride improved synaptic plasticity in STZ induced diabetic rats.

    PubMed

    Moghaddam, Hamid Kalalian; Baluchnejadmojarad, Tourandokht; Roghani, Mehrdad; Goshadrou, Fatemeh; Ronaghi, Abdolaziz

    2013-09-01

    Previous studies indicated that diabetes affects synaptic transmission in the hippocampus, leading to impairments of synaptic plasticity and defects in learning and memory. Although berberine treatment ameliorates memory impairment and improves synaptic plasticity in streptozotocin (STZ) induced diabetic rats, it is not clear if the effects are pre- or post-synaptic or both. The aim of this study was to evaluate the effects of berberine chloride on short-term plasticity in inhibitory interneurons in the dentate gyrus of STZ-induced diabetic rats. Experimental groups included: The control, control berberine treated (100 mg/kg), diabetic and diabetic berberine treated (50,100 mg/kg/day for 12 weeks) groups. The paired pulse paradigm was used to stimulate the perforant pathway and field excitatory post-synaptic potentials (fEPSP) were recorded in dentate gyrus (DG). In comparison with control, paired pulse facilitation in the diabetic group was significantly increased (P < 0.01) and this effect prevented by chronic berberine treatment (50,100 mg/kg). However, there were no differences between responses of the control berberine 100 mg/kg treated and diabetes berberine treated (50 and 100 mg/kg) groups as compared to the control group. The present results suggest that the pre-synaptic component of synaptic plasticity in the dentate gyrus is affected under diabetic conditions and that berberine prevents this effect.

  16. Cerebellar Synaptic Plasticity and the Credit Assignment Problem.

    PubMed

    Jörntell, Henrik

    2016-04-01

    The mechanism by which a learnt synaptic weight change can contribute to learning or adaptation of brain function is a type of credit assignment problem, which is a key issue for many parts of the brain. In the cerebellum, detailed knowledge not only of the local circuitry connectivity but also of the topography of different sources of afferent/external information makes this problem particularly tractable. In addition, multiple forms of synaptic plasticity and their general rules of induction have been identified. In this review, we will discuss the possible roles of synaptic and cellular plasticity at specific locations in contributing to behavioral changes. Focus will be on the parts of the cerebellum that are devoted to limb control, which constitute a large proportion of the cortex and where the knowledge of the external connectivity is particularly well known. From this perspective, a number of sites of synaptic plasticity appear to primarily have the function of balancing the overall level of activity in the cerebellar circuitry, whereas the locations at which synaptic plasticity leads to functional changes in terms of limb control are more limited. Specifically, the postsynaptic forms of long-term potentiation (LTP) and long-term depression (LTD) at the parallel fiber synapses made on interneurons and Purkinje cells, respectively, are the types of plasticity that mediate the widest associative capacity and the tightest link between the synaptic change and the external functions that are to be controlled.

  17. Synaptic plasticity model of therapeutic sleep deprivation in major depression.

    PubMed

    Wolf, Elias; Kuhn, Marion; Normann, Claus; Mainberger, Florian; Maier, Jonathan G; Maywald, Sarah; Bredl, Aliza; Klöppel, Stefan; Biber, Knut; van Calker, Dietrich; Riemann, Dieter; Sterr, Annette; Nissen, Christoph

    2016-12-01

    Therapeutic sleep deprivation (SD) is a rapid acting treatment for major depressive disorder (MDD). Within hours, SD leads to a dramatic decrease in depressive symptoms in 50-60% of patients with MDD. Scientifically, therapeutic SD presents a unique paradigm to study the neurobiology of MDD. Yet, up to now, the neurobiological basis of the antidepressant effect, which is most likely different from today's first-line treatments, is not sufficiently understood. This article puts the idea forward that sleep/wake-dependent shifts in synaptic plasticity, i.e., the neural basis of adaptive network function and behavior, represent a critical mechanism of therapeutic SD in MDD. Particularly, this article centers on two major hypotheses of MDD and sleep, the synaptic plasticity hypothesis of MDD and the synaptic homeostasis hypothesis of sleep-wake regulation, and on how they can be integrated into a novel synaptic plasticity model of therapeutic SD in MDD. As a major component, the model proposes that therapeutic SD, by homeostatically enhancing cortical synaptic strength, shifts the initially deficient inducibility of associative synaptic long-term potentiation (LTP) in patients with MDD in a more favorable window of associative plasticity. Research on the molecular effects of SD in animals and humans, including observations in the neurotrophic, adenosinergic, monoaminergic, and glutamatergic system, provides some support for the hypothesis of associative synaptic plasticity facilitation after therapeutic SD in MDD. The model proposes a novel framework for a mechanism of action of therapeutic SD that can be further tested in humans based on non-invasive indices and in animals based on direct studies of synaptic plasticity. Further determining the mechanisms of action of SD might contribute to the development of novel fast acting treatments for MDD, one of the major health problems worldwide. Copyright © 2015 Elsevier Ltd. All rights reserved.

  18. Modulation of Synaptic Plasticity by Glutamatergic Gliotransmission: A Modeling Study

    PubMed Central

    De Pittà, Maurizio; Brunel, Nicolas

    2016-01-01

    Glutamatergic gliotransmission, that is, the release of glutamate from perisynaptic astrocyte processes in an activity-dependent manner, has emerged as a potentially crucial signaling pathway for regulation of synaptic plasticity, yet its modes of expression and function in vivo remain unclear. Here, we focus on two experimentally well-identified gliotransmitter pathways, (i) modulations of synaptic release and (ii) postsynaptic slow inward currents mediated by glutamate released from astrocytes, and investigate their possible functional relevance on synaptic plasticity in a biophysical model of an astrocyte-regulated synapse. Our model predicts that both pathways could profoundly affect both short- and long-term plasticity. In particular, activity-dependent glutamate release from astrocytes could dramatically change spike-timing-dependent plasticity, turning potentiation into depression (and vice versa) for the same induction protocol. PMID:27195153

  19. AMPARs and synaptic plasticity: the last 25 years.

    PubMed

    Huganir, Richard L; Nicoll, Roger A

    2013-10-30

    The study of synaptic plasticity and specifically LTP and LTD is one of the most active areas of research in neuroscience. In the last 25 years we have come a long way in our understanding of the mechanisms underlying synaptic plasticity. In 1988, AMPA and NMDA receptors were not even molecularly identified and we only had a simple model of the minimal requirements for the induction of plasticity. It is now clear that the modulation of the AMPA receptor function and membrane trafficking is critical for many forms of synaptic plasticity and a large number of proteins have been identified that regulate this complex process. Here we review the progress over the last two and a half decades and discuss the future challenges in the field.

  20. Glutamatergic synaptic plasticity in the mesocorticolimbic system in addiction

    PubMed Central

    van Huijstee, Aile N.; Mansvelder, Huibert D.

    2015-01-01

    Addictive drugs remodel the brain’s reward circuitry, the mesocorticolimbic dopamine (DA) system, by inducing widespread adaptations of glutamatergic synapses. This drug-induced synaptic plasticity is thought to contribute to both the development and the persistence of addiction. This review highlights the synaptic modifications that are induced by in vivo exposure to addictive drugs and describes how these drug-induced synaptic changes may contribute to the different components of addictive behavior, such as compulsive drug use despite negative consequences and relapse. Initially, exposure to an addictive drug induces synaptic changes in the ventral tegmental area (VTA). This drug-induced synaptic potentiation in the VTA subsequently triggers synaptic changes in downstream areas of the mesocorticolimbic system, such as the nucleus accumbens (NAc) and the prefrontal cortex (PFC), with further drug exposure. These glutamatergic synaptic alterations are then thought to mediate many of the behavioral symptoms that characterize addiction. The later stages of glutamatergic synaptic plasticity in the NAc and in particular in the PFC play a role in maintaining addiction and drive relapse to drug-taking induced by drug-associated cues. Remodeling of PFC glutamatergic circuits can persist into adulthood, causing a lasting vulnerability to relapse. We will discuss how these neurobiological changes produced by drugs of abuse may provide novel targets for potential treatment strategies for addiction. PMID:25653591

  1. Cellular and molecular connections between sleep and synaptic plasticity.

    PubMed

    Benington, Joel H; Frank, Marcos G

    2003-02-01

    The hypothesis that sleep promotes learning and memory has long been a subject of active investigation. This hypothesis implies that sleep must facilitate synaptic plasticity in some way, and recent studies have provided evidence for such a function. Our knowledge of both the cellular neurophysiology of sleep states and of the cellular and molecular mechanisms underlying synaptic plasticity has expanded considerably in recent years. In this article, we review findings in these areas and discuss possible mechanisms whereby the neurophysiological processes characteristic of sleep states may serve to facilitate synaptic plasticity. We address this issue first on the cellular level, considering how activation of T-type Ca(2+) channels in nonREM sleep may promote either long-term depression or long-term potentiation, as well as how cellular events of REM sleep may influence these processes. We then consider how synchronization of neuronal activity in thalamocortical and hippocampal-neocortical networks in nonREM sleep and REM sleep could promote differential strengthening of synapses according to the degree to which activity in one neuron is synchronized with activity in other neurons in the network. Rather than advocating one specific cellular hypothesis, we have intentionally taken a broad approach, describing a range of possible mechanisms whereby sleep may facilitate synaptic plasticity on the cellular and/or network levels. We have also provided a general review of evidence for and against the hypothesis that sleep does indeed facilitate learning, memory, and synaptic plasticity.

  2. Hebbian Wiring Plasticity Generates Efficient Network Structures for Robust Inference with Synaptic Weight Plasticity

    PubMed Central

    Hiratani, Naoki; Fukai, Tomoki

    2016-01-01

    In the adult mammalian cortex, a small fraction of spines are created and eliminated every day, and the resultant synaptic connection structure is highly nonrandom, even in local circuits. However, it remains unknown whether a particular synaptic connection structure is functionally advantageous in local circuits, and why creation and elimination of synaptic connections is necessary in addition to rich synaptic weight plasticity. To answer these questions, we studied an inference task model through theoretical and numerical analyses. We demonstrate that a robustly beneficial network structure naturally emerges by combining Hebbian-type synaptic weight plasticity and wiring plasticity. Especially in a sparsely connected network, wiring plasticity achieves reliable computation by enabling efficient information transmission. Furthermore, the proposed rule reproduces experimental observed correlation between spine dynamics and task performance. PMID:27303271

  3. ECM receptors in neuronal structure, synaptic plasticity, and behavior

    PubMed Central

    Kerrisk, Meghan E.; Cingolani, Lorenzo A.; Koleske, Anthony J.

    2015-01-01

    During central nervous system development, extracellular matrix (ECM) receptors and their ligands play key roles as guidance molecules, informing neurons where and when to send axonal and dendritic projections, establish connections, and form synapses between pre- and postsynaptic cells. Once stable synapses are formed, many ECM receptors transition in function to control the maintenance of stable connections between neurons and regulate synaptic plasticity. These receptors bind to and are activated by ECM ligands. In turn, ECM receptor activation modulates downstream signaling cascades that control cytoskeletal dynamics and synaptic activity to regulate neuronal structure and function and thereby impact animal behavior. The activities of cell adhesion receptors that mediate interactions between pre- and post-synaptic partners are also strongly influenced by ECM composition. This chapter highlights a number of ECM receptors, their roles in the control of synapse structure and function, and the impact of these receptors on synaptic plasticity and animal behavior. PMID:25410355

  4. Synaptic adhesion molecule IgSF11 regulates synaptic transmission and plasticity

    PubMed Central

    Shin, Hyewon; van Riesen, Christoph; Whitcomb, Daniel; Warburton, Julia M.; Jo, Jihoon; Kim, Doyoun; Kim, Sun Gyun; Um, Seung Min; Kwon, Seok-kyu; Kim, Myoung-Hwan; Roh, Junyeop Daniel; Woo, Jooyeon; Jun, Heejung; Lee, Dongmin; Mah, Won; Kim, Hyun; Kaang, Bong-Kiun; Cho, Kwangwook; Rhee, Jeong-Seop; Choquet, Daniel; Kim, Eunjoon

    2016-01-01

    Summary Synaptic adhesion molecules regulate synapse development and plasticity through mechanisms including trans-synaptic adhesion and recruitment of diverse synaptic proteins. We report here that the immunoglobulin superfamily member 11 (IgSF11), a homophilic adhesion molecule preferentially expressed in the brain, is a novel and dual-binding partner of the postsynaptic scaffolding protein PSD-95 and AMPAR glutamate receptors (AMPARs). IgSF11 requires PSD-95 binding for its excitatory synaptic localization. In addition, IgSF11 stabilizes synaptic AMPARs, as shown by IgSF11 knockdown-induced suppression of AMPAR-mediated synaptic transmission and increased surface mobility of AMPARs, measured by high-throughput, single-molecule tracking. IgSF11 deletion in mice leads to suppression of AMPAR-mediated synaptic transmission in the dentate gyrus and long-term potentiation in the CA1 region of the hippocampus. IgSF11 does not regulate the functional characteristics of AMPARs, including desensitization, deactivation, or recovery. These results suggest that IgSF11 regulates excitatory synaptic transmission and plasticity through its tripartite interactions with PSD-95 and AMPARs. PMID:26595655

  5. The electrical geometry, electrical properties and synaptic connections onto rat V motoneurones in vitro.

    PubMed Central

    Curtis, J C; Appenteng, K

    1993-01-01

    1. We have developed a tissue slice preparation which allows the study of the actions of single presynaptic neurones onto single trigeminal motoneurones in the immature rat. Our aim in this first stage of the work has been to assess the validity of this preparation as a model for responses obtained in vivo from trigeminal motoneurones in adult rats. We have quantified the integrative properties of the motoneurones and also the variability in transmission at synapses of single presynaptic neurones onto the motoneurones. This data has then been compared to similar published data obtained from adult (rat) trigeminal motoneurones in vivo. 2. Quantitative reconstructions were made of the morphology of three motoneurones which had been labelled with biocytin by intracellular injection. The neurones gave off six to nine dendrites, of mean length 522 microns (S.D. = 160; n = 22), which branched on average 10.5 times to produce 11.45 end-terminations per dendrite (S.D. = 8.57; n = 22). The mean surface area of the dendrites was 0.92 x 10(4) microns2 (S.D. = 0.67; n = 22), and, for individual cells, the ratio of the combined dendritic surface area to the total neuronal surface area ranged from 98.3 to 99.2% (n = 3). At dendritic branch points the ratio of the summed diameters of the daughter dendrites to the 3/2 power against the parent dendrite to the 3/2 power was 1.09 (S.D. = 0.21; n = 217), allowing branch points to be collapsed into a single cylinder. The equivalent cylinder diameter of the combined dendritic tree remained approximately constant over the proximal 25-40% of the equivalent electrical length of the dendritic tree and then showed tapering. The tapering could be ascribed to termination of dendrites at different electrical distances from the soma. 3. Electrical properties were determined for a total of eighty-seven motoneurones, all with membrane potentials more negative than 60 mV (mean = 66.0 mV; S.D. = 5.2) and spikes which overshot zero (mean spike

  6. Cross-modal synaptic plasticity in adult primary sensory cortices.

    PubMed

    Lee, Hey-Kyoung; Whitt, Jessica L

    2015-12-01

    Sensory loss leads to widespread adaptation of brain circuits to allow an organism to navigate its environment with its remaining senses, which is broadly referred to as cross-modal plasticity. Such adaptation can be observed even in the primary sensory cortices, and falls into two distinct categories: recruitment of the deprived sensory cortex for processing the remaining senses, which we term 'cross-modal recruitment', and experience-dependent refinement of the spared sensory cortices referred to as 'compensatory plasticity.' Here we will review recent studies demonstrating that cortical adaptation to sensory loss involves LTP/LTD and homeostatic synaptic plasticity. Cross-modal synaptic plasticity is observed in adults, hence cross-modal sensory deprivation may be an effective way to promote plasticity in adult primary sensory cortices.

  7. 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.

  8. Circuit reactivation dynamically regulates synaptic plasticity in neocortex

    NASA Astrophysics Data System (ADS)

    Kruskal, Peter B.; Li, Lucy; Maclean, Jason N.

    2013-10-01

    Circuit reactivations involve a stereotyped sequence of neuronal firing and have been behaviourally linked to memory consolidation. Here we use multiphoton imaging and patch-clamp recording, and observe sparse and stereotyped circuit reactivations that correspond to UP states within active neurons. To evaluate the effect of the circuit on synaptic plasticity, we trigger a single spike-timing-dependent plasticity (STDP) pairing once per circuit reactivation. The pairings reliably fall within a particular epoch of the circuit sequence and result in long-term potentiation. During reactivation, the amplitude of plasticity significantly correlates with the preceding 20-25 ms of membrane depolarization rather than the depolarization at the time of pairing. This circuit-dependent plasticity provides a natural constraint on synaptic potentiation, regulating the inherent instability of STDP in an assembly phase-sequence model. Subthreshold voltage during endogenous circuit reactivations provides a critical informative context for plasticity and facilitates the stable consolidation of a spatiotemporal sequence.

  9. Diffusion dynamics of synaptic molecules during inhibitory postsynaptic plasticity

    PubMed Central

    Petrini, Enrica Maria; Barberis, Andrea

    2014-01-01

    The plasticity of inhibitory transmission is expected to play a key role in the modulation of neuronal excitability and network function. Over the last two decades, the investigation of the determinants of inhibitory synaptic plasticity has allowed distinguishing presynaptic and postsynaptic mechanisms. While there has been a remarkable progress in the characterization of presynaptically-expressed plasticity of inhibition, the postsynaptic mechanisms of inhibitory long-term synaptic plasticity only begin to be unraveled. At postsynaptic level, the expression of inhibitory synaptic plasticity involves the rearrangement of the postsynaptic molecular components of the GABAergic synapse, including GABAA receptors, scaffold proteins and structural molecules. This implies a dynamic modulation of receptor intracellular trafficking and receptor surface lateral diffusion, along with regulation of the availability and distribution of scaffold proteins. This Review will focus on the mechanisms of the multifaceted molecular reorganization of the inhibitory synapse during postsynaptic plasticity, with special emphasis on the key role of protein dynamics to ensure prompt and reliable activity-dependent adjustments of synaptic strength. PMID:25294987

  10. Synaptic plasticity mediating cocaine relapse requires matrix metalloproteinases.

    PubMed

    Smith, Alexander C W; Kupchik, Yonatan M; Scofield, Michael D; Gipson, Cassandra D; Wiggins, Armina; Thomas, Charles A; Kalivas, Peter W

    2014-12-01

    Relapse to cocaine use necessitates remodeling excitatory synapses in the nucleus accumbens and synaptic reorganization requires matrix metalloproteinase (MMP) degradation of the extracellular matrix proteins. We found enduring increases in MMP-2 activity in rats after withdrawal from self-administered cocaine and transient increases in MMP-9 during cue-induced cocaine relapse. Cue-induced heroin and nicotine relapse increased MMP activity, and increased MMP activity was required for both cocaine relapse and relapse-associated synaptic plasticity.

  11. Modulation of synaptic plasticity by stress and antidepressants.

    PubMed

    Popoli, Maurizio; Gennarelli, Massimo; Racagni, Giorgio

    2002-06-01

    Recent preclinical and clinical studies have shown that mechanisms underlying neuronal plasticity and survival are involved in both the outcome of stressful experiences and the action of antidepressants. Whereas most antidepressants predominantly affect the brain levels of monoamine neurotransmitters, it is increasingly appreciated that they also modulate neurotransmission at synapses using the neurotransmitter glutamate (the most abundant in the brain). In the hippocampus, a main area of the limbic system involved in cognitive functions as well as attention and affect, specific molecules enriched at glutamatergic synapses mediate major changes in synaptic plasticity induced by stress paradigms or antidepressant treatments. We analyze here the modifications induced by stress or antidepressants in the strength of synaptic transmission in hippocampus, and the molecular modifications induced by antidepressants in two main mediators of synaptic plasticity: the N-methyl-D-aspartate (NMDA) receptor complex for glutamate and the Ca2+/calmodulin-dependent protein kinase II (CaM kinase II). Both stress and antidepressants induce alterations in long-term potentiation of hippocampal glutamatergic synapses, which may be partly accounted for by the influence of environmental or drug-induced stimulation of monoaminergic pathways projecting to the hippocampus. In the course of antidepressant treatments significant changes have been described in both the NMDA receptor and CaM kinase II, which may account for the physiological changes observed. A central role in these synaptic changes is exerted by brain-derived neurotrophic factor (BDNF), which modulates both synaptic plasticity and its molecular mediators, as well as inducing morphological synaptic changes. The role of these molecular effectors in synaptic plasticity is discussed in relation to the action of antidepressants and the search for new molecular targets of drug action in the therapy of mood disorders.

  12. Synaptic plasticity of NMDA receptors: mechanisms and functional implications

    PubMed Central

    Hunt, David L.; Castillo, Pablo E.

    2012-01-01

    Beyond their well-established role as triggers for LTP and LTD of fast synaptic transmission mediated by AMPA receptors, an expanding body of evidence indicates that NMDA receptors (NMDARs) themselves are also dynamically regulated and subject to activity-dependent long-term plasticity. NMDARs can significantly contribute to information transfer at synapses particularly during periods of repetitive activity. It is also increasingly recognized that NMDARs participate in dendritic synaptic integration and are critical for generating persistent activity of neural assemblies. Here we review recent advances on the mechanisms and functional consequences of NMDAR plasticity. Given the unique biophysical properties of NMDARs, synaptic plasticity of NMDAR-mediated transmission emerges as a particularly powerful mechanism for the fine tuning of information encoding and storage throughout the brain. PMID:22325859

  13. Abnormal plasticity in dystonia: Disruption of synaptic homeostasis.

    PubMed

    Quartarone, Angelo; Pisani, Antonio

    2011-05-01

    Work over the past two decades lead to substantial changes in our understanding of dystonia, which was, until recently, considered an exclusively sporadic movement disorder. The discovery of several gene mutations responsible for many inherited forms of dystonia has prompted much effort in the generation of transgenic mouse models bearing mutations found in patients. The large majority of these rodent models do not exhibit overt phenotypic abnormalities, or neuronal loss in specific brain areas. Nevertheless, both subtle motor abnormalities and significant alterations of synaptic plasticity have been recorded in mice, suggestive of an altered basal ganglia circuitry. In addition, robust evidence from experimental and clinical work supports the assumption that dystonia may indeed be considered a disorder linked to the disruption of synaptic "scaling", with a prevailing facilitation of synaptic potentiation, together with the loss of synaptic inhibitory processes. Notably, neurophysiological studies from patients carrying gene mutations as well as from non-manifesting carriers have shown the presence of synaptic plasticity abnormalities, indicating the presence of specific endophenotypic traits in carriers of the gene mutation. In this survey, we review findings from a broad range of data, obtained both from animal models and human research, and propose that the abnormalities of synaptic plasticity described in mice and humans may be considered an endophenotype to dystonia, and a valid and powerful tool to investigate the pathogenic mechanisms underlying this movement disorder. This article is part of a Special Issue entitled "Advances in dystonia".

  14. Coordination of Protein Phosphorylation and Dephosphorylation in Synaptic Plasticity*

    PubMed Central

    Woolfrey, Kevin M.; Dell'Acqua, Mark L.

    2015-01-01

    A central theme in nervous system function is equilibrium: synaptic strengths wax and wane, neuronal firing rates adjust up and down, and neural circuits balance excitation with inhibition. This push/pull regulatory theme carries through to the molecular level at excitatory synapses, where protein function is controlled through phosphorylation and dephosphorylation by kinases and phosphatases. However, these opposing enzymatic activities are only part of the equation as scaffolding interactions and assembly of multi-protein complexes are further required for efficient, localized synaptic signaling. This review will focus on coordination of postsynaptic serine/threonine kinase and phosphatase signaling by scaffold proteins during synaptic plasticity. PMID:26453308

  15. Synaptic plasticity in the auditory system: a review.

    PubMed

    Friauf, Eckhard; Fischer, Alexander U; Fuhr, Martin F

    2015-07-01

    Synaptic transmission via chemical synapses is dynamic, i.e., the strength of postsynaptic responses may change considerably in response to repeated synaptic activation. Synaptic strength is increased during facilitation, augmentation and potentiation, whereas a decrease in synaptic strength is characteristic for depression and attenuation. This review attempts to discuss the literature on short-term and long-term synaptic plasticity in the auditory brainstem of mammals and birds. One hallmark of the auditory system, particularly the inner ear and lower brainstem stations, is information transfer through neurons that fire action potentials at very high frequency, thereby activating synapses >500 times per second. Some auditory synapses display morphological specializations of the presynaptic terminals, e.g., calyceal extensions, whereas other auditory synapses do not. The review focuses on short-term depression and short-term facilitation, i.e., plastic changes with durations in the millisecond range. Other types of short-term synaptic plasticity, e.g., posttetanic potentiation and depolarization-induced suppression of excitation, will be discussed much more briefly. The same holds true for subtypes of long-term plasticity, like prolonged depolarizations and spike-time-dependent plasticity. We also address forms of plasticity in the auditory brainstem that do not comprise synaptic plasticity in a strict sense, namely short-term suppression, paired tone facilitation, short-term adaptation, synaptic adaptation and neural adaptation. Finally, we perform a meta-analysis of 61 studies in which short-term depression (STD) in the auditory system is opposed to short-term depression at non-auditory synapses in order to compare high-frequency neurons with those that fire action potentials at a lower rate. This meta-analysis reveals considerably less STD in most auditory synapses than in non-auditory ones, enabling reliable, failure-free synaptic transmission even at

  16. A Calcium-Dependent Plasticity Rule for HCN Channels Maintains Activity Homeostasis and Stable Synaptic Learning

    PubMed Central

    Honnuraiah, Suraj; Narayanan, Rishikesh

    2013-01-01

    Theoretical and computational frameworks for synaptic plasticity and learning have a long and cherished history, with few parallels within the well-established literature for plasticity of voltage-gated ion channels. In this study, we derive rules for plasticity in the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, and assess the synergy between synaptic and HCN channel plasticity in establishing stability during synaptic learning. To do this, we employ a conductance-based model for the hippocampal pyramidal neuron, and incorporate synaptic plasticity through the well-established Bienenstock-Cooper-Munro (BCM)-like rule for synaptic plasticity, wherein the direction and strength of the plasticity is dependent on the concentration of calcium influx. Under this framework, we derive a rule for HCN channel plasticity to establish homeostasis in synaptically-driven firing rate, and incorporate such plasticity into our model. In demonstrating that this rule for HCN channel plasticity helps maintain firing rate homeostasis after bidirectional synaptic plasticity, we observe a linear relationship between synaptic plasticity and HCN channel plasticity for maintaining firing rate homeostasis. Motivated by this linear relationship, we derive a calcium-dependent rule for HCN-channel plasticity, and demonstrate that firing rate homeostasis is maintained in the face of synaptic plasticity when moderate and high levels of cytosolic calcium influx induced depression and potentiation of the HCN-channel conductance, respectively. Additionally, we show that such synergy between synaptic and HCN-channel plasticity enhances the stability of synaptic learning through metaplasticity in the BCM-like synaptic plasticity profile. Finally, we demonstrate that the synergistic interaction between synaptic and HCN-channel plasticity preserves robustness of information transfer across the neuron under a rate-coding schema. Our results establish specific physiological roles

  17. Molecular mechanisms of synaptic plasticity and memory.

    PubMed

    Elgersma, Y; Silva, A J

    1999-04-01

    To unravel the molecular and cellular bases of learning and memory is one of the most ambitious goals of modern science. The progress of recent years has not only brought us closer to understanding the molecular mechanisms underlying stable, long-lasting changes in synaptic strength, but it has also provided further evidence that these mechanisms are required for memory formation.

  18. Emergence of Functional Specificity in Balanced Networks with Synaptic Plasticity

    PubMed Central

    Sadeh, Sadra; Clopath, Claudia; Rotter, Stefan

    2015-01-01

    In rodent visual cortex, synaptic connections between orientation-selective neurons are unspecific at the time of eye opening, and become to some degree functionally specific only later during development. An explanation for this two-stage process was proposed in terms of Hebbian plasticity based on visual experience that would eventually enhance connections between neurons with similar response features. For this to work, however, two conditions must be satisfied: First, orientation selective neuronal responses must exist before specific recurrent synaptic connections can be established. Second, Hebbian learning must be compatible with the recurrent network dynamics contributing to orientation selectivity, and the resulting specific connectivity must remain stable for unspecific background activity. Previous studies have mainly focused on very simple models, where the receptive fields of neurons were essentially determined by feedforward mechanisms, and where the recurrent network was small, lacking the complex recurrent dynamics of large-scale networks of excitatory and inhibitory neurons. Here we studied the emergence of functionally specific connectivity in large-scale recurrent networks with synaptic plasticity. Our results show that balanced random networks, which already exhibit highly selective responses at eye opening, can develop feature-specific connectivity if appropriate rules of synaptic plasticity are invoked within and between excitatory and inhibitory populations. If these conditions are met, the initial orientation selectivity guides the process of Hebbian learning and, as a result, functionally specific and a surplus of bidirectional connections emerge. Our results thus demonstrate the cooperation of synaptic plasticity and recurrent dynamics in large-scale functional networks with realistic receptive fields, highlight the role of inhibition as a critical element in this process, and paves the road for further computational studies of sensory

  19. Energy Efficient Sparse Connectivity from Imbalanced Synaptic Plasticity Rules

    PubMed Central

    Sacramento, João; Wichert, Andreas; van Rossum, Mark C. W.

    2015-01-01

    It is believed that energy efficiency is an important constraint in brain evolution. As synaptic transmission dominates energy consumption, energy can be saved by ensuring that only a few synapses are active. It is therefore likely that the formation of sparse codes and sparse connectivity are fundamental objectives of synaptic plasticity. In this work we study how sparse connectivity can result from a synaptic learning rule of excitatory synapses. Information is maximised when potentiation and depression are balanced according to the mean presynaptic activity level and the resulting fraction of zero-weight synapses is around 50%. However, an imbalance towards depression increases the fraction of zero-weight synapses without significantly affecting performance. We show that imbalanced plasticity corresponds to imposing a regularising constraint on the L 1-norm of the synaptic weight vector, a procedure that is well-known to induce sparseness. Imbalanced plasticity is biophysically plausible and leads to more efficient synaptic configurations than a previously suggested approach that prunes synapses after learning. Our framework gives a novel interpretation to the high fraction of silent synapses found in brain regions like the cerebellum. PMID:26046817

  20. The ubiquitin-proteasome pathway and synaptic plasticity

    PubMed Central

    Hegde, Ashok N.

    2010-01-01

    Proteolysis by the ubiquitin-proteasome pathway (UPP) has emerged as a new molecular mechanism that controls wide-ranging functions in the nervous system, including fine-tuning of synaptic connections during development and synaptic plasticity in the adult organism. In the UPP, attachment of a small protein, ubiquitin, tags the substrates for degradation by a multisubunit complex called the proteasome. Linkage of ubiquitin to protein substrates is highly specific and occurs through a series of well-orchestrated enzymatic steps. The UPP regulates neurotransmitter receptors, protein kinases, synaptic proteins, transcription factors, and other molecules critical for synaptic plasticity. Accumulating evidence indicates that the operation of the UPP in neurons is not homogeneous and is subject to tightly managed local regulation in different neuronal subcompartments. Investigations on both invertebrate and vertebrate model systems have revealed local roles for enzymes that attach ubiquitin to substrate proteins, as well as for enzymes that remove ubiquitin from substrates. The proteasome also has been shown to possess disparate functions in different parts of the neuron. Here I give a broad overview of the role of the UPP in synaptic plasticity and highlight the local roles and regulation of the proteolytic pathway in neurons. PMID:20566674

  1. Cell-specific synaptic plasticity induced by network oscillations

    PubMed Central

    Zarnadze, Shota; Bäuerle, Peter; Santos-Torres, Julio; Böhm, Claudia; Schmitz, Dietmar; Geiger, Jörg RP

    2016-01-01

    Gamma rhythms are known to contribute to the process of memory encoding. However, little is known about the underlying mechanisms at the molecular, cellular and network levels. Using local field potential recording in awake behaving mice and concomitant field potential and whole-cell recordings in slice preparations we found that gamma rhythms lead to activity-dependent modification of hippocampal networks, including alterations in sharp wave-ripple complexes. Network plasticity, expressed as long-lasting increases in sharp wave-associated synaptic currents, exhibits enhanced excitatory synaptic strength in pyramidal cells that is induced postsynaptically and depends on metabotropic glutamate receptor-5 activation. In sharp contrast, alteration of inhibitory synaptic strength is independent of postsynaptic activation and less pronounced. Further, we found a cell type-specific, directionally biased synaptic plasticity of two major types of GABAergic cells, parvalbumin- and cholecystokinin-expressing interneurons. Thus, we propose that gamma frequency oscillations represent a network state that introduces long-lasting synaptic plasticity in a cell-specific manner. DOI: http://dx.doi.org/10.7554/eLife.14912.001 PMID:27218453

  2. Reactive Oxygen Species: Physiological and Physiopathological Effects on Synaptic Plasticity

    PubMed Central

    Beckhauser, Thiago Fernando; Francis-Oliveira, José; De Pasquale, Roberto

    2016-01-01

    In the mammalian central nervous system, reactive oxygen species (ROS) generation is counterbalanced by antioxidant defenses. When large amounts of ROS accumulate, antioxidant mechanisms become overwhelmed and oxidative cellular stress may occur. Therefore, ROS are typically characterized as toxic molecules, oxidizing membrane lipids, changing the conformation of proteins, damaging nucleic acids, and causing deficits in synaptic plasticity. High ROS concentrations are associated with a decline in cognitive functions, as observed in some neurodegenerative disorders and age-dependent decay of neuroplasticity. Nevertheless, controlled ROS production provides the optimal redox state for the activation of transductional pathways involved in synaptic changes. Since ROS may regulate neuronal activity and elicit negative effects at the same time, the distinction between beneficial and deleterious consequences is unclear. In this regard, this review assesses current research and describes the main sources of ROS in neurons, specifying their involvement in synaptic plasticity and distinguishing between physiological and pathological processes implicated. PMID:27625575

  3. Synaptic Plasticity in Mouse Models of Autism Spectrum Disorders

    PubMed Central

    Bey, Alexandra L.; Jiang, Yong-Hui

    2012-01-01

    Analysis of synaptic plasticity together with behavioral and molecular studies have become a popular approach to model autism spectrum disorders in order to gain insight into the pathosphysiological mechanisms and to find therapeutic targets. Abnormalities of specific types of synaptic plasticity have been revealed in numerous genetically modified mice that have molecular construct validity to human autism spectrum disorders. Constrained by the feasibility of technique, the common regions analyzed in most studies are hippocampus and visual cortex. The relevance of the synaptic defects in these regions to the behavioral abnormalities of autistic like behaviors is still a subject of debate. Because the exact regions or circuits responsible for the core features of autistic behaviors in humans are still poorly understood, investigation using region-specific conditional mutant mice may help to provide the insight into the neuroanatomical basis of autism in the future. PMID:23269898

  4. Synaptic plasticity in dendrites: complications and coping strategies.

    PubMed

    Mel, Bartlett W; Schiller, Jackie; Poirazi, Panayiota

    2017-04-01

    The elaborate morphology, nonlinear membrane mechanisms and spatiotemporally varying synaptic activation patterns of dendrites complicate the expression, compartmentalization and modulation of synaptic plasticity. To grapple with this complexity, we start with the observation that neurons in different brain areas face markedly different learning problems, and dendrites of different neuron types contribute to the cell's input-output function in markedly different ways. By committing to specific assumptions regarding a neuron's learning problem and its input-output function, specific inferences can be drawn regarding the synaptic plasticity mechanisms and outcomes that we 'ought' to expect for that neuron. Exploiting this assumption-driven approach can help both in interpreting existing experimental data and designing future experiments aimed at understanding the brain's myriad learning processes. Copyright © 2017 Elsevier Ltd. All rights reserved.

  5. ECM receptors in neuronal structure, synaptic plasticity, and behavior.

    PubMed

    Kerrisk, Meghan E; Cingolani, Lorenzo A; Koleske, Anthony J

    2014-01-01

    During central nervous system development, extracellular matrix (ECM) receptors and their ligands play key roles as guidance molecules, informing neurons where and when to send axonal and dendritic projections, establish connections, and form synapses between pre- and postsynaptic cells. Once stable synapses are formed, many ECM receptors transition in function to control the maintenance of stable connections between neurons and regulate synaptic plasticity. These receptors bind to and are activated by ECM ligands. In turn, ECM receptor activation modulates downstream signaling cascades that control cytoskeletal dynamics and synaptic activity to regulate neuronal structure and function and thereby impact animal behavior. The activities of cell adhesion receptors that mediate interactions between pre- and postsynaptic partners are also strongly influenced by ECM composition. This chapter highlights a number of ECM receptors, their roles in the control of synapse structure and function, and the impact of these receptors on synaptic plasticity and animal behavior.

  6. Transferrin Receptor Controls AMPA Receptor Trafficking Efficiency and Synaptic Plasticity

    PubMed Central

    Liu, Ke; Lei, Run; Li, Qiong; Wang, Xin-Xin; Wu, Qian; An, Peng; Zhang, Jianchao; Zhu, Minyan; Xu, Zhiheng; Hong, Yang; Wang, Fudi; Shen, Ying; Li, Hongchang; Li, Huashun

    2016-01-01

    Transferrin receptor (TFR) is an important iron transporter regulating iron homeostasis and has long been used as a marker for clathrin mediated endocytosis. However, little is known about its additional function other than iron transport in the development of central nervous system (CNS). Here we demonstrate that TFR functions as a regulator to control AMPA receptor trafficking efficiency and synaptic plasticity. The conditional knockout (KO) of TFR in neural progenitor cells causes mice to develop progressive epileptic seizure, and dramatically reduces basal synaptic transmission and long-term potentiation (LTP). We further demonstrate that TFR KO remarkably reduces the binding efficiency of GluR2 to AP2 and subsequently decreases AMPA receptor endocytosis and recycling. Thus, our study reveals that TFR functions as a novel regulator to control AMPA trafficking efficiency and synaptic plasticity. PMID:26880306

  7. Formation and maintenance of neuronal assemblies through synaptic plasticity.

    PubMed

    Litwin-Kumar, Ashok; Doiron, Brent

    2014-11-14

    The architecture of cortex is flexible, permitting neuronal networks to store recent sensory experiences as specific synaptic connectivity patterns. However, it is unclear how these patterns are maintained in the face of the high spike time variability associated with cortex. Here we demonstrate, using a large-scale cortical network model, that realistic synaptic plasticity rules coupled with homeostatic mechanisms lead to the formation of neuronal assemblies that reflect previously experienced stimuli. Further, reverberation of past evoked states in spontaneous spiking activity stabilizes, rather than erases, this learned architecture. Spontaneous and evoked spiking activity contains a signature of learned assembly structures, leading to testable predictions about the effect of recent sensory experience on spike train statistics. Our work outlines requirements for synaptic plasticity rules capable of modifying spontaneous dynamics and shows that this modification is beneficial for stability of learned network architectures.

  8. Isoform Specificity of Protein Kinase Cs in Synaptic Plasticity

    ERIC Educational Resources Information Center

    Sossin, Wayne S.

    2007-01-01

    Protein kinase Cs (PKCs) are implicated in many forms of synaptic plasticity. However, the specific isoform(s) of PKC that underlie(s) these events are often not known. We have used "Aplysia" as a model system in order to investigate the isoform specificity of PKC actions due to the presence of fewer isoforms and a large number of documented…

  9. 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…

  10. 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…

  11. Molecular bases of caloric restriction regulation of neuronal synaptic plasticity.

    PubMed

    Fontán-Lozano, Angela; López-Lluch, Guillermo; Delgado-García, José María; Navas, Placido; Carrión, Angel Manuel

    2008-10-01

    Aging is associated with the decline of cognitive properties. This situation is magnified when neurodegenerative processes associated with aging appear in human patients. Neuronal synaptic plasticity events underlie cognitive properties in the central nervous system. Caloric restriction (CR; either a decrease in food intake or an intermittent fasting diet) can extend life span and increase disease resistance. Recent studies have shown that CR can have profound effects on brain function and vulnerability to injury and disease. Moreover, CR can stimulate the production of new neurons from stem cells (neurogenesis) and can enhance synaptic plasticity, which modulate pain sensation, enhance cognitive function, and may increase the ability of the brain to resist aging. The beneficial effects of CR appear to be the result of a cellular stress response stimulating the production of proteins that enhance neuronal plasticity and resistance to oxidative and metabolic insults; they include neurotrophic factors, neurotransmitter receptors, protein chaperones, and mitochondrial biosynthesis regulators. In this review, we will present and discuss the effect of CR in synaptic processes underlying analgesia and cognitive improvement in healthy, sick, and aging animals. We will also discuss the possible role of mitochondrial biogenesis induced by CR in regulation of neuronal synaptic plasticity.

  12. Modeling Ketamine Effects on Synaptic Plasticity During the Mismatch Negativity

    PubMed Central

    Schmidt, André; Diaconescu, Andreea O.; Kometer, Michael; Friston, Karl J.; Stephan, Klaas E.; Vollenweider, Franz X.

    2013-01-01

    This paper presents a model-based investigation of mechanisms underlying the reduction of mismatch negativity (MMN) amplitudes under the NMDA-receptor antagonist ketamine. We applied dynamic causal modeling and Bayesian model selection to data from a recent ketamine study of the roving MMN paradigm, using a cross-over, double-blind, placebo-controlled design. Our modeling was guided by a predictive coding framework that unifies contemporary “adaptation” and “model adjustment” MMN theories. Comparing a series of dynamic causal models that allowed for different expressions of neuronal adaptation and synaptic plasticity, we obtained 3 major results: 1) We replicated previous results that both adaptation and short-term plasticity are necessary to explain MMN generation per se; 2) we found significant ketamine effects on synaptic plasticity, but not adaptation, and a selective ketamine effect on the forward connection from left primary auditory cortex to superior temporal gyrus; 3) this model-based estimate of ketamine effects on synaptic plasticity correlated significantly with ratings of ketamine-induced impairments in cognition and control. Our modeling approach thus suggests a concrete mechanism for ketamine effects on MMN that correlates with drug-induced psychopathology. More generally, this demonstrates the potential of modeling for inferring on synaptic physiology, and its pharmacological modulation, from electroencephalography data. PMID:22875863

  13. Isoform Specificity of Protein Kinase Cs in Synaptic Plasticity

    ERIC Educational Resources Information Center

    Sossin, Wayne S.

    2007-01-01

    Protein kinase Cs (PKCs) are implicated in many forms of synaptic plasticity. However, the specific isoform(s) of PKC that underlie(s) these events are often not known. We have used "Aplysia" as a model system in order to investigate the isoform specificity of PKC actions due to the presence of fewer isoforms and a large number of documented…

  14. Long Term Synaptic Plasticity and Learning in Neuronal Networks.

    DTIC Science & Technology

    1987-09-14

    2312/Al Al -p 1. TITLE (Include Security Classification) ’a LONG TERM SYNAPTIC PLASTICITY AND LEARNING IN NEURONAL NETWORKS 12. PERSONAL AUTHOR(S...Analysis of Simple Neuronal Networks " (2nd Annual Symposium on Networks in Brain and Computer Architecture, North Texas State University, Denton, TX

  15. proBDNF negatively regulates neuronal remodeling, synaptic transmission, and synaptic plasticity in hippocampus.

    PubMed

    Yang, Jianmin; Harte-Hargrove, Lauren C; Siao, Chia-Jen; Marinic, Tina; Clarke, Roshelle; Ma, Qian; Jing, Deqiang; Lafrancois, John J; Bath, Kevin G; Mark, Willie; Ballon, Douglas; Lee, Francis S; Scharfman, Helen E; Hempstead, Barbara L

    2014-05-08

    Experience-dependent plasticity shapes postnatal development of neural circuits, but the mechanisms that refine dendritic arbors, remodel spines, and impair synaptic activity are poorly understood. Mature brain-derived neurotrophic factor (BDNF) modulates neuronal morphology and synaptic plasticity, including long-term potentiation (LTP) via TrkB activation. BDNF is initially translated as proBDNF, which binds p75(NTR). In vitro, recombinant proBDNF modulates neuronal structure and alters hippocampal long-term plasticity, but the actions of endogenously expressed proBDNF are unclear. Therefore, we generated a cleavage-resistant probdnf knockin mouse. Our results demonstrate that proBDNF negatively regulates hippocampal dendritic complexity and spine density through p75(NTR). Hippocampal slices from probdnf mice exhibit depressed synaptic transmission, impaired LTP, and enhanced long-term depression (LTD) in area CA1. These results suggest that proBDNF acts in vivo as a biologically active factor that regulates hippocampal structure, synaptic transmission, and plasticity, effects that are distinct from those of mature BDNF. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

  16. ProBDNF negatively regulates neuronal remodeling, synaptic transmission and synaptic plasticity in hippocampus

    PubMed Central

    Yang, Jianmin; Harte-Hargrove, Lauren C.; Siao, Chia-Jen; Marinic, Tina; Clarke, Roshelle; Ma, Qian; Jing, Deqiang; LaFrancois, John J.; Bath, Kevin G.; Mark, Willie; Ballon, Douglas; Lee, Francis S.; Scharfman, Helen E.; Hempstead, Barbara L.

    2014-01-01

    Summary Experience-dependent plasticity shapes postnatal development of neural circuits, but the mechanisms that refine dendritic arbors, remodel spines, and impair synaptic activity are poorly understood. Mature brain-derived neurotrophic factor (BDNF) modulates neuronal morphology and synaptic plasticity, including long-term potentiation (LTP) via TrkB activation. BDNF is initially translated as proBDNF which binds p75NTR. In vitro, recombinant proBDNF modulates neuronal structure and alters hippocampal long-term plasticity, but the actions of endogenously expressed proBDNF are unclear. Therefore, we generated a cleavage-resistant probdnf knock-in mouse. Our results demonstrate that proBDNF negatively regulates hippocampal dendritic complexity and spine density through p75NTR. Hippocampal slices from probdnf mice exhibit depressed synaptic transmission, impaired LTP and enhanced long-term depression (LTD) in area CA1. These results suggest that proBDNF acts in vivo as a biologically active factor that regulates hippocampal structure, synaptic transmission and plasticity, effects that are distinct from mature BDNF. PMID:24746813

  17. Functional consequences of pre- and postsynaptic expression of synaptic plasticity.

    PubMed

    Costa, Rui Ponte; Mizusaki, Beatriz E P; Sjöström, P Jesper; van Rossum, Mark C W

    2017-03-05

    Growing experimental evidence shows that both homeostatic and Hebbian synaptic plasticity can be expressed presynaptically as well as postsynaptically. In this review, we start by discussing this evidence and methods used to determine expression loci. Next, we discuss the functional consequences of this diversity in pre- and postsynaptic expression of both homeostatic and Hebbian synaptic plasticity. In particular, we explore the functional consequences of a biologically tuned model of pre- and postsynaptically expressed spike-timing-dependent plasticity complemented with postsynaptic homeostatic control. The pre- and postsynaptic expression in this model predicts (i) more reliable receptive fields and sensory perception, (ii) rapid recovery of forgotten information (memory savings), and (iii) reduced response latencies, compared with a model with postsynaptic expression only. Finally, we discuss open questions that will require a considerable research effort to better elucidate how the specific locus of expression of homeostatic and Hebbian plasticity alters synaptic and network computations.This article is part of the themed issue 'Integrating Hebbian and homeostatic plasticity'.

  18. Neural ECM molecules in synaptic plasticity, learning, and memory.

    PubMed

    Senkov, Oleg; Andjus, Pavle; Radenovic, Lidija; Soriano, Eduardo; Dityatev, Alexander

    2014-01-01

    Neural extracellular matrix (ECM) molecules derived from neurons and glial cells accumulate in the extracellular space and regulate synaptic plasticity through modulation of perisomal GABAergic inhibition, intrinsic neuronal excitability, integrin signaling, and activities of L-type Ca(2+) channels, NMDA receptors, and Rho-associated kinase. Genetic or enzymatic targeting of ECM molecules proved to bidirectionally modulate acquisition of memories, depending on experimental conditions, and to promote cognitive flexibility and extinction of fear and drug memories. Furthermore, evidence is accumulating that dysregulation of ECM is linked to major psychiatric and neurodegenerative diseases and that targeting ECM molecules may rescue cognitive deficits in animal models of these diseases. Thus, the ECM emerged as a key component of synaptic plasticity, learning, and memory and as an attractive target for developing new generation of synapse plasticizing drugs.

  19. The synaptic plasticity and memory hypothesis: encoding, storage and persistence

    PubMed Central

    Takeuchi, Tomonori; Duszkiewicz, Adrian J.; Morris, Richard G. M.

    2014-01-01

    The synaptic plasticity and memory hypothesis asserts that activity-dependent synaptic plasticity is induced at appropriate synapses during memory formation and is both necessary and sufficient for the encoding and trace storage of the type of memory mediated by the brain area in which it is observed. Criteria for establishing the necessity and sufficiency of such plasticity in mediating trace storage have been identified and are here reviewed in relation to new work using some of the diverse techniques of contemporary neuroscience. Evidence derived using optical imaging, molecular-genetic and optogenetic techniques in conjunction with appropriate behavioural analyses continues to offer support for the idea that changing the strength of connections between neurons is one of the major mechanisms by which engrams are stored in the brain. PMID:24298167

  20. Synaptic plasticity in cephalopods; more than just learning and memory?

    PubMed

    Brown, Euan R; Piscopo, Stefania

    2013-06-01

    The outstanding behavioural capacity of cephalopods is underpinned by a highly sophisticated nervous system anatomy and neural mechanisms that often differ significantly from similarly complex systems in vertebrates and insects. Cephalopods exhibit considerable behavioural flexibility and adaptability, and it might be expected that this should be supported by evident cellular and synaptic plasticity. Here, we review what little is known of the cellular mechanisms that underlie plasticity in cephalopods, particularly from the point of view of synaptic function. We conclude that cephalopods utilise short-, medium-, and long-term plasticity mechanisms that are superficially similar to those so far described in vertebrate and insect synapses. These mechanisms, however, often differ significantly from those in other animals at the biophysical level and are deployed not just in the central nervous system, but also to a limited extent in the peripheral nervous system and neuromuscular junctions.

  1. Frequency-Dependent Changes in NMDAR-Dependent Synaptic Plasticity

    PubMed Central

    Kumar, Arvind; Mehta, Mayank R.

    2011-01-01

    The NMDAR-dependent synaptic plasticity is thought to mediate several forms of learning, and can be induced by spike trains containing a small number of spikes occurring with varying rates and timing, as well as with oscillations. We computed the influence of these variables on the plasticity induced at a single NMDAR containing synapse using a reduced model that was analytically tractable, and these findings were confirmed using detailed, multi-compartment model. In addition to explaining diverse experimental results about the rate and timing dependence of synaptic plasticity, the model made several novel and testable predictions. We found that there was a preferred frequency for inducing long-term potentiation (LTP) such that higher frequency stimuli induced lesser LTP, decreasing as 1/f when the number of spikes in the stimulus was kept fixed. Among other things, the preferred frequency for inducing LTP varied as a function of the distance of the synapse from the soma. In fact, same stimulation frequencies could induce LTP or long-term depression depending on the dendritic location of the synapse. Next, we found that rhythmic stimuli induced greater plasticity then irregular stimuli. Furthermore, brief bursts of spikes significantly expanded the timing dependence of plasticity. Finally, we found that in the ∼5–15-Hz frequency range both rate- and timing-dependent plasticity mechanisms work synergistically to render the synaptic plasticity most sensitive to spike timing. These findings provide computational evidence that oscillations can have a profound influence on the plasticity of an NMDAR-dependent synapse, and show a novel role for the dendritic morphology in this process. PMID:21994493

  2. Emerging Link between Alzheimer's Disease and Homeostatic Synaptic Plasticity

    PubMed Central

    Jang, Sung-Soo; Chung, Hee Jung

    2016-01-01

    Alzheimer's disease (AD) is an irreversible brain disorder characterized by progressive cognitive decline and neurodegeneration of brain regions that are crucial for learning and memory. Although intracellular neurofibrillary tangles and extracellular senile plaques, composed of insoluble amyloid-β (Aβ) peptides, have been the hallmarks of postmortem AD brains, memory impairment in early AD correlates better with pathological accumulation of soluble Aβ oligomers and persistent weakening of excitatory synaptic strength, which is demonstrated by inhibition of long-term potentiation, enhancement of long-term depression, and loss of synapses. However, current, approved interventions aiming to reduce Aβ levels have failed to retard disease progression; this has led to a pressing need to identify and target alternative pathogenic mechanisms of AD. Recently, it has been suggested that the disruption of Hebbian synaptic plasticity in AD is due to aberrant metaplasticity, which is a form of homeostatic plasticity that tunes the magnitude and direction of future synaptic plasticity based on previous neuronal or synaptic activity. This review examines emerging evidence for aberrant metaplasticity in AD. Putative mechanisms underlying aberrant metaplasticity in AD will also be discussed. We hope this review inspires future studies to test the extent to which these mechanisms contribute to the etiology of AD and offer therapeutic targets. PMID:27019755

  3. Dystroglycan mediates homeostatic synaptic plasticity at GABAergic synapses.

    PubMed

    Pribiag, Horia; Peng, Huashan; Shah, Waris Ali; Stellwagen, David; Carbonetto, Salvatore

    2014-05-06

    Dystroglycan (DG), a cell adhesion molecule well known to be essential for skeletal muscle integrity and formation of neuromuscular synapses, is also present at inhibitory synapses in the central nervous system. Mutations that affect DG function not only result in muscular dystrophies, but also in severe cognitive deficits and epilepsy. Here we demonstrate a role of DG during activity-dependent homeostatic regulation of hippocampal inhibitory synapses. Prolonged elevation of neuronal activity up-regulates DG expression and glycosylation, and its localization to inhibitory synapses. Inhibition of protein synthesis prevents the activity-dependent increase in synaptic DG and GABAA receptors (GABAARs), as well as the homeostatic scaling up of GABAergic synaptic transmission. RNAi-mediated knockdown of DG blocks homeostatic scaling up of inhibitory synaptic strength, as does knockdown of like-acetylglucosaminyltransferase (LARGE)--a glycosyltransferase critical for DG function. In contrast, DG is not required for the bicuculline-induced scaling down of excitatory synaptic strength or the tetrodotoxin-induced scaling down of inhibitory synaptic strength. The DG ligand agrin increases GABAergic synaptic strength in a DG-dependent manner that mimics homeostatic scaling up induced by increased activity, indicating that activation of this pathway alone is sufficient to regulate GABAAR trafficking. These data demonstrate that DG is regulated in a physiologically relevant manner in neurons and that DG and its glycosylation are essential for homeostatic plasticity at inhibitory synapses.

  4. Genetic Rescue of Functional Senescence in Synaptic and Behavioral Plasticity

    PubMed Central

    Donlea, Jeffrey M.; Ramanan, Narendrakumar; Silverman, Neal; Shaw, Paul J.

    2014-01-01

    Study Objectives: Aging has been linked with decreased neural plasticity and memory formation in humans and in laboratory model species such as the fruit fly, Drosophila melanogaster. Here, we examine plastic responses following social experience in Drosophila as a high-throughput method to identify interventions that prevent these impairments. Patients or Participants: Wild-type and transgenic Drosophila melanogaster. Design and Interventions: Young (5-day old) or aged (20-day old) adult female Drosophila were housed in socially enriched (n = 35-40) or isolated environments, then assayed for changes in sleep and for structural markers of synaptic terminal growth in the ventral lateral neurons (LNVs) of the circadian clock. Measurements and Results: When young flies are housed in a socially enriched environment, they exhibit synaptic elaboration within a component of the circadian circuitry, the LNVs, which is followed by increased sleep. Aged flies, however, no longer exhibit either of these plastic changes. Because of the tight correlation between neural plasticity and ensuing increases in sleep, we use sleep after enrichment as a high-throughput marker for neural plasticity to identify interventions that prolong youthful plasticity in aged flies. To validate this strategy, we find three independent genetic manipulations that delay age-related losses in plasticity: (1) elevation of dopaminergic signaling, (2) over-expression of the transcription factor blistered (bs) in the LNVs, and (3) reduction of the Imd immune signaling pathway. These findings provide proof-of-principle evidence that measuring changes in sleep in flies after social enrichment may provide a highly scalable assay for the study of age-related deficits in synaptic plasticity. Conclusions: These studies demonstrate that Drosophila provides a promising model for the study of age-related loss of neural plasticity and begin to identify genes that might be manipulated to delay the onset of functional

  5. Different dynamin blockers interfere with distinct phases of synaptic endocytosis during stimulation in motoneurones

    PubMed Central

    Linares-Clemente, Pedro; Rozas, José L; Mircheski, Josif; García-Junco-Clemente, Pablo; Martínez-López, José A; Nieto-González, José L; Vázquez, M Eugenio; Pintado, C Oscar; Fernández-Chacón, Rafael

    2015-01-01

    Key points Neurotransmitter release requires a tight coupling between synaptic vesicle exocytosis and endocytosis with dynamin being a key protein in that process. We used imaging techniques to examine the time course of endocytosis at mouse motor nerve terminals expressing synaptopHluorin, a genetically encoded reporter of the synaptic vesicle cycle. We separated two sequential phases of endocytosis taking place during the stimulation train: early and late endocytosis. Freshly released synaptic vesicle proteins are preferentially retrieved during the early phase, which is very sensitive to dynasore, an inhibitor of dynamin GTPase activity. Synaptic vesicle proteins pre-existing at the plasma membrane before the stimulation are preferentially retrieved during the late phase, which is very sensitive to myristyl trimethyl ammonium bromide (MitMAB), an inhibitor of the dynamin–phospholipid interaction. Abstract Synaptic endocytosis is essential at nerve terminals to maintain neurotransmitter release by exocytosis. Here, at the neuromuscular junction of synaptopHluorin (spH) transgenic mice, we have used imaging to study exo- and endocytosis occurring simultaneously during nerve stimulation. We observed two endocytosis components, which occur sequentially during stimulation. The early component of endocytosis apparently internalizes spH molecules freshly exocytosed. This component was sensitive to dynasore, a blocker of dynamin 1 GTPase activity. In contrast, this early component was resistant to myristyl trimethyl ammonium bromide (MiTMAB), a competitive agent that blocks dynamin binding to phospholipid membranes. The late component of endocytosis is likely to internalize spH molecules that pre-exist at the plasma membrane before stimulation starts. This component was blocked by MiTMAB, perhaps by impairing the binding of dynamin or other key endocytic proteins to phospholipid membranes. Our study suggests the co-existence of two sequential synaptic endocytosis

  6. N- and P/Q-type Ca2+ channels regulate synaptic efficacy between spinal dorsolateral funiculus terminals and motoneurons.

    PubMed

    Aguilar, Justo; Escobedo, Lourdes; Bautista, Wendy; Felix, Ricardo; Delgado-Lezama, Rodolfo

    2004-04-30

    Ca2+ influx through voltage-gated Ca2+ channels mediates synaptic transmission at numerous central synapses. However, electrophysiological and pharmacological evidence linking Ca+ channel activity with neurotransmitter release in the vertebrate mature spinal cord is scarce. In the current report, we investigated in a slice preparation from the adult turtle spinal cord, the effects of various Ca+ channel antagonists on neurotransmission at terminals from the dorsolateral funiculus synapsing motoneurons. Bath application of tetrodotoxin or NiCl2 prevented the monosynaptic excitatory postsynaptic potentials (EPSPs), and this effect was mimicked by exposure to a zero-Ca2+ solution. Application of polypeptide toxins that block N- and P/Q-type channels (omega-CTx-GVIA and omega-Aga-IVA) reduced the EPSP amplitude in a dose-dependent manner. By analyzing the input resistance and the EPSP time course, and using a paired pulse protocol we determined that both toxins act at presynaptic level to modulate neurotransmitter release. RT-PCR studies showed the expression of N- and P/Q-type channel mRNAs in the turtle spinal cord. Together, these results indicate that N- and P/Q-type Ca2+ channels may play a central role in the regulation of neurotransmitter release in the adult turtle spinal cord.

  7. Functional consequences of pre- and postsynaptic expression of synaptic plasticity

    PubMed Central

    Mizusaki, Beatriz E. P.

    2017-01-01

    Growing experimental evidence shows that both homeostatic and Hebbian synaptic plasticity can be expressed presynaptically as well as postsynaptically. In this review, we start by discussing this evidence and methods used to determine expression loci. Next, we discuss the functional consequences of this diversity in pre- and postsynaptic expression of both homeostatic and Hebbian synaptic plasticity. In particular, we explore the functional consequences of a biologically tuned model of pre- and postsynaptically expressed spike-timing-dependent plasticity complemented with postsynaptic homeostatic control. The pre- and postsynaptic expression in this model predicts (i) more reliable receptive fields and sensory perception, (ii) rapid recovery of forgotten information (memory savings), and (iii) reduced response latencies, compared with a model with postsynaptic expression only. Finally, we discuss open questions that will require a considerable research effort to better elucidate how the specific locus of expression of homeostatic and Hebbian plasticity alters synaptic and network computations. This article is part of the themed issue ‘Integrating Hebbian and homeostatic plasticity’. PMID:28093547

  8. Astrocyte plasticity: implications for synaptic and neuronal activity.

    PubMed

    Pirttimaki, Tiina M; Parri, H Rheinallt

    2013-12-01

    Astrocytes are increasingly implicated in a range of functions in the brain, many of which were previously ascribed to neurons. Much of the prevailing interest centers on the role of astrocytes in the modulation of synaptic transmission and their involvement in the induction of forms of plasticity such as long-term potentiation and long-term depression. However, there is also an increasing realization that astrocytes themselves can undergo plasticity. This plasticity may be manifest as changes in protein expression which may modify calcium activity within the cells, changes in morphology that affect the environment of the synapse and the extracellular space, or changes in gap junction astrocyte coupling that modify the transfer of ions and metabolites through astrocyte networks. Plasticity in the way that astrocytes release gliotransmitters can also have direct effects on synaptic activity and neuronal excitability. Astrocyte plasticity can potentially have profound effects on neuronal network activity and be recruited in pathological conditions. An emerging principle of astrocyte plasticity is that it is often induced by neuronal activity, reinforcing our emerging understanding of the working brain as a constant interaction between neurons and glial cells.

  9. Properties of synaptic transmission from the reticular formation dorsal to the facial nucleus to trigeminal motoneurons during early postnatal development in rats.

    PubMed

    Gemba-Nishimura, A; Inoue, T; Nakamura, S; Nakayama, K; Mochizuki, A; Shintani, S; Yoshimura, S

    2010-03-31

    We previously reported that electrical stimulation of the reticular formation dorsal to the facial nucleus (RdVII) elicited excitatory masseter responses at short latencies and that RdVII neurons were antidromically activated by stimulation of the trigeminal motor nucleus (MoV), suggesting that excitatory premotor neurons targeting the MoV are likely located in the RdVII. We thus examined the properties of synaptic transmission from the RdVII to jaw-closing and jaw-opening motoneurons in horizontal brainstem preparations from developing rats using voltage-sensitive dye, patch-clamp recordings and laser photostimulation. Electrical stimulation of the RdVII evoked optical responses in the MoV. Combined bath application of the non-N-methyl-d-aspartate (non-NMDA) receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), and the NMDA receptor antagonist DL-2-amino-5-phosphonopentanoic acid (APV) reduced these optical responses, and addition of the glycine receptor antagonist strychnine and the GABA(A) receptor antagonist bicuculline further reduced the remaining responses. Electrical stimulation of the RdVII evoked postsynaptic currents (PSCs) in all 19 masseter motoneurons tested in postnatal day (P)1-4 rats, and application of CNQX and the NMDA receptor antagonist (+/-)-3(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) reduced the PSC amplitudes by more than 50%. In the presence of CNQX and CPP, the GABA(A) receptor antagonist SR95531 further reduced PSC amplitude, and addition of strychnine abolished the remaining PSCs. Photostimulation of the RdVII with caged glutamate also evoked PSCs in masseter motoneurons of P3-4 rats. In P8-11 rats, electrical stimulation of the RdVII also evoked PSCs in all 14 masseter motoneurons tested, and the effects of the antagonists on the PSCs were similar to those in P1-4 rats. On the other hand, RdVII stimulation evoked PSCs in only three of 16 digastric motoneurons tested. These results suggest that both neonatal and

  10. 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

  11. Amyloid Beta as a Modulator of Synaptic Plasticity

    PubMed Central

    Parihar, Mordhwaj S; Brewer, Gregory J

    2011-01-01

    Alzheimer’s disease is associated with synapse loss, memory dysfunction and pathological accumulation of amyloid beta in plaques. However, an exclusively pathological role for amyloid beta is being challenged by new evidence for an essential function of amyloid beta at the synapse. Amyloid beta protein exists in different assembly states in the central nervous system and plays distinct roles ranging from synapse and memory formation to memory loss and neuronal cell death. Amyloid beta is present in the brain of symptom-free people where it likely performs important physiological roles. New evidence indicates that synaptic activity directly evokes the release of amyloid beta at the synapse. At physiological levels, amyloid beta is a normal, soluble product of neuronal metabolism that regulates synaptic function beginning early in life. Monomeric amyloid beta 40 and 42 are the predominant forms required for synaptic plasticity and neuronal survival. With age, some assemblies of amyloid beta are associated with synaptic failure and Alzheimer’s disease pathology, possibly targeting the N-methyl-D-aspartic acid (NMDA) receptor through the α7-nicotinic acetylcholine receptor (α7-nAChR), mitochondrial amyloid-β alcohol dehydrogenase (ABAD) and cyclophilin D. But emerging data suggests a distinction between age effects on the target response in contrast to the assembly state or the accumulation of the peptide. Both aging and beta amyloid independently decrease neuronal plasticity. Our laboratory has reported that amyloid beta, glutamate and lactic acid are each increasingly toxic with neuron age. The basis of the age-related toxicity partly resides in age-related mitochondrial dysfunction and an oxidative shift in mitochondrial and cytoplasmic redox potential. In turn, signaling through phosphorylated extracellular signal-regulated protein kinases (pERK) is affected along with an age-independent increase in phosphorylated cAMP response element-binding protein (p

  12. Aging and Synaptic Plasticity: A Review

    PubMed Central

    Bergado, Jorge A.; Almaguer, William

    2002-01-01

    Aging affects all systems, but the brain seems to be particularly vulnerable to the action of negative, age-dependent factors. A gradual loss of memory functions is one of the earliest and most widespread consequences of brain aging. The causes for such impairment are still unclear. Long-term potentiation (LTP) is one form of neural plasticity, which has been proposed as the cellular correlate for memory. LTP is affected by aging, and such alteration might be causally related to memory dysfunction. In the present paper, we review the evidence sustaining the existence of a causal link between cognitive and LTP impairments, as well as the possible mechanisms involved. New results indicate a possible involvement of a deficient reinforcement of LTP by affective influences. PMID:12959152

  13. Synaptic Plasticity and Neurological Disorders in Neurotropic Viral Infections

    PubMed Central

    Atluri, Venkata Subba Rao; Hidalgo, Melissa; Samikkannu, Thangavel; Kurapati, Kesava Rao Venkata; Nair, Madhavan

    2015-01-01

    Based on the type of cells or tissues they tend to harbor or attack, many of the viruses are characterized. But, in case of neurotropic viruses, it is not possible to classify them based on their tropism because many of them are not primarily neurotropic. While rabies and poliovirus are considered as strictly neurotropic, other neurotropic viruses involve nervous tissue only secondarily. Since the AIDS pandemic, the interest in neurotropic viral infections has become essential for all clinical neurologists. Although these neurotropic viruses are able to be harbored in or infect the nervous system, not all the neurotropic viruses have been reported to cause disrupted synaptic plasticity and impaired cognitive functions. In this review, we have discussed the neurotropic viruses, which play a major role in altered synaptic plasticity and neurological disorders. PMID:26649202

  14. Does autophagy work in synaptic plasticity and memory?

    PubMed

    Shehata, Mohammad; Inokuchi, Kaoru

    2014-01-01

    Many studies have reported the roles played by regulated proteolysis in neural plasticity and memory. Within this context, most of the research focused on the ubiquitin-proteasome system and the endosome-lysosome system while giving lesser consideration to another major protein degradation system, namely, autophagy. Although autophagy intersects with many of the pathways known to underlie synaptic plasticity and memory, only few reports related autophagy to synaptic remodeling. These pathways include PI3K-mTOR pathway and endosome-dependent proteolysis. In this review, we will discuss several lines of evidence supporting a physiological role of autophagy in memory processes, and the possible mechanistic scenarios for how autophagy could fulfill this function.

  15. Synaptic plasticity in sleep: learning, homeostasis, and disease

    PubMed Central

    Wang, Gordon; Grone, Brian; Colas, Damien; Appelbaum, Lior; Mourrain, Philippe

    2012-01-01

    Sleep is a fundamental and evolutionarily conserved aspect of animal life. Recent studies have shed light on the role of sleep in synaptic plasticity. Demonstrations of memory replay and synapse homeostasis suggest that one essential role of sleep is in the consolidation and optimization of synaptic circuits to retain salient memory traces despite the noise of daily experience. Here, we review this recent evidence, and suggest that sleep creates a heightened state of plasticity, which may be essential for this optimization. Furthermore, we discuss how sleep deficits seen in diseases such as Alzheimer’s disease and autism spectrum disorders might not just reflect underlying circuit malfunction, but could also play a direct role in the progression of those disorders. PMID:21840068

  16. Neuropsin--a possible modulator of synaptic plasticity.

    PubMed

    Shiosaka, Sadao; Ishikawa, Yasuyuki

    2011-09-01

    Accumulating evidence has suggested pivotal roles for neural proteases in development, maturation, aging, and cognitive functions. Among such proteases, neuropsin, a kallikrein gene-related (KLK) endoprotease, appears to have a significant plasticity function that has been analyzed primarily in the hippocampal Schaffer-collateral pathway. In this article, after reviewing the general features of neuropsin, its role in Schaffer-collateral synaptic plasticity is discussed in some detail. Enzymatically active neuropsin is necessary to establish the early phase of long-term potentiation (LTP). This type of LTP, which can be elicited by rather weak tetanic stimulation, is significant in synaptic late association between two independent hippocampal synapses. Neuropsin deficiency completely impaired the early phase of LTP, leading to the absence of late associativity. Associations between early and persistent-LTP synapses may be related to mammalian working memory and consequently integration in learning and memory.

  17. Translational regulatory mechanisms in persistent forms of synaptic plasticity.

    PubMed

    Kelleher, Raymond J; Govindarajan, Arvind; Tonegawa, Susumu

    2004-09-30

    Memory and synaptic plasticity exhibit distinct temporal phases, with long-lasting forms distinguished by their dependence on macromolecular synthesis. Prevailing models for the molecular mechanisms underlying long-lasting synaptic plasticity have largely focused on transcriptional regulation. However, a growing body of evidence now supports a crucial role for neuronal activity-dependent mRNA translation, which may occur in dendrites for a subset of neuronal mRNAs. Recent work has begun to define the signaling mechanisms coupling synaptic activation to the protein synthesis machinery. The ERK and mTOR signaling pathways have been shown to regulate the activity of the general translational machinery, while the translation of particular classes of mRNAs is additionally controlled by gene-specific mechanisms. Rapid enhancement of the synthesis of a diverse array of neuronal proteins through such mechanisms provides the components necessary for persistent forms of LTP and LTD. These findings have important implications for the synapse specificity and associativity of protein synthesis-dependent changes in synaptic strength.

  18. Aquaporin-4 water channels and synaptic plasticity in the hippocampus

    PubMed Central

    Scharfman, Helen E.; Binder, Devin K.

    2013-01-01

    Aquaporin-4 (AQP4) is the major water channel expressed in the central nervous system (CNS) and is primarily expressed in glial cells. Many studies have shown that AQP4 regulates the response of the CNS to insults or injury, but far less is known about the potential for AQP4 to influence synaptic plasticity or behavior. Recent studies have examined long-term potentiation (LTP), long-term depression (LTD), and behavior in AQP4 knockout (KO) and wild-type mice to gain more insight into its potential role. The results showed a selective effect of AQP4 deletion on LTP of the Schaffer collateral pathway in hippocampus using an LTP induction protocol that simulates pyramidal cell firing during theta oscillations (theta-burst stimulation; TBS). However, a different LTP induction protocol was unaffected by AQP4 deletion. There was also a defect in LTD after low frequency stimulation (LFS) in AQP4 KO mice. Interestingly, some slices from AQP4 KO mice exhibited LTD after TBS instead of LTP, or LTP following LFS instead of LTD. These data suggest that AQP4 and astrocytes influence the polarity of long-term synaptic plasticity (potentiation or depression). These potentially powerful roles expand the influence of AQP4 and astrocytes beyond the original suggestions related to regulation of extracellular potassium and water balance. Remarkably, AQP4 KO mice did not show deficits in basal transmission, suggesting specificity for long-term synaptic plasticity. The mechanism appears to be related to neurotrophins and specifically brain-derived neurotrophic factor (BDNF) because pharmacological blockade of neurotrophin trk receptors or scavenging ligands such as BDNF restored plasticity. The in vitro studies predicted effects in vivo of AQP4 deletion because AQP4 KO mice performed worse using a task that requires memory for the location of objects (object placement). However, performance on other hippocampal-dependent tasks was spared. The results suggest an unanticipated and

  19. Aquaporin-4 water channels and synaptic plasticity in the hippocampus.

    PubMed

    Scharfman, Helen E; Binder, Devin K

    2013-12-01

    Aquaporin-4 (AQP4) is the major water channel expressed in the central nervous system (CNS) and is primarily expressed in glial cells. Many studies have shown that AQP4 regulates the response of the CNS to insults or injury, but far less is known about the potential for AQP4 to influence synaptic plasticity or behavior. Recent studies have examined long-term potentiation (LTP), long-term depression (LTD), and behavior in AQP4 knockout (KO) and wild-type mice to gain more insight into its potential role. The results showed a selective effect of AQP4 deletion on LTP of the Schaffer collateral pathway in hippocampus using an LTP induction protocol that simulates pyramidal cell firing during theta oscillations (theta-burst stimulation; TBS). However, LTP produced by a different induction protocol was unaffected. There was also a defect in LTD after low frequency stimulation (LFS) in AQP4 KO mice. Interestingly, some slices from AQP4 KO mice exhibited LTD after TBS instead of LTP, or LTP following LFS instead of LTD. These data suggest that AQP4 and astrocytes influence the polarity of long-term synaptic plasticity (potentiation or depression). These potentially powerful roles expand the influence of AQP4 and astrocytes beyond the original suggestions related to regulation of extracellular potassium and water balance. Remarkably, AQP4 KO mice did not show deficits in basal transmission, suggesting specificity for long-term synaptic plasticity. The mechanism appears to be related to neurotrophins and specifically brain-derived neurotrophic factor (BDNF) because pharmacological blockade of neurotrophin trk receptors or scavenging ligands such as BDNF restored plasticity. The in vitro studies predicted effects in vivo of AQP4 deletion because AQP4 KO mice performed worse using a task that requires memory for the location of objects (object placement). However, performance on other hippocampal-dependent tasks was spared. The results suggest an unanticipated and selective

  20. Sensory Deprivation Triggers Synaptic and Intrinsic Plasticity in the Hippocampus.

    PubMed

    Milshtein-Parush, Hila; Frere, Samuel; Regev, Limor; Lahav, Coren; Benbenishty, Amit; Ben-Eliyahu, Shamgar; Goshen, Inbal; Slutsky, Inna

    2017-04-12

    Hippocampus, a temporal lobe structure involved in learning and memory, receives information from all sensory modalities. Despite extensive research on the role of sensory experience in cortical map plasticity, little is known about whether and how sensory experience regulates functioning of the hippocampal circuits. Here, we show that 9 ± 2 days of whisker deprivation during early mouse development depresses activity of CA3 pyramidal neurons by several principal mechanisms: decrease in release probability, increase in the fraction of silent synapses, and reduction in intrinsic excitability. As a result of deprivation-induced presynaptic inhibition, CA3-CA1 synaptic facilitation was augmented at high frequencies, shifting filtering properties of synapses. The changes in the AMPA-mediated synaptic transmission were accompanied by an increase in NR2B-containing NMDA receptors and a reduction in the AMPA/NMDA ratio. The observed reconfiguration of the CA3-CA1 connections may represent a homeostatic adaptation to augmentation in synaptic activity during the initial deprivation phase. In adult mice, tactile disuse diminished intrinsic excitability without altering synaptic facilitation. We suggest that sensory experience regulates computations performed by the hippocampus by tuning its synaptic and intrinsic characteristics.

  1. AKAP Signaling Complexes in Regulation of Excitatory Synaptic Plasticity

    PubMed Central

    Sanderson, Jennifer L.; Dell'Acqua, Mark L.

    2011-01-01

    Plasticity at excitatory glutamatergic synapses in the central nervous system is believed to be critical for neuronal circuits to process and encode information allowing animals to perform complex behaviors such as learning and memory. In addition, alterations in synaptic plasticity are associated with human diseases including Alzheimer's, epilepsy, chronic pain, drug addiction, and schizophrenia. Long-term potentiation (LTP) and depression (LTD) in the hippocampal region of the brain are two forms of synaptic plasticity that increase or decrease, respectively, the strength of synaptic transmission by postsynaptic AMPA-type glutamate receptors. Both LTP and LTD are induced by activation of NMDA-type glutamate receptors but differ in the level and duration of Ca2+ influx through the NMDA receptor and the subsequent engagement of downstream signaling by protein kinases including PKA, PKC, and CaMKII and phosphatases including PP1 and calcineurin-PP2B (CaN). This review addresses the important emerging roles of the A-kinase anchoring protein (AKAP) family of scaffold proteins in regulating localization of PKA and other kinases and phosphatases to postsynaptic multi-protein complexes that control NMDA and AMPA receptor function during LTP and LTD. PMID:21498812

  2. AKAP signaling complexes in regulation of excitatory synaptic plasticity.

    PubMed

    Sanderson, Jennifer L; Dell'Acqua, Mark L

    2011-06-01

    Plasticity at excitatory glutamatergic synapses in the central nervous system is believed to be critical for neuronal circuits to process and encode information, allowing animals to perform complex behaviors such as learning and memory. In addition, alterations in synaptic plasticity are associated with human diseases, including Alzheimer disease, epilepsy, chronic pain, drug addiction, and schizophrenia. Long-term potentiation (LTP) and depression (LTD) in the hippocampal region of the brain are two forms of synaptic plasticity that increase or decrease, respectively, the strength of synaptic transmission by postsynaptic AMPA-type glutamate receptors. Both LTP and LTD are induced by activation of NMDA-type glutamate receptors but differ in the level and duration of Ca(2+) influx through the NMDA receptor and the subsequent engagement of downstream signaling by protein kinases, including PKA, PKC, and CaMKII, and phosphatases, including PP1 and calcineurin-PP2B (CaN). This review addresses the important emerging roles of the A-kinase anchoring protein family of scaffold proteins in regulating localization of PKA and other kinases and phosphatases to postsynaptic multiprotein complexes that control NMDA and AMPA receptor function during LTP and LTD.

  3. HDAC2 negatively regulates memory formation and synaptic plasticity

    PubMed Central

    Guan, Ji-Song; Haggarty, Stephen J.; Giacometti, Emanuela; Dannenberg, Jan-Hermen; Joseph, Nadine; Gao, Jun; Nieland, Thomas J.F.; Zhou, Ying; Wang, Xinyu; Mazitschek, Ralph; Bradner, James E.; DePinho, Ronald A.; Jaenisch, Rudolf; Tsai, Li-Huei

    2012-01-01

    Chromatin modifications, especially histone-tail acetylation, have been implicated in memory formation. Increased histone-tail acetylation induced by inhibitors of histone deacetylases (HDACis) facilitates learning and memory in wildtype mice as well as in mouse models of neurodegeneration. Harnessing the therapeutic potential of HDACi requires knowledge of the specific HDAC family member(s) linked to cognitive enhancement. Here we show that neuron-specific overexpression of HDAC2, but not HDAC1, reduced dendritic spine density, synapse number, synaptic plasticity, and memory formation. Conversely, HDAC2 deficiency resulted in increased synapse number and memory facilitation, similar to chronic HDACi treatment in mice. Notably, reduced synapse number and learning impairment of HDAC2-overexpressing mice were ameliorated by chronic HDACi treatment. Correspondingly, HDACi treatment failed to further facilitate memory formation in HDAC2-deficient mice. Furthermore, analysis of promoter occupancy revealed association of HDAC2 with the promoters of genes implicated in synaptic plasticity and memory formation. Together, our results suggest that HDAC2 plays a role in modulating synaptic plasticity and long-lasting changes of neural circuits, which in turn negatively regulates learning and memory. These observations encourage the development and testing of HDAC2-selective inhibitors for human diseases associated with memory impairment. PMID:19424149

  4. The immunomodulator glatiramer acetate influences spinal motoneuron plasticity during the course of multiple sclerosis in an animal model.

    PubMed

    Marques, K B; Scorisa, J M; Zanon, R; Freria, C M; Santos, L M B; Damasceno, B P; Oliveira, A L R

    2009-02-01

    The immunomodulador glatiramer acetate (GA) has been shown to significantly reduce the severity of symptoms during the course of multiple sclerosis and in its animal model--experimental autoimmune encephalomyelitis (EAE). Since GA may influence the response of non-neuronal cells in the spinal cord, it is possible that, to some extent, this drug affects the synaptic changes induced during the exacerbation of EAE. In the present study, we investigated whether GA has a positive influence on the loss of inputs to the motoneurons during the course of EAE in rats. Lewis rats were subjected to EAE associated with GA or placebo treatment. The animals were sacrificed after 15 days of treatment and the spinal cords processed for immunohistochemical analysis and transmission electron microscopy. A correlation between the synaptic changes and glial activation was obtained by performing labeling of synaptophysin and glial fibrillary acidic protein using immunohistochemical analysis. Ultrastructural analysis of the terminals apposed to alpha motoneurons was also performed by electron transmission microscopy. Interestingly, although the GA treatment preserved synaptophysin labeling, it did not significantly reduce the glial reaction, indicating that inflammatory activity was still present. Also, ultrastructural analysis showed that GA treatment significantly prevented retraction of both F and S type terminals compared to placebo. The present results indicate that the immunomodulator GA has an influence on the stability of nerve terminals in the spinal cord, which in turn may contribute to its neuroprotective effects during the course of multiple sclerosis.

  5. Convergent evidence for abnormal striatal synaptic plasticity in dystonia

    PubMed Central

    Peterson, David A.; Sejnowski, Terrence J.; Poizner, Howard

    2010-01-01

    Dystonia is a functionally disabling movement disorder characterized by abnormal movements and postures. Although substantial recent progress has been made in identifying genetic factors, the pathophysiology of the disease remains a mystery. A provocative suggestion gaining broader acceptance is that some aspect of neural plasticity may be abnormal. There is also evidence that, at least in some forms of dystonia, sensorimotor “use” may be a contributing factor. Most empirical evidence of abnormal plasticity in dystonia comes from measures of sensorimotor cortical organization and physiology. However, the basal ganglia also play a critical role in sensorimotor function. Furthermore, the basal ganglia are prominently implicated in traditional models of dystonia, are the primary targets of stereotactic neurosurgical interventions, and provide a neural substrate for sensorimotor learning influenced by neuromodulators. Our working hypothesis is that abnormal plasticity in the basal ganglia is a critical link between the etiology and pathophysiology of dystonia. In this review we set up the background for this hypothesis by integrating a large body of disparate indirect evidence that dystonia may involve abnormalities in synaptic plasticity in the striatum. After reviewing evidence implicating the striatum in dystonia, we focus on the influence of two neuromodulatory systems: dopamine and acetylcholine. For both of these neuromodulators, we first describe the evidence for abnormalities in dystonia and then the means by which it may influence striatal synaptic plasticity. Collectively, the evidence suggests that many different forms of dystonia may involve abnormal plasticity in the striatum. An improved understanding of these altered plastic processes would help inform our understanding of the pathophysiology of dystonia, and, given the role of the striatum in sensorimotor learning, provide a principled basis for designing therapies aimed at the dynamic processes

  6. 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…

  7. 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…

  8. Spectrotemporal Dynamics of Auditory Cortical Synaptic Receptive Field Plasticity

    PubMed Central

    Froemke, Robert C.; Martins, Ana Raquel O.

    2011-01-01

    The nervous system must dynamically represent sensory information in order for animals to perceive and operate within a complex, changing environment. Receptive field plasticity in the auditory cortex allows cortical networks to organize around salient features of the sensory environment during postnatal development, and then subsequently refine these representations depending on behavioral context later in life. Here we review the major features of auditory cortical receptive field plasticity in young and adult animals, focusing on modifications to frequency tuning of synaptic inputs. Alteration in the patterns of acoustic input, including sensory deprivation and tonal exposure, leads to rapid adjustments of excitatory and inhibitory strengths that collectively determine the suprathreshold tuning curves of cortical neurons. Long-term cortical plasticity also requires co-activation of subcortical neuromodulatory control nuclei such as the cholinergic nucleus basalis, particularly in adults. Regardless of developmental stage, regulation of inhibition seems to be a general mechanism by which changes in sensory experience and neuromodulatory state can remodel cortical receptive fields. We discuss recent findings suggesting that the microdynamics of synaptic receptive field plasticity unfold as a multi-phase set of distinct phenomena, initiated by disrupting the balance between excitation and inhibition, and eventually leading to wide-scale changes to many synapses throughout the cortex. These changes are coordinated to enhance the representations of newly-significant stimuli, possibly for improved signal processing and language learning in humans. PMID:21426927

  9. Endocannabinoid-mediated synaptic plasticity and addiction-related behavior.

    PubMed

    Sidhpura, Nimish; Parsons, Loren H

    2011-12-01

    Endogenous cannabinoids (eCBs) are retrograde messengers that provide feedback inhibition of both excitatory and inhibitory transmission in brain through the activation of presynaptic CB₁ receptors. Substantial evidence indicates that eCBs mediate various forms of short- and long-term plasticity in brain regions involved in the etiology of addiction. The present review provides an overview of the mechanisms through which eCBs mediate various forms of synaptic plasticity and discusses evidence that eCB-mediated plasticity is disrupted following exposure to a variety of abused substances that differ substantially in pharmacodynamic mechanism including alcohol, psychostimulants and cannabinoids. The possible involvement of dysregulated eCB signaling in maladaptive behaviors that evolve over long-term drug exposure is also discussed, with a particular focus on altered behavioral responses to drug exposure, deficient extinction of drug-related memories, increased drug craving and relapse, heightened stress sensitivity and persistent affective disruption (anxiety and depression).

  10. Endocannabinoid-mediated synaptic plasticity and addiction-related behavior

    PubMed Central

    Sidhpura, Nimish; Parsons, Loren H.

    2011-01-01

    Endogenous cannabinoids (eCBs) are retrograde messengers that provide feedback inhibition of both excitatory and inhibitory transmission in brain through the activation of presynaptic CB1 receptors. Substantial evidence indicates that eCBs mediate various forms of short- and long-term plasticity in brain regions involved in the etiology of addiction. The present review provides an overview of the mechanisms through which eCBs mediate various forms of synaptic plasticity and discusses evidence that eCB-mediated plasticity is disrupted following exposure to a variety of abused substances that differ substantially in pharmacodynamic mechanism including alcohol, psychostimulants and cannabinoids. The possible involvement of dysregulated eCB signaling in maladaptive behaviors that evolve over long-term drug exposure is also discussed, with a particular focus on altered behavioral responses to drug exposure, deficient extinction of drug-related memories, increased drug craving and relapse, heightened stress sensitivity and persistent affective disruption (anxiety and depression). PMID:21669214

  11. A putative lysophosphatidylinositol receptor GPR55 modulates hippocampal synaptic plasticity.

    PubMed

    Hurst, Katrina; Badgley, Corinne; Ellsworth, Tanner; Bell, Spencer; Friend, Lindsey; Prince, Brad; Welch, Jacob; Cowan, Zack; Williamson, Ryan; Lyon, Chris; Anderson, Brandon; Poole, Brian; Christensen, Michael; McNeil, Michael; Call, Jarrod; Edwards, Jeffrey G

    2017-09-01

    GPR55, an orphan G-protein coupled receptor, is activated by lysophosphatidylinositol (LPI) and the endocannabinoid anandamide, as well as by other compounds including THC. LPI is a potent endogenous ligand of GPR55 and neither GPR55 nor LPIs' functions in the brain are well understood. While endocannabinoids are well known to modulate brain synaptic plasticity, the potential role LPI could have on brain plasticity has never been demonstrated. Therefore, we examined not only GPR55 expression, but also the role its endogenous ligand could play in long-term potentiation, a common form of synaptic plasticity. Using quantitative RT-PCR, electrophysiology, and behavioral assays, we examined hippocampal GPR55 expression and function. qRT-PCR results indicate that GPR55 is expressed in hippocampi of both rats and mice. Immunohistochemistry and single cell PCR demonstrates GPR55 protein in pyramidal cells of CA1 and CA3 layers in the hippocampus. Application of the GPR55 endogenous agonist LPI to hippocampal slices of GPR55(+/+) mice significantly enhanced CA1 LTP. This effect was absent in GPR55(-/-) mice, and blocked by the GPR55 antagonist CID 16020046. We also examined paired-pulse ratios of GPR55(-/-) and GPR55(+/+) mice with or without LPI and noted significant enhancement in paired-pulse ratios by LPI in GPR55(+/+) mice. Behaviorally, GPR55(-/-) and GPR55(+/+) mice did not differ in memory tasks including novel object recognition, radial arm maze, or Morris water maze. However, performance on radial arm maze and elevated plus maze task suggests GPR55(-/-) mice have a higher frequency of immobile behavior. This is the first demonstration of LPI involvement in hippocampal synaptic plasticity. © 2017 Wiley Periodicals, Inc.

  12. The computational power of astrocyte mediated synaptic plasticity

    PubMed Central

    Min, Rogier; Santello, Mirko; Nevian, Thomas

    2012-01-01

    Research in the last two decades has made clear that astrocytes play a crucial role in the brain beyond their functions in energy metabolism and homeostasis. Many studies have shown that astrocytes can dynamically modulate neuronal excitability and synaptic plasticity, and might participate in higher brain functions like learning and memory. With the plethora of astrocyte mediated signaling processes described in the literature today, the current challenge is to identify, which of these processes happen under what physiological condition, and how this shapes information processing and, ultimately, behavior. To answer these questions will require a combination of advanced physiological, genetical, and behavioral experiments. Additionally, mathematical modeling will prove crucial for testing predictions on the possible functions of astrocytes in neuronal networks, and to generate novel ideas as to how astrocytes can contribute to the complexity of the brain. Here, we aim to provide an outline of how astrocytes can interact with neurons. We do this by reviewing recent experimental literature on astrocyte-neuron interactions, discussing the dynamic effects of astrocytes on neuronal excitability and short- and long-term synaptic plasticity. Finally, we will outline the potential computational functions that astrocyte-neuron interactions can serve in the brain. We will discuss how astrocytes could govern metaplasticity in the brain, how they might organize the clustering of synaptic inputs, and how they could function as memory elements for neuronal activity. We conclude that astrocytes can enhance the computational power of neuronal networks in previously unexpected ways. PMID:23125832

  13. A Nonlinear Cable Framework for Bidirectional Synaptic Plasticity

    PubMed Central

    Iannella, Nicolangelo; Launey, Thomas; Abbott, Derek; Tanaka, Shigeru

    2014-01-01

    Finding the rules underlying how axons of cortical neurons form neural circuits and modify their corresponding synaptic strength is the still subject of intense research. Experiments have shown that internal calcium concentration, and both the precise timing and temporal order of pre and postsynaptic action potentials, are important constituents governing whether the strength of a synapse located on the dendrite is increased or decreased. In particular, previous investigations focusing on spike timing-dependent plasticity (STDP) have typically observed an asymmetric temporal window governing changes in synaptic efficacy. Such a temporal window emphasizes that if a presynaptic spike, arriving at the synaptic terminal, precedes the generation of a postsynaptic action potential, then the synapse is potentiated; however if the temporal order is reversed, then depression occurs. Furthermore, recent experimental studies have now demonstrated that the temporal window also depends on the dendritic location of the synapse. Specifically, it was shown that in distal regions of the apical dendrite, the magnitude of potentiation was smaller and the window for depression was broader, when compared to observations from the proximal region of the dendrite. To date, the underlying mechanism(s) for such a distance-dependent effect is (are) currently unknown. Here, using the ionic cable theory framework in conjunction with the standard calcium based plasticity model, we show for the first time that such distance-dependent inhomogeneities in the temporal learning window for STDP can be largely explained by both the spatial and active properties of the dendrite. PMID:25148478

  14. Structural Components of Synaptic Plasticity and Memory Consolidation

    PubMed Central

    Bailey, Craig H.; Kandel, Eric R.; Harris, Kristen M.

    2015-01-01

    Consolidation of implicit memory in the invertebrate Aplysia and explicit memory in the mammalian hippocampus are associated with remodeling and growth of preexisting synapses and the formation of new synapses. Here, we compare and contrast structural components of the synaptic plasticity that underlies these two distinct forms of memory. In both cases, the structural changes involve time-dependent processes. Thus, some modifications are transient and may contribute to early formative stages of long-term memory, whereas others are more stable, longer lasting, and likely to confer persistence to memory storage. In addition, we explore the possibility that trans-synaptic signaling mechanisms governing de novo synapse formation during development can be reused in the adult for the purposes of structural synaptic plasticity and memory storage. Finally, we discuss how these mechanisms set in motion structural rearrangements that prepare a synapse to strengthen the same memory and, perhaps, to allow it to take part in other memories as a basis for understanding how their anatomical representation results in the enhanced expression and storage of memories in the brain. PMID:26134321

  15. Important roles of Vilse in dendritic architecture and synaptic plasticity

    PubMed Central

    Lee, Jin-Yu; Lee, Li-Jen; Fan, Chih-Chen; Chang, Ho-Ching; Shih, Hsin-An; Min, Ming-Yuan; Chang, Mau-Sun

    2017-01-01

    Vilse/Arhgap39 is a Rho GTPase activating protein (RhoGAP) and utilizes its WW domain to regulate Rac/Cdc42-dependent morphogenesis in Drosophila and murine hippocampal neurons. However, the function of Vilse in mammalian dendrite architecture and synaptic plasticity remained unclear. In the present study, we aimed to explore the possible role of Vilse in dendritic structure and synaptic function in the brain. Homozygous knockout of Vilse resulted in premature embryonic lethality in mice. Changes in dendritic complexity and spine density were noticed in hippocampal neurons of Camk2a-Cre mediated forebrain-specific Vilse knockout (VilseΔ/Δ) mice. VilseΔ/Δ mice displayed impaired spatial memory in water maze and Y-maze tests. Electrical stimulation in hippocampal CA1 region revealed that the synaptic transmission and plasticity were defected in VilseΔ/Δ mice. Collectively, our results demonstrate that Vilse is essential for embryonic development and required for spatial memory. PMID:28368047

  16. The computational power of astrocyte mediated synaptic plasticity.

    PubMed

    Min, Rogier; Santello, Mirko; Nevian, Thomas

    2012-01-01

    Research in the last two decades has made clear that astrocytes play a crucial role in the brain beyond their functions in energy metabolism and homeostasis. Many studies have shown that astrocytes can dynamically modulate neuronal excitability and synaptic plasticity, and might participate in higher brain functions like learning and memory. With the plethora of astrocyte mediated signaling processes described in the literature today, the current challenge is to identify, which of these processes happen under what physiological condition, and how this shapes information processing and, ultimately, behavior. To answer these questions will require a combination of advanced physiological, genetical, and behavioral experiments. Additionally, mathematical modeling will prove crucial for testing predictions on the possible functions of astrocytes in neuronal networks, and to generate novel ideas as to how astrocytes can contribute to the complexity of the brain. Here, we aim to provide an outline of how astrocytes can interact with neurons. We do this by reviewing recent experimental literature on astrocyte-neuron interactions, discussing the dynamic effects of astrocytes on neuronal excitability and short- and long-term synaptic plasticity. Finally, we will outline the potential computational functions that astrocyte-neuron interactions can serve in the brain. We will discuss how astrocytes could govern metaplasticity in the brain, how they might organize the clustering of synaptic inputs, and how they could function as memory elements for neuronal activity. We conclude that astrocytes can enhance the computational power of neuronal networks in previously unexpected ways.

  17. A nonlinear cable framework for bidirectional synaptic plasticity.

    PubMed

    Iannella, Nicolangelo; Launey, Thomas; Abbott, Derek; Tanaka, Shigeru

    2014-01-01

    Finding the rules underlying how axons of cortical neurons form neural circuits and modify their corresponding synaptic strength is the still subject of intense research. Experiments have shown that internal calcium concentration, and both the precise timing and temporal order of pre and postsynaptic action potentials, are important constituents governing whether the strength of a synapse located on the dendrite is increased or decreased. In particular, previous investigations focusing on spike timing-dependent plasticity (STDP) have typically observed an asymmetric temporal window governing changes in synaptic efficacy. Such a temporal window emphasizes that if a presynaptic spike, arriving at the synaptic terminal, precedes the generation of a postsynaptic action potential, then the synapse is potentiated; however if the temporal order is reversed, then depression occurs. Furthermore, recent experimental studies have now demonstrated that the temporal window also depends on the dendritic location of the synapse. Specifically, it was shown that in distal regions of the apical dendrite, the magnitude of potentiation was smaller and the window for depression was broader, when compared to observations from the proximal region of the dendrite. To date, the underlying mechanism(s) for such a distance-dependent effect is (are) currently unknown. Here, using the ionic cable theory framework in conjunction with the standard calcium based plasticity model, we show for the first time that such distance-dependent inhomogeneities in the temporal learning window for STDP can be largely explained by both the spatial and active properties of the dendrite.

  18. Fragile X Syndrome: Keys to the Molecular Genetics of Synaptic Plasticity

    ERIC Educational Resources Information Center

    Lombroso, Paul J.; Ogren, Marilee P.

    2008-01-01

    Fragile X syndrome, the most common form of inherited mental retardation is discussed. The relationship between specific impairments in synaptic plasticity and Fragile X syndrome is investigated as it strengthens synaptic contacts between neurons.

  19. Fragile X Syndrome: Keys to the Molecular Genetics of Synaptic Plasticity

    ERIC Educational Resources Information Center

    Lombroso, Paul J.; Ogren, Marilee P.

    2008-01-01

    Fragile X syndrome, the most common form of inherited mental retardation is discussed. The relationship between specific impairments in synaptic plasticity and Fragile X syndrome is investigated as it strengthens synaptic contacts between neurons.

  20. Dynamic learning and memory, synaptic plasticity and neurogenesis: an update

    PubMed Central

    Stuchlik, Ales

    2014-01-01

    Mammalian memory is the result of the interaction of millions of neurons in the brain and their coordinated activity. Candidate mechanisms for memory are synaptic plasticity changes, such as long-term potentiation (LTP). LTP is essentially an electrophysiological phenomenon manifested in hours-lasting increase on postsynaptic potentials after synapse tetanization. It is thought to ensure long-term changes in synaptic efficacy in distributed networks, leading to persistent changes in the behavioral patterns, actions and choices, which are often interpreted as the retention of information, i.e., memory. Interestingly, new neurons are born in the mammalian brain and adult hippocampal neurogenesis is proposed to provide a substrate for dynamic and flexible aspects of behavior such as pattern separation, prevention of interference, flexibility of behavior and memory resolution. This work provides a brief review on the memory and involvement of LTP and adult neurogenesis in memory phenomena. PMID:24744707

  1. Neural ECM proteases in learning and synaptic plasticity.

    PubMed

    Tsilibary, Effie; Tzinia, Athina; Radenovic, Lidija; Stamenkovic, Vera; Lebitko, Tomasz; Mucha, Mariusz; Pawlak, Robert; Frischknecht, Renato; Kaczmarek, Leszek

    2014-01-01

    Recent studies implicate extracellular proteases in synaptic plasticity, learning, and memory. The data are especially strong for such serine proteases as thrombin, tissue plasminogen activator, neurotrypsin, and neuropsin as well as matrix metalloproteinases, MMP-9 in particular. The role of those enzymes in the aforementioned phenomena is supported by the experimental results on the expression patterns (at the gene expression and protein and enzymatic activity levels) and functional studies, including knockout mice, specific inhibitors, etc. Counterintuitively, the studies have shown that the extracellular proteolysis is not responsible mainly for an overall degradation of the extracellular matrix (ECM) and loosening perisynaptic structures, but rather allows for releasing signaling molecules from the ECM, transsynaptic proteins, and latent form of growth factors. Notably, there are also indications implying those enzymes in the major neuropsychiatric disorders, probably by contributing to synaptic aberrations underlying such diseases as schizophrenia, bipolar, autism spectrum disorders, and drug addiction.

  2. Dendritic spine actin dynamics in neuronal maturation and synaptic plasticity.

    PubMed

    Hlushchenko, Iryna; Koskinen, Mikko; Hotulainen, Pirta

    2016-09-01

    The majority of the postsynaptic terminals of excitatory synapses in the central nervous system exist on small bulbous structures on dendrites known as dendritic spines. The actin cytoskeleton is a structural element underlying the proper development and morphology of dendritic spines. Synaptic activity patterns rapidly change actin dynamics, leading to morphological changes in dendritic spines. In this mini-review, we will discuss recent findings on neuronal maturation and synaptic plasticity-induced changes in the dendritic spine actin cytoskeleton. We propose that actin dynamics in dendritic spines decrease through actin filament crosslinking during neuronal maturation. In long-term potentiation, we evaluate the model of fast breakdown of actin filaments through severing and rebuilding through polymerization and later stabilization through crosslinking. We will discuss the role of Ca(2+) in long-term depression, and suggest that actin filaments are dissolved through actin filament severing. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  3. Information processing and synaptic plasticity at hippocampal mossy fiber terminals.

    PubMed

    Evstratova, Alesya; Tóth, Katalin

    2014-01-01

    Granule cells of the dentate gyrus receive cortical information and they transform and transmit this code to the CA3 area via their axons, the mossy fibers (MFs). Structural and functional complexity of this network has been extensively studied at various organizational levels. This review is focused on the anatomical and physiological properties of the MF system. We will discuss the mechanism by which dentate granule cells process signals from single action potentials (APs), short bursts and longer stimuli. Various parameters of synaptic interactions at different target cells such as quantal transmission, short- and long-term plasticity (LTP) will be summarized. Different types of synaptic contacts formed by MFs have unique sets of rules for information processing during different rates of granule cell activity. We will investigate the complex interactions between key determinants of information transfer between the dentate gyrus and the CA3 area of the hippocampus.

  4. Information processing and synaptic plasticity at hippocampal mossy fiber terminals

    PubMed Central

    Evstratova, Alesya; Tóth, Katalin

    2014-01-01

    Granule cells of the dentate gyrus receive cortical information and they transform and transmit this code to the CA3 area via their axons, the mossy fibers (MFs). Structural and functional complexity of this network has been extensively studied at various organizational levels. This review is focused on the anatomical and physiological properties of the MF system. We will discuss the mechanism by which dentate granule cells process signals from single action potentials (APs), short bursts and longer stimuli. Various parameters of synaptic interactions at different target cells such as quantal transmission, short- and long-term plasticity (LTP) will be summarized. Different types of synaptic contacts formed by MFs have unique sets of rules for information processing during different rates of granule cell activity. We will investigate the complex interactions between key determinants of information transfer between the dentate gyrus and the CA3 area of the hippocampus. PMID:24550783

  5. Spike-Timing Dependent Plasticity Beyond Synapse – Pre- and Post-Synaptic Plasticity of Intrinsic Neuronal Excitability

    PubMed Central

    Debanne, Dominique; Poo, Mu-Ming

    2010-01-01

    Long-lasting plasticity of synaptic transmission is classically thought to be the cellular substrate for information storage in the brain. Recent data indicate however that it is not the whole story and persistent changes in the intrinsic neuronal excitability have been shown to occur in parallel to the induction of long-term synaptic modifications. This form of plasticity depends on the regulation of voltage-gated ion channels. Here we review the experimental evidence for plasticity of neuronal excitability induced at pre- or postsynaptic sites when long-term plasticity of synaptic transmission is induced with Spike-Timing Dependent Plasticity (STDP) protocols. We describe the induction and expression mechanisms of the induced changes in excitability. Finally, the functional synergy between synaptic and non-synaptic plasticity and their spatial extent are discussed. PMID:21423507

  6. Natural Firing Patterns Imply Low Sensitivity of Synaptic Plasticity to Spike Timing Compared with Firing Rate.

    PubMed

    Graupner, Michael; Wallisch, Pascal; Ostojic, Srdjan

    2016-11-02

    Synaptic plasticity is sensitive to the rate and the timing of presynaptic and postsynaptic action potentials. In experimental protocols inducing plasticity, the imposed spike trains are typically regular and the relative timing between every presynaptic and postsynaptic spike is fixed. This is at odds with firing patterns observed in the cortex of intact animals, where cells fire irregularly and the timing between presynaptic and postsynaptic spikes varies. To investigate synaptic changes elicited by in vivo-like firing, we used numerical simulations and mathematical analysis of synaptic plasticity models. We found that the influence of spike timing on plasticity is weaker than expected from regular stimulation protocols. Moreover, when neurons fire irregularly, synaptic changes induced by precise spike timing can be equivalently induced by a modest firing rate variation. Our findings bridge the gap between existing results on synaptic plasticity and plasticity occurring in vivo, and challenge the dominant role of spike timing in plasticity.

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

    SciTech Connect

    Zhu Guoqi; Chen Ying; Huang Yuying; Li Qinglin; Behnisch, Thomas

    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 at 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 f

  8. Endocannabinoid Signaling and Long-term Synaptic Plasticity

    PubMed Central

    Heifets, Boris D.; Castillo, Pablo E.

    2015-01-01

    Endocannabinoids (eCBs) are key activity-dependent signals regulating synaptic transmission throughout the CNS. Accordingly, eCBs are involved in neural functions ranging from feeding homeostasis to cognition. There is great interest in understanding how exogenous (e.g. cannabis) and endogenous cannabinoids affect behavior. As behavioral adaptations are widely considered to rely on changes in synaptic strength, the prevalence of eCB-mediated long term depression (eCB-LTD) at synapses throughout the brain merits close attention. The induction and expression of eCB-LTD, while remarkably similar at various synapses, is controlled by an array of regulatory influences which we are just beginning to uncover. This complexity endows eCB-LTD with important computational properties, such as coincidence detection and input specificity, critical for higher CNS functions like learning and memory. In this article, we review the major molecular and cellular mechanisms underlying eCB-LTD, as well as the potential physiological relevance of this widespread form of synaptic plasticity. PMID:19575681

  9. Interneuron- and GABAA receptor-specific inhibitory synaptic plasticity in cerebellar Purkinje cells

    PubMed Central

    He, Qionger; Duguid, Ian; Clark, Beverley; Panzanelli, Patrizia; Patel, Bijal; Thomas, Philip; Fritschy, Jean-Marc; Smart, Trevor G.

    2015-01-01

    Inhibitory synaptic plasticity is important for shaping both neuronal excitability and network activity. Here we investigate the input and GABAA receptor subunit specificity of inhibitory synaptic plasticity by studying cerebellar interneuron–Purkinje cell (PC) synapses. Depolarizing PCs initiated a long-lasting increase in GABA-mediated synaptic currents. By stimulating individual interneurons, this plasticity was observed at somatodendritic basket cell synapses, but not at distal dendritic stellate cell synapses. Basket cell synapses predominantly express β2-subunit-containing GABAA receptors; deletion of the β2-subunit ablates this plasticity, demonstrating its reliance on GABAA receptor subunit composition. The increase in synaptic currents is dependent upon an increase in newly synthesized cell surface synaptic GABAA receptors and is abolished by preventing CaMKII phosphorylation of GABAA receptors. Our results reveal a novel GABAA receptor subunit- and input-specific form of inhibitory synaptic plasticity that regulates the temporal firing pattern of the principal output cells of the cerebellum. PMID:26179122

  10. Interneuron- and GABAA receptor-specific inhibitory synaptic plasticity in cerebellar Purkinje cells

    NASA Astrophysics Data System (ADS)

    He, Qionger; Duguid, Ian; Clark, Beverley; Panzanelli, Patrizia; Patel, Bijal; Thomas, Philip; Fritschy, Jean-Marc; Smart, Trevor G.

    2015-07-01

    Inhibitory synaptic plasticity is important for shaping both neuronal excitability and network activity. Here we investigate the input and GABAA receptor subunit specificity of inhibitory synaptic plasticity by studying cerebellar interneuron-Purkinje cell (PC) synapses. Depolarizing PCs initiated a long-lasting increase in GABA-mediated synaptic currents. By stimulating individual interneurons, this plasticity was observed at somatodendritic basket cell synapses, but not at distal dendritic stellate cell synapses. Basket cell synapses predominantly express β2-subunit-containing GABAA receptors; deletion of the β2-subunit ablates this plasticity, demonstrating its reliance on GABAA receptor subunit composition. The increase in synaptic currents is dependent upon an increase in newly synthesized cell surface synaptic GABAA receptors and is abolished by preventing CaMKII phosphorylation of GABAA receptors. Our results reveal a novel GABAA receptor subunit- and input-specific form of inhibitory synaptic plasticity that regulates the temporal firing pattern of the principal output cells of the cerebellum.

  11. Ras and Rap signaling in synaptic plasticity and mental disorders.

    PubMed

    Stornetta, Ruth L; Zhu, J Julius

    2011-02-01

    The Ras family GTPases (Ras, Rap1, and Rap2) and their downstream mitogen-activated protein kinases (ERK, JNK, and p38MAPK) and PI3K signaling cascades control various physiological processes. In neuronal cells, recent studies have shown that these parallel cascades signal distinct forms of AMPA-sensitive glutamate receptor trafficking during experience-dependent synaptic plasticity and adaptive behavior. Interestingly, both hypo- and hyperactivation of Ras/ Rap signaling impair the capacity of synaptic plasticity, underscoring the importance of a "happy-medium" dynamic regulation of the signaling. Moreover, accumulating reports have linked various genetic defects that either up- or down-regulate Ras/Rap signaling with several mental disorders associated with learning disability (e.g., Alzheimer's disease, Angelman syndrome, autism, cardio-facio-cutaneous syndrome, Coffin-Lowry syndrome, Costello syndrome, Cowden and Bannayan-Riley-Ruvalcaba syndromes, fragile X syndrome, neurofibromatosis type 1, Noonan syndrome, schizophrenia, tuberous sclerosis, and X-linked mental retardation), highlighting the necessity of happy-medium dynamic regulation of Ras/Rap signaling in learning behavior. Thus, the recent advances in understanding of neuronal Ras/Rap signaling provide a useful guide for developing novel treatments for mental diseases.

  12. Emerging links between homeostatic synaptic plasticity and neurological disease.

    PubMed

    Wondolowski, Joyce; Dickman, Dion

    2013-11-21

    Homeostatic signaling systems are ubiquitous forms of biological regulation, having been studied for hundreds of years in the context of diverse physiological processes including body temperature and osmotic balance. However, only recently has this concept been brought to the study of excitatory and inhibitory electrical activity that the nervous system uses to establish and maintain stable communication. Synapses are a primary target of neuronal regulation with a variety of studies over the past 15 years demonstrating that these cellular junctions are under bidirectional homeostatic control. Recent work from an array of diverse systems and approaches has revealed exciting new links between homeostatic synaptic plasticity and a variety of seemingly disparate neurological and psychiatric diseases. These include autism spectrum disorders, intellectual disabilities, schizophrenia, and Fragile X Syndrome. Although the molecular mechanisms through which defective homeostatic signaling may lead to disease pathogenesis remain unclear, rapid progress is likely to be made in the coming years using a powerful combination of genetic, imaging, electrophysiological, and next generation sequencing approaches. Importantly, understanding homeostatic synaptic plasticity at a cellular and molecular level may lead to developments in new therapeutic innovations to treat these diseases. In this review we will examine recent studies that demonstrate homeostatic control of postsynaptic protein translation, retrograde signaling, and presynaptic function that may contribute to the etiology of complex neurological and psychiatric diseases.

  13. 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

  14. Lithium rescues synaptic plasticity and memory in Down syndrome mice

    PubMed Central

    Contestabile, Andrea; Greco, Barbara; Ghezzi, Diego; Tucci, Valter; Benfenati, Fabio; Gasparini, Laura

    2012-01-01

    Down syndrome (DS) patients exhibit abnormalities of hippocampal-dependent explicit memory, a feature that is replicated in relevant mouse models of the disease. Adult hippocampal neurogenesis, which is impaired in DS and other neuropsychiatric diseases, plays a key role in hippocampal circuit plasticity and has been implicated in learning and memory. However, it remains unknown whether increasing adult neurogenesis improves hippocampal plasticity and behavioral performance in the multifactorial context of DS. We report that, in the Ts65Dn mouse model of DS, chronic administration of lithium, a clinically used mood stabilizer, promoted the proliferation of neuronal precursor cells through the pharmacological activation of the Wnt/β-catenin pathway and restored adult neurogenesis in the hippocampal dentate gyrus (DG) to physiological levels. The restoration of adult neurogenesis completely rescued the synaptic plasticity of newborn neurons in the DG and led to the full recovery of behavioral performance in fear conditioning, object location, and novel object recognition tests. These findings indicate that reestablishing a functional population of hippocampal newborn neurons in adult DS mice rescues hippocampal plasticity and memory and implicate adult neurogenesis as a promising therapeutic target to alleviate cognitive deficits in DS patients. PMID:23202733

  15. Synaptic plasticity enables adaptive self-tuning critical networks.

    PubMed

    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.

  16. MicroRNAs regulate synaptic plasticity underlying drug addiction.

    PubMed

    Smith, A C W; Kenny, P J

    2017-09-05

    Chronic use of drugs of abuse results in neurochemical, morphological and behavioral plasticity that underlies the emergence of compulsive drug seeking and vulnerability to relapse during periods of attempted abstinence. Identifying and reversing addiction-relevant plasticity is seen as a potential point of pharmacotherapeutic intervention in drug-addicted individuals. Despite considerable advances in our understanding of the actions of drugs of abuse in the brain this information has thus far yielded few novel treatment options addicted individuals. MicroRNAs are small non-coding RNAs that can each regulate the translation of hundreds to thousands of messenger RNAs. The highly pleiotropic nature of miRNAs has focused attention on their contribution to addiction-relevant structural and functional plasticity in the brain and their potential utility as targets for medications development. In this review, we discuss the roles of miRNAs in synaptic plasticity underlying the development of addiction and then briefly discuss the possibility of using circulating miRNA as biomarkers for addiction. This article is protected by copyright. All rights reserved.

  17. Spike-driven synaptic plasticity: theory, simulation, VLSI implementation.

    PubMed

    Fusi, S; Annunziato, M; Badoni, D; Salamon, A; Amit, D J

    2000-10-01

    We present a model for spike-driven dynamics of a plastic synapse, suited for aVLSI implementation. The synaptic device behaves as a capacitor on short timescales and preserves the memory of two stable states (efficacies) on long timescales. The transitions (LTP/LTD) are stochastic because both the number and the distribution of neural spikes in any finite (stimulation) interval fluctuate, even at fixed pre- and postsynaptic spike rates. The dynamics of the single synapse is studied analytically by extending the solution to a classic problem in queuing theory (Takacs process). The model of the synapse is implemented in aVLSI and consists of only 18 transistors. It is also directly simulated. The simulations indicate that LTP/LTD probabilities versus rates are robust to fluctuations of the electronic parameters in a wide range of rates. The solutions for these probabilities are in very good agreement with both the simulations and measurements. Moreover, the probabilities are readily manipulable by variations of the chip's parameters, even in ranges where they are very small. The tests of the electronic device cover the range from spontaneous activity (3-4 Hz) to stimulus-driven rates (50 Hz). Low transition probabilities can be maintained in all ranges, even though the intrinsic time constants of the device are short (approximately 100 ms). Synaptic transitions are triggered by elevated presynaptic rates: for low presynaptic rates, there are essentially no transitions. The synaptic device can preserve its memory for years in the absence of stimulation. Stochasticity of learning is a result of the variability of interspike intervals; noise is a feature of the distributed dynamics of the network. The fact that the synapse is binary on long timescales solves the stability problem of synaptic efficacies in the absence of stimulation. Yet stochastic learning theory ensures that it does not affect the collective behavior of the network, if the transition probabilities are

  18. Obesity elicits interleukin 1-mediated deficits in hippocampal synaptic plasticity.

    PubMed

    Erion, Joanna R; Wosiski-Kuhn, Marlena; Dey, Aditi; Hao, Shuai; Davis, Catherine L; Pollock, Norman K; Stranahan, Alexis M

    2014-02-12

    Adipose tissue is a known source of proinflammatory cytokines in obese humans and animal models, including the db/db mouse, in which obesity arises as a result of leptin receptor insensitivity. Inflammatory cytokines induce cognitive deficits across numerous conditions, but no studies have determined whether obesity-induced inflammation mediates synaptic dysfunction. To address this question, we used a treadmill training paradigm in which mice were exposed to daily training sessions or an immobile belt, with motivation achieved by delivery of compressed air on noncompliance. Treadmill training prevented hippocampal microgliosis, abolished expression of microglial activation markers, and also blocked the functional sensitization observed in isolated cells after ex vivo exposure to lipopolysaccharide. Reduced microglial reactivity with exercise was associated with reinstatement of hippocampus-dependent memory, reversal of deficits in long-term potentiation, and normalization of hippocampal dendritic spine density. Because treadmill training evokes broad responses not limited to the immune system, we next assessed whether directly manipulating adiposity through lipectomy and fat transplantation influences inflammation, cognition, and synaptic plasticity. Lipectomy prevents and fat transplantation promotes systemic and central inflammation, with associated alterations in cognitive and synaptic function. Levels of interleukin 1β (IL1β) emerged as a correlate of adiposity and cognitive impairment across both the treadmill and lipectomy studies, so we manipulated hippocampal IL1 signaling using intrahippocampal delivery of IL1 receptor antagonist (IL1ra). Intrahippocampal IL1ra prevented synaptic dysfunction, proinflammatory priming, and cognitive impairment. This pattern supports a central role for IL1-mediated neuroinflammation as a mechanism for cognitive deficits in obesity and diabetes.

  19. Alterations in hippocampal excitability, synaptic transmission and synaptic plasticity in a neurodevelopmental model of schizophrenia.

    PubMed

    Sanderson, Thomas M; Cotel, Marie-Caroline; O'Neill, Michael J; Tricklebank, Mark D; Collingridge, Graham L; Sher, Emanuele

    2012-03-01

    The risk of developing schizophrenia has been linked to perturbations in embryonic development, but the physiological alterations that result from such insults are incompletely understood. Here, we have investigated aspects of hippocampal physiology in a proposed neurodevelopmental model of schizophrenia, induced during gestation in rats by injection of the antimitotic agent methylazoxymethanol acetate (MAM) at embryonic day 17 (MAM(E17)). We observed a reduction in synaptic innervation and synaptic transmission in the dorsal hippocampus of MAM(E17) treated rats, accompanied by a pronounced increase in CA1 pyramidal neuron excitability. Pharmacological investigations suggested that a deficit in GABAergic inhibition could account for the increase in excitability; furthermore, some aspects of the hyper-excitability could be normalised by the GABA(A) receptor (GABA(A)R) potentiator diazepam. Despite these alterations, two major forms of synaptic plasticity, long-term potentiation (LTP) and long-term depression (LTD) could be readily induced. In contrast, there was a substantial deficit in the reversal of LTP, depotentiation. These findings suggest that delivering neurodevelopmental insults at E17 may offer insights into some of the physiological alterations that underlie behavioural and cognitive symptoms observed in schizophrenia.

  20. The Role of Short Term Synaptic Plasticity in Temporal Coding of Neuronal Networks

    ERIC Educational Resources Information Center

    Chandrasekaran, Lakshmi

    2008-01-01

    Short term synaptic plasticity is a phenomenon which is commonly found in the central nervous system. It could contribute to functions of signal processing namely, temporal integration and coincidence detection by modulating the input synaptic strength. This dissertation has two parts. First, we study the effects of short term synaptic plasticity…

  1. The Role of Short Term Synaptic Plasticity in Temporal Coding of Neuronal Networks

    ERIC Educational Resources Information Center

    Chandrasekaran, Lakshmi

    2008-01-01

    Short term synaptic plasticity is a phenomenon which is commonly found in the central nervous system. It could contribute to functions of signal processing namely, temporal integration and coincidence detection by modulating the input synaptic strength. This dissertation has two parts. First, we study the effects of short term synaptic plasticity…

  2. Mammalian Vestibular Macular Synaptic Plasticity: Results from SLS-2 Spaceflight

    NASA Technical Reports Server (NTRS)

    Ross, Muriel D.D.

    1994-01-01

    The effects of exposure to microgravity were studied in rat utricular maculas collected inflight (IF, day 13), post-flight on day of orbiter landing (day 14, R+O) and after 14 days (R+ML). Controls were collected at corresponding times. The objectives were 1) to learn whether hair cell ribbon synapses counts would be higher in tissues collected in space than in tissues collected postflight during or after readaptation to Earth's gravity; and 2) to compare results with those of SLS-1. Maculas were fixed by immersion, micro-dissected, dehydrated and prepared for ultrastructural study by usual methods. Synapses were counted in 100 serial sections 150 nm thick and were located to specific hair cells in montages of every 7th section. Counts were analyzed for statistical significance using analysis of variance. Results in maculas of IF dissected rats, one 13 day control (IFC), and one R + 0 rat have been analyzed. Study of an R+ML macula is nearly completed. For type I cells, IF mean is 2.3 +/-1.6; IFC mean is 1.6 +/-1.0; R+O mean is 2.3 +/- 1.6. For type II cells, IF mean is 11.4 +/- 17.1; IFC mean is 5.5 +/-3.5; R+O mean is 10.1 +/- 7.4. The difference between IF and IFC means for type I cells is statistically significant (p less than 0.0464). For type It cells, IF compared to IFC means, p less than 0.0003; and for IFC to R+O means, p less than 0.0139. Shifts toward spheres (p less than 0.0001) and pairs (p less than 0.0139) were significant in type II cells of IF rats. The results are largely replicating findings from SLS-1 and indicate that spaceflight affects synaptic number, form and distribution, particularly in type II hair cells. The increases in synaptic number and in sphere-like ribbons are interpreted to improve synaptic efficacy, to help return afferent discharges to a more normal state. Findings indicate that a great capacity for synaptic plasticity exists in mammalian gravity sensors, and that this plasticity is more dominant in the local circuitry. The

  3. Mammalian Vestibular Macular Synaptic Plasticity: Results from SLS-2 Spaceflight

    NASA Technical Reports Server (NTRS)

    Ross, Muriel D.D.

    1994-01-01

    The effects of exposure to microgravity were studied in rat utricular maculas collected inflight (IF, day 13), post-flight on day of orbiter landing (day 14, R+O) and after 14 days (R+ML). Controls were collected at corresponding times. The objectives were 1) to learn whether hair cell ribbon synapses counts would be higher in tissues collected in space than in tissues collected postflight during or after readaptation to Earth's gravity; and 2) to compare results with those of SLS-1. Maculas were fixed by immersion, micro-dissected, dehydrated and prepared for ultrastructural study by usual methods. Synapses were counted in 100 serial sections 150 nm thick and were located to specific hair cells in montages of every 7th section. Counts were analyzed for statistical significance using analysis of variance. Results in maculas of IF dissected rats, one 13 day control (IFC), and one R + 0 rat have been analyzed. Study of an R+ML macula is nearly completed. For type I cells, IF mean is 2.3 +/-1.6; IFC mean is 1.6 +/-1.0; R+O mean is 2.3 +/- 1.6. For type II cells, IF mean is 11.4 +/- 17.1; IFC mean is 5.5 +/-3.5; R+O mean is 10.1 +/- 7.4. The difference between IF and IFC means for type I cells is statistically significant (p less than 0.0464). For type It cells, IF compared to IFC means, p less than 0.0003; and for IFC to R+O means, p less than 0.0139. Shifts toward spheres (p less than 0.0001) and pairs (p less than 0.0139) were significant in type II cells of IF rats. The results are largely replicating findings from SLS-1 and indicate that spaceflight affects synaptic number, form and distribution, particularly in type II hair cells. The increases in synaptic number and in sphere-like ribbons are interpreted to improve synaptic efficacy, to help return afferent discharges to a more normal state. Findings indicate that a great capacity for synaptic plasticity exists in mammalian gravity sensors, and that this plasticity is more dominant in the local circuitry. The

  4. NFAT regulates pre-synaptic development and activity-dependent plasticity in Drosophila

    PubMed Central

    Freeman, Amanda; Franciscovich, Amy; Bowers, Mallory; Sandstrom, David J.; Sanyal, Subhabrata

    2010-01-01

    The calcium-regulated transcription factor NFAT is emerging as a key regulator of neuronal development and plasticity but precise cellular consequences of NFAT function remain poorly understood. Here, we report that the single Drosophila NFAT homolog is widely expressed in the nervous system including motor neurons and unexpectedly controls neural excitability. Likely due to this effect on excitability, NFAT regulates overall larval locomotion and both chronic and acute forms of activity-dependent plasticity at the larval glutamatergic neuro-muscular synapse. Specifically, NFAT-dependent synaptic phenotypes include changes in the number of pre-synaptic boutons, stable modifications in synaptic microtubule architecture and pre-synaptic transmitter release, while no evidence is found for synaptic retraction or alterations in the level of the synaptic cell adhesion molecule FasII. We propose that NFAT regulates pre-synaptic development and constraints long-term plasticity by dampening neuronal excitability. PMID:21185939

  5. Plastic changes in spinal synaptic transmission following botulinum toxin A in patients with post-stroke spasticity.

    PubMed

    Kerzoncuf, Marjorie; Bensoussan, Laurent; Delarque, Alain; Durand, Jacques; Viton, Jean-Michel; Rossi-Durand, Christiane

    2015-11-01

    The therapeutic effects of intramuscular injections of botulinum toxin-type A on spasticity can largely be explained by its blocking action at the neuromuscular junction. Botulinum toxin-type A is also thought to have a central action on the functional organization of the central nervous system. This study assessed the action of botulinum toxin-type A on spinal motor networks by investigating post-activation depression of the soleus H-reflex in post-stroke patients. Post-activation depression, a presynaptic mechanism controlling the synaptic efficacy of Ia-motoneuron transmission, is involved in the pathophysiology of spasticity. Eight patients with chronic hemiplegia post-stroke presenting with lower limb spasticity and requiring botulinum toxin-type A injection in the ankle extensor muscle. Post-activation depression of soleus H-reflex assessed as frequency-related depression of H-reflex was investigated before and 3, 6 and 12 weeks after botulinum toxin-type A injections in the triceps surae. Post-activation depression was quantified as the ratio between H-reflex amplitude at 0.5 and 0.1 Hz. Post-activation depression of soleus H-reflex, which is reduced on the paretic leg, was affected 3 weeks after botulinum toxin-type A injection. Depending on the residual motor capacity of the post-stroke patients, post-activation depression was either restored in patients with preserved voluntary motor control or further reduced in patients with no residual voluntary control. Botulinum toxin treatment induces synaptic plasticity at the Ia-motoneuron synapse in post-stroke paretic patients, which suggests that the effectiveness of botulinum toxin-type A in post-stroke rehabilitation might be partly due to its central effects.

  6. Reelin Supplementation Enhances Cognitive Ability, Synaptic Plasticity, and Dendritic Spine Density

    ERIC Educational Resources Information Center

    Rogers, Justin T.; Rusiana, Ian; Trotter, Justin; Zhao, Lisa; Donaldson, Erika; Pak, Daniel T.S.; Babus, Lenard W.; Peters, Melinda; Banko, Jessica L.; Chavis, Pascale; Rebeck, G. William; Hoe, Hyang-Sook; Weeber, Edwin J.

    2011-01-01

    Apolipoprotein receptors belong to an evolutionarily conserved surface receptor family that has intimate roles in the modulation of synaptic plasticity and is necessary for proper hippocampal-dependent memory formation. The known lipoprotein receptor ligand Reelin is important for normal synaptic plasticity, dendritic morphology, and cognitive…

  7. Histone Deacetylase Inhibition Facilitates Massed Pattern-Induced Synaptic Plasticity and Memory

    ERIC Educational Resources Information Center

    Pandey, Kiran; Sharma, Kaushik P.; Sharma, Shiv K.

    2015-01-01

    Massed training is less effective for long-term memory formation than the spaced training. The role of acetylation in synaptic plasticity and memory is now well established. However, the role of this important protein modification in synaptic plasticity induced by massed pattern of stimulation or memory induced by massed training is not well…

  8. Histone Deacetylase Inhibition Facilitates Massed Pattern-Induced Synaptic Plasticity and Memory

    ERIC Educational Resources Information Center

    Pandey, Kiran; Sharma, Kaushik P.; Sharma, Shiv K.

    2015-01-01

    Massed training is less effective for long-term memory formation than the spaced training. The role of acetylation in synaptic plasticity and memory is now well established. However, the role of this important protein modification in synaptic plasticity induced by massed pattern of stimulation or memory induced by massed training is not well…

  9. Reelin Supplementation Enhances Cognitive Ability, Synaptic Plasticity, and Dendritic Spine Density

    ERIC Educational Resources Information Center

    Rogers, Justin T.; Rusiana, Ian; Trotter, Justin; Zhao, Lisa; Donaldson, Erika; Pak, Daniel T.S.; Babus, Lenard W.; Peters, Melinda; Banko, Jessica L.; Chavis, Pascale; Rebeck, G. William; Hoe, Hyang-Sook; Weeber, Edwin J.

    2011-01-01

    Apolipoprotein receptors belong to an evolutionarily conserved surface receptor family that has intimate roles in the modulation of synaptic plasticity and is necessary for proper hippocampal-dependent memory formation. The known lipoprotein receptor ligand Reelin is important for normal synaptic plasticity, dendritic morphology, and cognitive…

  10. Spike timing analysis in neural networks with unsupervised synaptic plasticity

    NASA Astrophysics Data System (ADS)

    Mizusaki, B. E. P.; Agnes, E. J.; Brunnet, L. G.; Erichsen, R., Jr.

    2013-01-01

    The synaptic plasticity rules that sculpt a neural network architecture are key elements to understand cortical processing, as they may explain the emergence of stable, functional activity, while avoiding runaway excitation. For an associative memory framework, they should be built in a way as to enable the network to reproduce a robust spatio-temporal trajectory in response to an external stimulus. Still, how these rules may be implemented in recurrent networks and the way they relate to their capacity of pattern recognition remains unclear. We studied the effects of three phenomenological unsupervised rules in sparsely connected recurrent networks for associative memory: spike-timing-dependent-plasticity, short-term-plasticity and an homeostatic scaling. The system stability is monitored during the learning process of the network, as the mean firing rate converges to a value determined by the homeostatic scaling. Afterwards, it is possible to measure the recovery efficiency of the activity following each initial stimulus. This is evaluated by a measure of the correlation between spike fire timings, and we analysed the full memory separation capacity and limitations of this system.

  11. Endocannabinoid System and Synaptic Plasticity: Implications for Emotional Responses

    PubMed Central

    Viveros, María-Paz; Marco, Eva-María; Llorente, Ricardo; López-Gallardo, Meritxell

    2007-01-01

    The endocannabinoid system has been involved in the regulation of anxiety, and proposed as an inhibitory modulator of neuronal, behavioral and adrenocortical responses to stressful stimuli. Brain regions such as the amygdala, hippocampus and cortex, which are directly involved in the regulation of emotional behavior, contain high densities of cannabinoid CB1 receptors. Mutant mice lacking CB1 receptors show anxiogenic and depressive-like behaviors as well as an altered hypothalamus pituitary adrenal axis activity, whereas enhancement of endocannabinoid signaling produces anxiolytic and antidepressant-like effects. Genetic and pharmacological approaches also support an involvement of endocannabinoids in extinction of aversive memories. Thus, the endocannabinoid system appears to play a pivotal role in the regulation of emotional states. Endocannabinoids have emerged as mediators of short- and long-term synaptic plasticity in diverse brain structures. Despite the fact that most of the studies on this field have been performed using in vitro models, endocannabinoid-mediated plasticity might be considered as a plausible candidate underlying some of the diverse physiological functions of the endogenous cannabinoid system, including developmental, affective and cognitive processes. In this paper, we will focus on the functional relevance of endocannabinoid-mediated plasticity within the framework of emotional responses. Alterations of the endocannabinoid system may constitute an important factor in the aetiology of certain neuropsychiatric disorders, and, in turn, enhancers of endocannabinoid signaling could represent a potential therapeutical tool in the treatment of both anxiety and depressive symptoms. PMID:17641734

  12. Natural Firing Patterns Imply Low Sensitivity of Synaptic Plasticity to Spike Timing Compared with Firing Rate

    PubMed Central

    Wallisch, Pascal; Ostojic, Srdjan

    2016-01-01

    Synaptic plasticity is sensitive to the rate and the timing of presynaptic and postsynaptic action potentials. In experimental protocols inducing plasticity, the imposed spike trains are typically regular and the relative timing between every presynaptic and postsynaptic spike is fixed. This is at odds with firing patterns observed in the cortex of intact animals, where cells fire irregularly and the timing between presynaptic and postsynaptic spikes varies. To investigate synaptic changes elicited by in vivo-like firing, we used numerical simulations and mathematical analysis of synaptic plasticity models. We found that the influence of spike timing on plasticity is weaker than expected from regular stimulation protocols. Moreover, when neurons fire irregularly, synaptic changes induced by precise spike timing can be equivalently induced by a modest firing rate variation. Our findings bridge the gap between existing results on synaptic plasticity and plasticity occurring in vivo, and challenge the dominant role of spike timing in plasticity. SIGNIFICANCE STATEMENT Synaptic plasticity, the change in efficacy of connections between neurons, is thought to underlie learning and memory. The dominant paradigm posits that the precise timing of neural action potentials (APs) is central for plasticity induction. This concept is based on experiments using highly regular and stereotyped patterns of APs, in stark contrast with natural neuronal activity. Using synaptic plasticity models, we investigated how irregular, in vivo-like activity shapes synaptic plasticity. We found that synaptic changes induced by precise timing of APs are much weaker than suggested by regular stimulation protocols, and can be equivalently induced by modest variations of the AP rate alone. Our results call into question the dominant role of precise AP timing for plasticity in natural conditions. PMID:27807166

  13. Adenosine gates synaptic plasticity at hippocampal mossy fiber synapses

    NASA Astrophysics Data System (ADS)

    Moore, Kimberly A.; Nicoll, Roger A.; Schmitz, Dietmar

    2003-11-01

    The release properties of synapses in the central nervous system vary greatly, not only across anatomically distinct types of synapses but also among the same class of synapse. This variation manifests itself in large part by differences in the probability of transmitter release, which affects such activity-dependent presynaptic forms of plasticity as paired-pulse facilitation and frequency facilitation. This heterogeneity in presynaptic function reflects differences in the intrinsic properties of the synaptic terminal and the activation of presynaptic neurotransmitter receptors. Here we show that the unique presynaptic properties of the hippocampal mossy fiber synapse are largely imparted onto the synapse by the continuous local action of extracellular adenosine at presynaptic A1 adenosine receptors, which maintains a low basal probability of transmitter release.

  14. Circadian Mechanisms Underlying Reward-Related Neurophysiology and Synaptic Plasticity

    PubMed Central

    Parekh, Puja K.; McClung, Colleen A.

    2016-01-01

    Evidence from clinical and preclinical research provides an undeniable link between disruptions in the circadian clock and the development of psychiatric diseases, including mood and substance abuse disorders. The molecular clock, which controls daily patterns of physiological and behavioral activity in living organisms, when desynchronized, may exacerbate or precipitate symptoms of psychiatric illness. One of the outstanding questions remaining in this field is that of cause and effect in the relationship between circadian rhythm disruption and psychiatric disease. Focus has recently turned to uncovering the role of circadian proteins beyond the maintenance of homeostatic systems and outside of the suprachiasmatic nucleus (SCN), the master pacemaker region of the brain. In this regard, several groups, including our own, have sought to understand how circadian proteins regulate mechanisms of synaptic plasticity and neurotransmitter signaling in mesocorticolimbic brain regions, which are known to be critically involved in reward processing and mood. This regulation can come in the form of direct transcriptional control of genes central to mood and reward, including those associated with dopaminergic activity in the midbrain. It can also be seen at the circuit level through indirect connections of mesocorticolimbic regions with the SCN. Circadian misalignment paradigms as well as genetic models of circadian disruption have helped to elucidate some of the complex interactions between these systems and neural activity influencing behavior. In this review, we explore findings that link circadian protein function with synaptic adaptations underlying plasticity as it may contribute to the development of mood disorders and addiction. In light of recent advances in technology and sophisticated methods for molecular and circuit-level interrogation, we propose future directions aimed at teasing apart mechanisms through which the circadian system modulates mood and reward

  15. Pannexin1 Stabilizes Synaptic Plasticity and Is Needed for Learning

    PubMed Central

    Kurtenbach, Stefan; Wildförster, Verena; Dvoriantchikova, Galina; Hanske, Julian; Petrasch-Parwez, Elisabeth; Shestopalov, Valery I.; Dermietzel, Rolf; Manahan-Vaughan, Denise; Zoidl, Georg

    2012-01-01

    Pannexin 1 (Panx1) represents a class of vertebrate membrane channels, bearing significant sequence homology with the invertebrate gap junction proteins, the innexins and more distant similarities in the membrane topologies and pharmacological sensitivities with gap junction proteins of the connexin family. In the nervous system, cooperation among pannexin channels, adenosine receptors, and KATP channels modulating neuronal excitability via ATP and adenosine has been recognized, but little is known about the significance in vivo. However, the localization of Panx1 at postsynaptic sites in hippocampal neurons and astrocytes in close proximity together with the fundamental role of ATP and adenosine for CNS metabolism and cell signaling underscore the potential relevance of this channel to synaptic plasticity and higher brain functions. Here, we report increased excitability and potently enhanced early and persistent LTP responses in the CA1 region of acute slice preparations from adult Panx1−/− mice. Adenosine application and N-methyl-D-aspartate receptor (NMDAR)-blocking normalized this phenotype, suggesting that absence of Panx1 causes chronic extracellular ATP/adenosine depletion, thus facilitating postsynaptic NMDAR activation. Compensatory transcriptional up-regulation of metabotropic glutamate receptor 4 (grm4) accompanies these adaptive changes. The physiological modification, promoted by loss of Panx1, led to distinct behavioral alterations, enhancing anxiety and impairing object recognition and spatial learning in Panx1−/− mice. We conclude that ATP release through Panx1 channels plays a critical role in maintaining synaptic strength and plasticity in CA1 neurons of the adult hippocampus. This result provides the rationale for in-depth analysis of Panx1 function and adenosine based therapies in CNS disorders. PMID:23284764

  16. Synaptic potentials of primary afferent fibers and motoneurons evoked by single intermediate nucleus interneurons in the cat spinal cord.

    PubMed

    Rudomin, P; Solodkin, M; Jiménez, I

    1987-05-01

    Spike-triggered averaging of dorsal and ventral root potentials was used in anesthetized cats to disclose possible synaptic connections of spinal interneurons in the intermediate nucleus with afferent fibers and/or motoneurons. With this method we have been able to document the existence of a distinct group of interneurons whose activity was associated with the recording of inhibitory potentials in the ventral roots (iVRPs), but not with negative dorsal root potentials (nDRPs). The iVRPs had mean durations of 60.8 +/- 22.1 ms and latencies between 1.7 and 5.1 ms relative to the onset of the interneuronal spikes. Within this group of neurons it was possible to characterize two categories depending on their responses to segmental inputs. Most type A interneurons were mono- or disynaptically activated by group I muscle afferents and polysynaptically by low threshold (1.08-1.69 X T) cutaneous fibers. Type B interneurons were instead polysynaptically activated by group II muscle and by cutaneous fibers with thresholds ranging from 1.02 to 3.1 X T. Whenever tested, both type A and B interneurons could be antidromically activated from Clarke's columns. There was a second group of interneurons whose activity was associated with the generation of both iVRPs and nDRPs. These potentials had mean durations of 107.5 +/- 35.6 and 131.5 +/- 32 ms, respectively, and onset latencies between 1.7 and 6.1 ms. The interneurons belonging to this group, which appear not to send axonal projections to Clarke's column, could be classified in three categories depending on their responses to peripheral inputs. Type C interneurons responded mono- or disynaptically to group I muscle volleys and polysynaptically to intermediate threshold (1.22-2.7 X T) cutaneous afferents. Type D interneurons were polysynaptically activated by group II muscle afferents (2.3-8.5 X T) and by intermediate threshold (1.4-3 X T) cutaneous fibers and type E interneurons only by group I muscle afferents with mono- or

  17. Sleep recalibrates homeostatic and associative synaptic plasticity in the human cortex

    PubMed Central

    Kuhn, Marion; Wolf, Elias; Maier, Jonathan G.; Mainberger, Florian; Feige, Bernd; Schmid, Hanna; Bürklin, Jan; Maywald, Sarah; Mall, Volker; Jung, Nikolai H.; Reis, Janine; Spiegelhalder, Kai; Klöppel, Stefan; Sterr, Annette; Eckert, Anne; Riemann, Dieter; Normann, Claus; Nissen, Christoph

    2016-01-01

    Sleep is ubiquitous in animals and humans, but its function remains to be further determined. The synaptic homeostasis hypothesis of sleep–wake regulation proposes a homeostatic increase in net synaptic strength and cortical excitability along with decreased inducibility of associative synaptic long-term potentiation (LTP) due to saturation after sleep deprivation. Here we use electrophysiological, behavioural and molecular indices to non-invasively study net synaptic strength and LTP-like plasticity in humans after sleep and sleep deprivation. We demonstrate indices of increased net synaptic strength (TMS intensity to elicit a predefined amplitude of motor-evoked potential and EEG theta activity) and decreased LTP-like plasticity (paired associative stimulation induced change in motor-evoked potential and memory formation) after sleep deprivation. Changes in plasma BDNF are identified as a potential mechanism. Our study indicates that sleep recalibrates homeostatic and associative synaptic plasticity, believed to be the neural basis for adaptive behaviour, in humans. PMID:27551934

  18. Sleep recalibrates homeostatic and associative synaptic plasticity in the human cortex.

    PubMed

    Kuhn, Marion; Wolf, Elias; Maier, Jonathan G; Mainberger, Florian; Feige, Bernd; Schmid, Hanna; Bürklin, Jan; Maywald, Sarah; Mall, Volker; Jung, Nikolai H; Reis, Janine; Spiegelhalder, Kai; Klöppel, Stefan; Sterr, Annette; Eckert, Anne; Riemann, Dieter; Normann, Claus; Nissen, Christoph

    2016-08-23

    Sleep is ubiquitous in animals and humans, but its function remains to be further determined. The synaptic homeostasis hypothesis of sleep-wake regulation proposes a homeostatic increase in net synaptic strength and cortical excitability along with decreased inducibility of associative synaptic long-term potentiation (LTP) due to saturation after sleep deprivation. Here we use electrophysiological, behavioural and molecular indices to non-invasively study net synaptic strength and LTP-like plasticity in humans after sleep and sleep deprivation. We demonstrate indices of increased net synaptic strength (TMS intensity to elicit a predefined amplitude of motor-evoked potential and EEG theta activity) and decreased LTP-like plasticity (paired associative stimulation induced change in motor-evoked potential and memory formation) after sleep deprivation. Changes in plasma BDNF are identified as a potential mechanism. Our study indicates that sleep recalibrates homeostatic and associative synaptic plasticity, believed to be the neural basis for adaptive behaviour, in humans.

  19. Abnormal cortical synaptic plasticity in minimal hepatic encephalopathy.

    PubMed

    Golaszewski, Stefan; Langthaler, Patrick B; Schwenker, Kerstin; Florea, Cristina; Christova, Monica; Brigo, Francesco; Trinka, Eugen; Nardone, Raffaele

    2016-07-01

    Minimal hepatic encephalopathy (MHE) represents the earliest stage of hepatic encephalopathy (HE). MHE is characterized by cognitive function impairment in the domains of attention, vigilance and integrative function, while obvious clinical manifestations are lacking. In the present study, we aimed at assessing whether subjects with MHE showed alterations in synaptic plasticity within the motor cortex. Previous findings suggest that learning in human motor cortex occurs through long-term potentiation (LTP)-like mechanisms. We employed therefore the paired associative stimulation (PAS) protocol by transcranial magnetic stimulation (TMS), which is able to induce LTP-like effects in the motor cortex of normal subjects. Fifteen patients with MHE and 15 age- and sex-matched cirrhotic patients without MHE were recruited. PAS consisted of 180 electrical stimuli of the right median nerve paired with a single TMS over the hotspot of right abductor pollicis brevis (APB) at an ISI of 25ms (PAS25). We measured motor evoked potentials (MEPs) before and after each intervention for up to 30min. In healthy subjects the PAS25 protocol was followed by a significant increase of the MEP amplitude. On the contrary, in patients with MHE the MEP amplitude was slightly reduced after PAS. These findings demonstrated that associative sensorimotor plasticity, an indirect probe for motor learning, is impaired in MHE patients. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. 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

  1. Fructose consumption reduces hippocampal synaptic plasticity underlying cognitive performance.

    PubMed

    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

    2015-11-01

    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 7weeks. 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. Crown Copyright © 2015. Published by Elsevier B.V. All rights reserved.

  2. Neuromodulation and metamodulation by adenosine: Impact and subtleties upon synaptic plasticity regulation.

    PubMed

    Sebastião, Ana M; Ribeiro, Joaquim A

    2015-09-24

    Synaptic plasticity mechanisms, i.e. the sequence of events that underlies persistent changes in synaptic strength as a consequence of transient alteration in neuronal firing, are greatly influenced by the 'chemical atmosphere' of the synapses, that is to say by the presence of molecules at the synaptic cleft able to fine-tune the activity of other molecules more directly related to plasticity. One of those fine tuners is adenosine, known for a long time as an ubiquitous neuromodulator and metamodulator and recognized early as influencing synaptic plasticity. In this review we will refer to the mechanisms that adenosine can use to affect plasticity, emphasizing aspects of the neurobiology of adenosine relevant to its ability to control synaptic functioning. This article is part of a Special Issue entitled Brain and Memory.

  3. A unifying theory of synaptic long-term plasticity based on a sparse distribution of synaptic strength

    PubMed Central

    Krieg, Daniel; Triesch, Jochen

    2014-01-01

    Long-term synaptic plasticity is fundamental to learning and network function. It has been studied under various induction protocols and depends on firing rates, membrane voltage, and precise timing of action potentials. These protocols show different facets of a common underlying mechanism but they are mostly modeled as distinct phenomena. Here, we show that all of these different dependencies can be explained from a single computational principle. The objective is a sparse distribution of excitatory synaptic strength, which may help to reduce metabolic costs associated with synaptic transmission. Based on this objective we derive a stochastic gradient ascent learning rule which is of differential-Hebbian type. It is formulated in biophysical quantities and can be related to current mechanistic theories of synaptic plasticity. The learning rule accounts for experimental findings from all major induction protocols and explains a classic phenomenon of metaplasticity. Furthermore, our model predicts the existence of metaplasticity for spike-timing-dependent plasticity Thus, we provide a theory of long-term synaptic plasticity that unifies different induction protocols and provides a connection between functional and mechanistic levels of description. PMID:24624080

  4. Calcium dynamics predict direction of synaptic plasticity in striatal spiny projection neurons.

    PubMed

    Jędrzejewska-Szmek, Joanna; Damodaran, Sriraman; Dorman, Daniel B; Blackwell, Kim T

    2017-04-01

    The striatum is a major site of learning and memory formation for sensorimotor and cognitive association. One of the mechanisms used by the brain for memory storage is synaptic plasticity - the long-lasting, activity-dependent change in synaptic strength. All forms of synaptic plasticity require an elevation in intracellular calcium, and a common hypothesis is that the amplitude and duration of calcium transients can determine the direction of synaptic plasticity. The utility of this hypothesis in the striatum is unclear in part because dopamine is required for striatal plasticity and in part because of the diversity in stimulation protocols. To test whether calcium can predict plasticity direction, we developed a calcium-based plasticity rule using a spiny projection neuron model with sophisticated calcium dynamics including calcium diffusion, buffering and pump extrusion. We utilized three spike timing-dependent plasticity (STDP) induction protocols, in which postsynaptic potentials are paired with precisely timed action potentials and the timing of such pairing determines whether potentiation or depression will occur. Results show that despite the variation in calcium dynamics, a single, calcium-based plasticity rule, which explicitly considers duration of calcium elevations, can explain the direction of synaptic weight change for all three STDP protocols. Additional simulations show that the plasticity rule correctly predicts the NMDA receptor dependence of long-term potentiation and the L-type channel dependence of long-term depression. By utilizing realistic calcium dynamics, the model reveals mechanisms controlling synaptic plasticity direction, and shows that the dynamics of calcium, not just calcium amplitude, are crucial for synaptic plasticity. © 2016 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

  5. The origin of glutamatergic synaptic inputs controls synaptic plasticity and its modulation by alcohol in mice nucleus accumbens

    PubMed Central

    Ji, Xincai; Saha, Sucharita; Martin, Gilles E.

    2015-01-01

    It is widely accepted that long-lasting changes of synaptic strength in the nucleus accumbens (NAc), a brain region involved in drug reward, mediate acute and chronic effects of alcohol. However, our understanding of the mechanisms underlying the effects of alcohol on synaptic plasticity is limited by the fact that the NAc receives glutamatergic inputs from distinct brain regions (e.g., the prefrontal cortex (PFCx), the amygdala and the hippocampus), each region providing different information (e.g., spatial, emotional and cognitive). Combining whole-cell patch-clamp recordings and the optogenetic technique, we examined synaptic plasticity, and its regulation by alcohol, at cortical, hippocampal and amygdala inputs in fresh slices of mouse tissue. We showed that the origin of synaptic inputs determines the basic properties of glutamatergic synaptic transmission, the expression of spike-timing dependent long-term depression (tLTD) and long-term potentiation (LTP) and long-term potentiation (tLTP) and their regulation by alcohol. While we observed both tLTP and tLTD at amygadala and hippocampal synapses, we showed that cortical inputs only undergo tLTD. Functionally, we provide evidence that acute Ethyl Alcohol (EtOH) has little effects on higher order information coming from the PFCx, while severely impacting the ability of emotional and contextual information to induce long-lasting changes of synaptic strength. PMID:26257641

  6. Synaptic plasticity preserved with arachidonic acid diet in aged rats.

    PubMed

    Kotani, Susumu; Nakazawa, Hiroe; Tokimasa, Takayuki; Akimoto, Kengo; Kawashima, Hiroshi; Toyoda-Ono, Yoshiko; Kiso, Yoshinobu; Okaichi, Hiroshige; Sakakibara, Manabu

    2003-08-01

    We examined whether synaptic plasticity was preserved in aged rats administered an arachidonic acid (AA) containing diet. Young male Fischer-344 rats (2 mo of age), and two groups of aged rats of the same strain (2 y of age) who consumed either a control diet or an AA ethyl ester-containing diet for at least 3 mo were used. In the Morris water maze task, aged rats on the AA diet had tendency to show better performance than aged rats on the control diet. Long-term potentiation induced by tetanic stimulation was recorded from a 300 microm thick hippocampal slice with a 36 multi-electrode-array positioned at the dendrites of CA1 pyramidal neurons. The degree of potentiation after 1 h in aged rats on the AA diet was comparable as that of young controls. Phospholipid analysis revealed that AA and docosahexaenoic acid were the major fatty acids in the hippocampus in aged rats. There was a correlation between the behavioral measure and the changes in excitatory postsynaptic potential slope and between the physiologic measure and the total amount of AA in hippocampus.

  7. Synchrony arising from a balanced synaptic plasticity in a network of heterogeneous neural oscillators

    NASA Astrophysics Data System (ADS)

    Karbowski, Jan; Ermentrout, G. Bard

    2002-03-01

    We investigate the dynamics of a recurrent network of coupled heterogeneous neural oscillators with experimentally observed spike-timing-dependent synaptic plasticity. We show both theoretically and by computer simulations that, in a regime of a balance between synaptic potentiation and depression, the network of such oscillators converges to a stable synchronous state. The stability of this state is fostered by flexible synaptic weights which adjust themselves based on the relative timing of firing of pre- and postsynaptic oscillators.

  8. MYOSIN IIB REGULATES ACTIN DYNAMICS DURING SYNAPTIC PLASTICITY AND MEMORY FORMATION

    PubMed Central

    Rex, Christopher S.; Gavin, Cristin F.; Rubio, Maria D.; Kramar, Eniko A.; Chen, Lulu Y.; Jia, Yousheng; Huganir, Richard L.; Muzyczka, Nicholas; Gall, Christine M.; Miller, Courtney A.; Lynch, Gary; Rumbaugh, Gavin

    2010-01-01

    Reorganization of the actin cytoskeleton is essential for synaptic plasticity and memory formation. Presently, the mechanisms that trigger actin dynamics during these brain processes are poorly understood. In this study, we show that myosin II motor activity is downstream of LTP induction and is necessary for the emergence of specialized actin structures that stabilize an early phase of LTP. We also demonstrate that myosin II activity contributes importantly to an actin-dependent process that underlies memory consolidation. Pharmacological treatments that promote actin polymerization reversed the effects of a myosin II inhibitor on LTP and memory. We conclude that myosin II motors regulate plasticity by imparting mechanical forces onto the spine actin cytoskeleton in response to synaptic stimulation. These cytoskeletal forces trigger the emergence of actin structures that stabilize synaptic plasticity. Our studies provide a novel mechanical framework for understanding cytoskeletal dynamics associated with synaptic plasticity and memory formation. PMID:20797537

  9. Phosphorylation of Complexin by PKA Regulates Activity-dependent Spontaneous Neurotransmitter Release and Structural Synaptic Plasticity

    PubMed Central

    Cho, Richard W.; Buhl, Lauren K.; Volfson, Dina; Tran, Adrienne; Li, Feng; Akbergenova, Yulia; Littleton, J. Troy

    2016-01-01

    Summary Synaptic plasticity is a fundamental feature of the nervous system that allows adaptation to changing behavioral environments. Most studies of synaptic plasticity have examined the regulated trafficking of postsynaptic glutamate receptors that generates alterations in synaptic transmission. Whether and how changes in the presynaptic release machinery contribute to neuronal plasticity is less clear. The SNARE complex mediates neurotransmitter release in response to presynaptic Ca++ entry. Here we show that the SNARE fusion clamp Complexin undergoes activity-dependent phosphorylation that alters the basic properties of neurotransmission in Drosophila. Retrograde signaling following stimulation activates PKA-dependent phosphorylation of the Complexin C-terminus that selectively and transiently enhances spontaneous release. Enhanced spontaneous release is required for activity-dependent synaptic growth. These data indicate that SNARE-dependent fusion mechanisms can be regulated in an activity-dependent manner and highlight the key role of spontaneous neurotransmitter release as a mediator of functional and structural plasticity. PMID:26590346

  10. The Formation of Multi-synaptic Connections by the Interaction of Synaptic and Structural Plasticity and Their Functional Consequences

    PubMed Central

    Fauth, Michael; Wörgötter, Florentin; Tetzlaff, Christian

    2015-01-01

    Cortical connectivity emerges from the permanent interaction between neuronal activity and synaptic as well as structural plasticity. An important experimentally observed feature of this connectivity is the distribution of the number of synapses from one neuron to another, which has been measured in several cortical layers. All of these distributions are bimodal with one peak at zero and a second one at a small number (3–8) of synapses. In this study, using a probabilistic model of structural plasticity, which depends on the synaptic weights, we explore how these distributions can emerge and which functional consequences they have. We find that bimodal distributions arise generically from the interaction of structural plasticity with synaptic plasticity rules that fulfill the following biological realistic constraints: First, the synaptic weights have to grow with the postsynaptic activity. Second, this growth curve and/or the input-output relation of the postsynaptic neuron have to change sub-linearly (negative curvature). As most neurons show such input-output-relations, these constraints can be fulfilled by many biological reasonable systems. Given such a system, we show that the different activities, which can explain the layer-specific distributions, correspond to experimentally observed activities. Considering these activities as working point of the system and varying the pre- or postsynaptic stimulation reveals a hysteresis in the number of synapses. As a consequence of this, the connectivity between two neurons can be controlled by activity but is also safeguarded against overly fast changes. These results indicate that the complex dynamics between activity and plasticity will, already between a pair of neurons, induce a variety of possible stable synaptic distributions, which could support memory mechanisms. PMID:25590330

  11. Short-Term Synaptic Plasticity at Interneuronal Synapses Could Sculpt Rhythmic Motor Patterns

    PubMed Central

    Jia, Yan; Parker, David

    2016-01-01

    The output of a neuronal network depends on the organization and functional properties of its component cells and synapses. While the characterization of synaptic properties has lagged cellular analyses, a potentially important aspect in rhythmically active networks is how network synapses affect, and are in turn affected by, network activity. This could lead to a potential circular interaction where short-term activity-dependent synaptic plasticity is both influenced by and influences the network output. The analysis of synaptic plasticity in the lamprey locomotor network was extended here to characterize the short-term plasticity of connections between network interneurons and to try and address its potential network role. Paired recordings from identified interneurons in quiescent networks showed synapse-specific synaptic properties and plasticity that supported the presence of two hemisegmental groups that could influence bursting: depression in an excitatory interneuron group, and facilitation in an inhibitory feedback circuit. The influence of activity-dependent synaptic plasticity on network activity was investigated experimentally by changing Ringer Ca2+ levels, and in a simple computer model. A potential caveat of the experimental analyses was that changes in Ringer Ca2+ (and compensatory adjustments in Mg2+ in some cases) could alter several other cellular and synaptic properties. Several of these properties were tested, and while there was some variability, these were not usually significantly affected by the Ringer changes. The experimental analyses suggested that depression of excitatory inputs had the strongest influence on the patterning of network activity. The simulation supported a role for this effect, and also suggested that the inhibitory facilitating group could modulate the influence of the excitatory synaptic depression. Short-term activity-dependent synaptic plasticity has not generally been considered in spinal cord models. These results

  12. A single in-vivo exposure to delta 9THC blocks endocannabinoid-mediated synaptic plasticity.

    PubMed

    Mato, Susana; Chevaleyre, Vivien; Robbe, David; Pazos, Angel; Castillo, Pablo E; Manzoni, Olivier J

    2004-06-01

    Endogenous cannabinoids (eCB) mediate synaptic plasticity in brain regions involved in learning and reward. Here we show that in mice, a single in-vivo exposure to Delta 9-tetrahydrocannabinol (THC) abolishes the retrograde signaling that underlies eCB-mediated synaptic plasticity in both nucleus accumbens (NAc) and hippocampus in vitro. This effect is reversible within 3 days and is associated with a transient modification in the functional properties of cannabinoid receptors.

  13. Coexistence of Multiple Types of Synaptic Plasticity in Individual Hippocampal CA1 Pyramidal Neurons.

    PubMed

    Edelmann, Elke; Cepeda-Prado, Efrain; Leßmann, Volkmar

    2017-01-01

    Understanding learning and memory mechanisms is an important goal in neuroscience. To gain insights into the underlying cellular mechanisms for memory formation, synaptic plasticity processes are studied with various techniques in different brain regions. A valid model to scrutinize different ways to enhance or decrease synaptic transmission is recording of long-term potentiation (LTP) or long-term depression (LTD). At the single cell level, spike timing-dependent plasticity (STDP) protocols have emerged as a powerful tool to investigate synaptic plasticity with stimulation paradigms that also likely occur during memory formation in vivo. Such kind of plasticity can be induced by different STDP paradigms with multiple repeat numbers and stimulation patterns. They subsequently recruit or activate different molecular pathways and neuromodulators for induction and expression of STDP. Dopamine (DA) and brain-derived neurotrophic factor (BDNF) have been recently shown to be important modulators for hippocampal STDP at Schaffer collateral (SC)-CA1 synapses and are activated exclusively by distinguishable STDP paradigms. Distinct types of parallel synaptic plasticity in a given neuron depend on specific subcellular molecular prerequisites. Since the basal and apical dendrites of CA1 pyramidal neurons are known to be heterogeneous, and distance-dependent dendritic gradients for specific receptors and ion channels are described, the dendrites might provide domain specific locations for multiple types of synaptic plasticity in the same neuron. In addition to the distinct signaling and expression mechanisms of various types of LTP and LTD, activation of these different types of plasticity might depend on background brain activity states. In this article, we will discuss some ideas why multiple forms of synaptic plasticity can simultaneously and independently coexist and can contribute so effectively to increasing the efficacy of memory storage and processing capacity of the

  14. Actin Tyrosine-53-Phosphorylation in Neuronal Maturation and Synaptic Plasticity.

    PubMed

    Bertling, Enni; Englund, Jonas; Minkeviciene, Rimante; Koskinen, Mikko; Segerstråle, Mikael; Castrén, Eero; Taira, Tomi; Hotulainen, Pirta

    2016-05-11

    Rapid reorganization and stabilization of the actin cytoskeleton in dendritic spines enables cellular processes underlying learning, such as long-term potentiation (LTP). Dendritic spines are enriched in exceptionally short and dynamic actin filaments, but the studies so far have not revealed the molecular mechanisms underlying the high actin dynamics in dendritic spines. Here, we show that actin in dendritic spines is dynamically phosphorylated at tyrosine-53 (Y53) in rat hippocampal and cortical neurons. Our findings show that actin phosphorylation increases the turnover rate of actin filaments and promotes the short-term dynamics of dendritic spines. During neuronal maturation, actin phosphorylation peaks at the first weeks of morphogenesis, when dendritic spines form, and the amount of Y53-phosphorylated actin decreases when spines mature and stabilize. Induction of LTP transiently increases the amount of phosphorylated actin and LTP induction is deficient in neurons expressing mutant actin that mimics phosphorylation. Actin phosphorylation provides a molecular mechanism to maintain the high actin dynamics in dendritic spines during neuronal development and to induce fast reorganization of the actin cytoskeleton in synaptic plasticity. In turn, dephosphorylation of actin is required for the stabilization of actin filaments that is necessary for proper dendritic spine maturation and LTP maintenance. Dendritic spines are small protrusions from neuronal dendrites where the postsynaptic components of most excitatory synapses reside. Precise control of dendritic spine morphology and density is critical for normal brain function. Accordingly, aberrant spine morphology is linked to many neurological diseases. The actin cytoskeleton is a structural element underlying the proper morphology of dendritic spines. Therefore, defects in the regulation of the actin cytoskeleton in neurons have been implicated in neurological diseases. Here, we revealed a novel mechanism for

  15. Modulation of Synaptic Plasticity by Exercise Training as a Basis for Ischemic Stroke Rehabilitation.

    PubMed

    Nie, Jingjing; Yang, Xiaosu

    2017-01-01

    In recent years, rehabilitation of ischemic stroke draws more and more attention in the world, and has been linked to changes of synaptic plasticity. Exercise training improves motor function of ischemia as well as cognition which is associated with formation of learning and memory. The molecular basis of learning and memory might be synaptic plasticity. Research has therefore been conducted in an attempt to relate effects of exercise training to neuroprotection and neurogenesis adjacent to the ischemic injury brain. The present paper reviews the current literature addressing this question and discusses the possible mechanisms involved in modulation of synaptic plasticity by exercise training. This review shows the pathological process of synaptic dysfunction in ischemic roughly and then discusses the effects of exercise training on scaffold proteins and regulatory protein expression. The expression of scaffold proteins generally increased after training, but the effects on regulatory proteins were mixed. Moreover, the compositions of postsynaptic receptors were changed and the strength of synaptic transmission was enhanced after training. Finally, the recovery of cognition is critically associated with synaptic remodeling in an injured brain, and the remodeling occurs through a number of local regulations including mRNA translation, remodeling of cytoskeleton, and receptor trafficking into and out of the synapse. We do provide a comprehensive knowledge of synaptic plasticity enhancement obtained by exercise training in this review.

  16. Reelin supplementation recovers synaptic plasticity and cognitive deficits in a mouse model for Angelman syndrome.

    PubMed

    Hethorn, Whitney R; Ciarlone, Stephanie L; Filonova, Irina; Rogers, Justin T; Aguirre, Daniela; Ramirez, Raquel A; Grieco, Joseph C; Peters, Melinda M; Gulick, Danielle; Anderson, Anne E; L Banko, Jessica; Lussier, April L; Weeber, Edwin J

    2015-05-01

    The Reelin signaling pathway is implicated in processes controlling synaptic plasticity and hippocampus-dependent learning and memory. A single direct in vivo application of Reelin enhances long-term potentiation, increases dendritic spine density and improves associative and spatial learning and memory. Angelman syndrome (AS) is a neurological disorder that presents with an overall defect in synaptic function, including decreased long-term potentiation, reduced dendritic spine density, and deficits in learning and memory, making it an attractive model in which to examine the ability of Reelin to recover synaptic function and cognitive deficits. In this study, we investigated the effects of Reelin administration on synaptic plasticity and cognitive function in a mouse model of AS and demonstrated that bilateral, intraventricular injections of Reelin recover synaptic function and corresponding hippocampus-dependent associative and spatial learning and memory. Additionally, we describe alteration of the Reelin profile in tissue from both the AS mouse and post-mortem human brain.

  17. Bidirectional Synaptic Structural Plasticity after Chronic Cocaine Administration Occurs through Rap1 Small GTPase Signaling.

    PubMed

    Cahill, Michael E; Bagot, Rosemary C; Gancarz, Amy M; Walker, Deena M; Sun, HaoSheng; Wang, Zi-Jun; Heller, Elizabeth A; Feng, Jian; Kennedy, Pamela J; Koo, Ja Wook; Cates, Hannah M; Neve, Rachael L; Shen, Li; Dietz, David M; Nestler, Eric J

    2016-02-03

    Dendritic spines are the sites of most excitatory synapses in the CNS, and opposing alterations in the synaptic structure of medium spiny neurons (MSNs) of the nucleus accumbens (NAc), a primary brain reward region, are seen at early versus late time points after cocaine administration. Here we investigate the time-dependent molecular and biochemical processes that regulate this bidirectional synaptic structural plasticity of NAc MSNs and associated changes in cocaine reward in response to chronic cocaine exposure. Our findings reveal key roles for the bidirectional synaptic expression of the Rap1b small GTPase and an associated local synaptic protein translation network in this process. The transcriptional mechanisms and pathway-specific inputs to NAc that regulate Rap1b expression are also characterized. Collectively, these findings provide a precise mechanism by which nuclear to synaptic interactions induce "metaplasticity" in NAc MSNs, and we reveal the specific effects of this plasticity on reward behavior in a brain circuit-specific manner.

  18. Excitatory post-synaptic potentials from single muscle spindle afferents in external intercostal motoneurones of the cat.

    PubMed Central

    Kirkwood, P A; Sears, T A

    1982-01-01

    1. The discharges of muscle spindle afferents from the external intercostal muscles of anaesthetized, paralysed cats were recorded from dorsal roots in continuity. The dynamic responses, regularities of firing and conduction velocities of the afferents were measured and used to characterize the afferents as primary-like or secondary-like. 2. The synchronization of afferent discharges was investigated by the construction of cross-correlation histograms from the simultaneously recorded discharges of pairs of afferents. The discharges of primary-like afferents with high dynamic responses were found to be synchronized within a few msec. The cardiac pulse was a strong contributary factor in this synchronization. 3. Intracellular recordings were made from external intercostal motoneurones, and spike-triggered averaging was used to reveal unitary e.p.s.p.s evoked by muscle spindle afferents which were from the same spinal cord segment. Dorsal roots other than the rootlet containing the afferent were cut to prevent the synchronization of afferent discharges from affecting the averaged e.p.s.p.s. 4. For primary-like afferents the mean amplitude of the e.p.s.p.s was 171 microV and the mean connectivity (the proportion of motoneurones connected by one afferent) was between 42 and 48%. 5. The amplitudes and shapes of the e.p.s.p.s varied with the respiratory phase, usually being larger in inspiration than in expiration and sometimes also having a longer time course. In particular some e.p.s.p.s showed that components, only represent in inspiration, which were interpreted as indicating polysynaptic connexions gated by the respiratory cycle. 6. The results are discussed in comparison with the connexions of individual muscle spindle afferents from other muscles, with particular reference to the conduction velocities of the afferents. PMID:6461757

  19. Interplay of multiple synaptic plasticity features in filamentary memristive devices for neuromorphic computing

    PubMed Central

    La Barbera, Selina; Vincent, Adrien F.; Vuillaume, Dominique; Querlioz, Damien; Alibart, Fabien

    2016-01-01

    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. PMID:27982093

  20. Interplay of multiple synaptic plasticity features in filamentary memristive devices for neuromorphic computing.

    PubMed

    La Barbera, Selina; Vincent, Adrien F; Vuillaume, Dominique; Querlioz, Damien; Alibart, Fabien

    2016-12-16

    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.

  1. 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.

  2. Buyang Huanwu decoction facilitates neurorehabilitation through an improvement of synaptic plasticity in cerebral ischemic rats.

    PubMed

    Pan, Ruihuan; Cai, Jun; Zhan, Lechang; Guo, Youhua; Huang, Run-Yue; Li, Xiong; Zhou, Mingchao; Xu, Dandan; Zhan, Jie; Chen, Hongxia

    2017-03-28

    Loss of neural function is a critical but unsolved issue after cerebral ischemia insult. Neuronal plasticity and remodeling are crucial for recovery of neural functions after brain injury. Buyang Huanwu decoction, which is a classic formula in traditional Chinese medicine, can positively alter synaptic plasticity. This study assessed the effects of Buyang Huanwu decoction in combination with physical exercise on neuronal plasticity in cerebral ischemic rats. Cerebral ischemic rats were administered Buyang Huanwu decoction and participated in physical exercise after the induction of a permanent middle cerebral artery occlusion. The neurobehavioral functions and infarct volumes were evaluated. The presynaptic (SYN), postsynaptic (GAP-43) and cytoskeletal (MAP-2) proteins in the coronal brain samples were evaluated by immunohistochemistry and western blot analyses. The ultrastructure of the neuronal synaptic junctions in the same region were analyzed using transmission electron microscopy. Combination treatment of Buyang Huanwu decoction and physical exercise ameliorated the neurobehavioral deficits (p < 0.05), significantly enhanced the expression levels of SYN, GAP-43 and MAP-2 (p < 0.05), and maintained the synaptic ultrastructure. Buyang Huanwu decoction facilitated neurorehabilitation following a cerebral ischemia insult through an improvement in synaptic plasticity. Graphical abstract The Buyang Huanwu decoction (BYHWD) combined with physical exercise (PE) attenuates synaptic disruption and promotes synaptic plasticity following cerebral ischemia (stroke).

  3. Sapap3 deletion anomalously activates short-term endocannabinoid-mediated synaptic plasticity

    PubMed Central

    Chen, Meng; Wan, Yehong; Ade, Kristen; Ting, Jonathan; Feng, Guoping; Calakos, Nicole

    2011-01-01

    Retrograde synaptic signaling by endocannabinoids is a widespread mechanism for activity-dependent inhibition of synaptic strength in the brain. Although prevalent, the conditions for eliciting endocannabinoid (eCB)-mediated synaptic depression vary among brain circuits. As yet, relatively little is known about the molecular mechanisms underlying this variation, although the initial signaling events are likely dictated by postsynaptic proteins. SAPAPs are a family of postsynaptic proteins unique to excitatory synapses. Using Sapap3 knock-out (KO) mice, we find that, in the absence of SAPAP3, striatal medium spiny neuron (MSN) excitatory synapses exhibit eCB-mediated synaptic depression under conditions that do not normally activate this process. The anomalous synaptic plasticity requires type 5 metabotropic glutamate receptors (mGluR5), which are dysregulated in Sapap3 KO MSNs. Both surface expression and activity of mGluR5 are increased in Sapap3 KO MSNs, suggesting that enhanced mGluR5 activity may drive the anomalous synaptic plasticity. In direct support of this possibility, we find that, in wildtype (WT) MSNs, pharmacological enhancement of mGluR5 by a positive allosteric modulator is sufficient to reproduce the increased synaptic depression seen in Sapap3 KO MSNs. The same pharmacologic treatment, however, fails to elicit further depression in KO MSNs. Under conditions that are sufficient to engage eCB-mediated synaptic depression in WT MSNs, Sapap3 deletion does not alter the magnitude of the response. These results identify a role for SAPAP3 in the regulation of postsynaptic mGluRs and eCB-mediated synaptic plasticity. SAPAPs, through their effect on mGluR activity, may serve as regulatory molecules gating the threshold for inducing eCB-mediated synaptic plasticity. PMID:21715621

  4. The role of nitric oxide in pre-synaptic plasticity and homeostasis

    PubMed Central

    Hardingham, Neil; Dachtler, James; Fox, Kevin

    2013-01-01

    Since the observation that nitric oxide (NO) can act as an intercellular messenger in the brain, the past 25 years have witnessed the steady accumulation of evidence that it acts pre-synaptically at both glutamatergic and GABAergic synapses to alter release-probability in synaptic plasticity. NO does so by acting on the synaptic machinery involved in transmitter release and, in a coordinated fashion, on vesicular recycling mechanisms. In this review, we examine the body of evidence for NO acting as a retrograde factor at synapses, and the evidence from in vivo and in vitro studies that specifically establish NOS1 (neuronal nitric oxide synthase) as the important isoform of NO synthase in this process. The NOS1 isoform is found at two very different locations and at two different spatial scales both in the cortex and hippocampus. On the one hand it is located diffusely in the cytoplasm of a small population of GABAergic neurons and on the other hand the alpha isoform is located discretely at the post-synaptic density (PSD) in spines of pyramidal cells. The present evidence is that the number of NOS1 molecules that exist at the PSD are so low that a spine can only give rise to modest concentrations of NO and therefore only exert a very local action. The NO receptor guanylate cyclase is located both pre- and post-synaptically and this suggests a role for NO in the coordination of local pre- and post-synaptic function during plasticity at individual synapses. Recent evidence shows that NOS1 is also located post-synaptic to GABAergic synapses and plays a pre-synaptic role in GABAergic plasticity as well as glutamatergic plasticity. Studies on the function of NO in plasticity at the cellular level are corroborated by evidence that NO is also involved in experience-dependent plasticity in the cerebral cortex. PMID:24198758

  5. Loss of Cdc42 leads to defects in synaptic plasticity and remote memory recall.

    PubMed

    Kim, Il Hwan; Wang, Hong; Soderling, Scott H; Yasuda, Ryohei

    2014-07-08

    Cdc42 is a signaling protein important for reorganization of actin cytoskeleton and morphogenesis of cells. However, the functional role of Cdc42 in synaptic plasticity and in behaviors such as learning and memory are not well understood. Here we report that postnatal forebrain deletion of Cdc42 leads to deficits in synaptic plasticity and in remote memory recall using conditional knockout of Cdc42. We found that deletion of Cdc42 impaired LTP in the Schaffer collateral synapses and postsynaptic structural plasticity of dendritic spines in CA1 pyramidal neurons in the hippocampus. Additionally, loss of Cdc42 did not affect memory acquisition, but instead significantly impaired remote memory recall. Together these results indicate that the postnatal functions of Cdc42 may be crucial for the synaptic plasticity in hippocampal neurons, which contribute to the capacity for remote memory recall.

  6. 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

  7. 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.

  8. Fragile X mental retardation protein in learning-related synaptic plasticity.

    PubMed

    Mercaldo, Valentina; Descalzi, Giannina; Zhuo, Min

    2009-12-31

    Fragile X syndrome (FXS) is caused by a lack of the fragile X mental retardation protein (FMRP) due to silencing of the Fmr1 gene. As an RNA binding protein, FMRP is thought to contribute to synaptic plasticity by regulating plasticity-related protein synthesis and other signaling pathways. Previous studies have mostly focused on the roles of FMRP within the hippocampus--a key structure for spatial memory. However, recent studies indicate that FMRP may have a more general contribution to brain functions, including synaptic plasticity and modulation within the prefrontal cortex. In this brief review, we will focus on recent studies reported in the prefrontal cortex, including the anterior cingulate cortex (ACC). We hypothesize that alterations in ACC-related plasticity and synaptic modulation may contribute to various forms of cognitive deficits associated with FXS.

  9. Structurally dissimilar antimanic agents modulate synaptic plasticity by regulating AMPA glutamate receptor subunit GluR1 synaptic expression.

    PubMed

    Du, Jing; Gray, Neil A; Falke, Cynthia; Yuan, Peixiong; Szabo, Steven; Manji, Husseini K

    2003-11-01

    A growing body of data from clinical and preclinical studies suggests that the glutamatergic system may represent a novel therapeutic target for severe recurrent mood disorders. Since synapse-specific glutamate receptor expression/localization is known to play critical roles in synaptic plasticity, we investigated the effects of mood stabilizers on AMPA receptor expression. Rats were treated chronically with lithium or valproate, hippocampal synaptosomes were isolated, and GluR1 levels were determined. Additionally, hippocampal neurons were prepared from E18 rat embryos and treated with lithium or valproate. Surface expression of GluR1 was determined using a biotinylation assay, and double-immunostaining with anti-GluR1 and anti-synaptotagmin antibodies was used to determine synaptic GluR1 levels. The AMPA receptor subunit GluR1 expression in hippocampal synaptosomes was significantly reduced by both chronic lithium and valproate. Overall, these studies show that AMPA receptor subunit GluR1 is a common target for two structurally highly dissimilar, but highly efficacious, mood stabilizers, lithium and valproate. These studies suggest that regulation of glutamatergically mediated synaptic plasticity may play a role in the treatment of mood disorders, and raise the possibility that agents more directly affecting synaptic GluR1 may represent novel therapies for this devastating illness.

  10. Phosphorylation of AMPA receptors is required for sensory deprivation-induced homeostatic synaptic plasticity.

    PubMed

    Goel, Anubhuti; Xu, Linda W; Snyder, Kevin P; Song, Lihua; Goenaga-Vazquez, Yamila; Megill, Andrea; Takamiya, Kogo; Huganir, Richard L; Lee, Hey-Kyoung

    2011-03-31

    Sensory experience, and the lack thereof, can alter the function of excitatory synapses in the primary sensory cortices. Recent evidence suggests that changes in sensory experience can regulate the synaptic level of Ca(2+)-permeable AMPA receptors (CP-AMPARs). However, the molecular mechanisms underlying such a process have not been determined. We found that binocular visual deprivation, which is a well-established in vivo model to produce multiplicative synaptic scaling in visual cortex of juvenile rodents, is accompanied by an increase in the phosphorylation of AMPAR GluR1 (or GluA1) subunit at the serine 845 (S845) site and the appearance of CP-AMPARs at synapses. To address the role of GluR1-S845 in visual deprivation-induced homeostatic synaptic plasticity, we used mice lacking key phosphorylation sites on the GluR1 subunit. We found that mice specifically lacking the GluR1-S845 site (GluR1-S845A mutants), which is a substrate of cAMP-dependent kinase (PKA), show abnormal basal excitatory synaptic transmission and lack visual deprivation-induced homeostatic synaptic plasticity. We also found evidence that increasing GluR1-S845 phosphorylation alone is not sufficient to produce normal multiplicative synaptic scaling. Our study provides concrete evidence that a GluR1 dependent mechanism, especially S845 phosphorylation, is a necessary pre-requisite step for in vivo homeostatic synaptic plasticity.

  11. SIRT1 is essential for normal cognitive function and synaptic plasticity

    PubMed Central

    Michán, Shaday; Li, Ying; Chou, Maggie Meng-Hsiu; Parrella, Edoardo; Ge, Huanying; Long, Jeffrey M.; Allard, Joanne S.; Lewis, Kaitlyn; Miller, Marshall; Xu, Wei; Mervis, Ronald F.; Chen, Jing; Guerin, Karen I.; Smith, Lois E. H.; McBurney, Michael W.; Sinclair, David A.; Baudry, Michel; de Cabo, Rafael; Longo, Valter D.

    2010-01-01

    Conservation of normal cognitive functions relies on the proper performance of the nervous system at the cellular and molecular level. The mammalian NAD+-dependent deacetylase, SIRT1, impacts different processes potentially involved in the maintenance of brain integrity such as chromatin remodeling, DNA repair, cell survival and neurogenesis. Here we show that SIRT1 is expressed in neurons of the hippocampus, a key structure in learning and memory. Using a combination of behavioral and electrophysiological paradigms we analyzed the effects of SIRT1 deficiency and overexpression on mouse learning and memory as well as on synaptic plasticity. We demonstrated that the absence of SIRT1 impaired cognitive abilities, including immediate memory, classical conditioning and spatial learning. In addition, we found that the cognitive deficits in SIRT1 knockout mice were associated with defects in synaptic plasticity without alterations in basal synaptic transmission or NMDA receptor function. Brains of SIRT1-KO mice exhibited normal morphology and dendritic spine structure but display a decrease in dendritic branching, branch length and complexity of neuronal dendritic arbors. Also, a decrease in ERK1/2 phosphorylation and altered expression of hippocampal genes involved in synaptic function, lipid metabolism and myelination were detected in SIRT1-KO mice. In contrast, mice with high levels of SIRT1 expression in brain exhibited regular synaptic plasticity and memory. We conclude that SIRT1 is indispensable for normal learning, memory and synaptic plasticity in mice. PMID:20660252

  12. Synaptic plasticity along the sleep-wake cycle: implications for epilepsy.

    PubMed

    Romcy-Pereira, Rodrigo N; Leite, João P; Garcia-Cairasco, Norberto

    2009-01-01

    Activity-dependent changes in synaptic efficacy (i.e., synaptic plasticity) can alter the way neurons communicate and process information as a result of experience. Synaptic plasticity mechanisms involve both molecular and structural modifications that affect synaptic functioning, either enhancing or depressing neuronal transmission. They include redistribution of postsynaptic receptors, activation of intracellular signaling cascades, and formation/retraction of dendritic spines, among others. During the sleep-wake cycle, as the result of particular neurochemical and neuronal firing modes, distinct oscillatory patterns organize the activity of neuronal populations, modulating synaptic plasticity. Such modulation, for example, has been shown in the visual cortex following sleep deprivation and in the ability to induce hippocampal long-term potentiation during sleep. In epilepsy, synchronized behavioral states tend to contribute to the initiation of paroxystic discharges and are considered more epileptogenic than desynchronized states. Here, we review some of the current understandings of synaptic plasticity changes in wake and sleep states and how sleep may affect epileptic seizures.

  13. Ubiquitin ligase TRIM3 controls hippocampal plasticity and learning by regulating synaptic γ-actin levels

    PubMed Central

    Schreiber, Joerg; Végh, Marlene J.; Dawitz, Julia; Kroon, Tim; Loos, Maarten; Labonté, Dorthe; Li, Ka Wan; Van Nierop, Pim; Van Diepen, Michiel T.; De Zeeuw, Chris I.; Kneussel, Matthias; Meredith, Rhiannon M.; Smit, August B.

    2015-01-01

    Synaptic plasticity requires remodeling of the actin cytoskeleton. Although two actin isoforms, β- and γ-actin, are expressed in dendritic spines, the specific contribution of γ-actin in the expression of synaptic plasticity is unknown. We show that synaptic γ-actin levels are regulated by the E3 ubiquitin ligase TRIM3. TRIM3 protein and Actg1 transcript are colocalized in messenger ribonucleoprotein granules responsible for the dendritic targeting of messenger RNAs. TRIM3 polyubiquitylates γ-actin, most likely cotranslationally at synaptic sites. Trim3−/− mice consequently have increased levels of γ-actin at hippocampal synapses, resulting in higher spine densities, increased long-term potentiation, and enhanced short-term contextual fear memory consolidation. Interestingly, hippocampal deletion of Actg1 caused an increase in long-term fear memory. Collectively, our findings suggest that temporal control of γ-actin levels by TRIM3 is required to regulate the timing of hippocampal plasticity. We propose a model in which TRIM3 regulates synaptic γ-actin turnover and actin filament stability and thus forms a transient inhibitory constraint on the expression of hippocampal synaptic plasticity. PMID:26527743

  14. A neuromorphic implementation of multiple spike-timing synaptic plasticity rules for large-scale neural networks

    PubMed Central

    Wang, Runchun M.; Hamilton, Tara J.; Tapson, Jonathan C.; van Schaik, André

    2015-01-01

    We present a neuromorphic implementation of multiple synaptic plasticity learning rules, which include both Spike Timing Dependent Plasticity (STDP) and Spike Timing Dependent Delay Plasticity (STDDP). We present a fully digital implementation as well as a mixed-signal implementation, both of which use a novel dynamic-assignment time-multiplexing approach and support up to 226 (64M) synaptic plasticity elements. Rather than implementing dedicated synapses for particular types of synaptic plasticity, we implemented a more generic synaptic plasticity adaptor array that is separate from the neurons in the neural network. Each adaptor performs synaptic plasticity according to the arrival times of the pre- and post-synaptic spikes assigned to it, and sends out a weighted or delayed pre-synaptic spike to the post-synaptic neuron in the neural network. This strategy provides great flexibility for building complex large-scale neural networks, as a neural network can be configured for multiple synaptic plasticity rules without changing its structure. We validate the proposed neuromorphic implementations with measurement results and illustrate that the circuits are capable of performing both STDP and STDDP. We argue that it is practical to scale the work presented here up to 236 (64G) synaptic adaptors on a current high-end FPGA platform. PMID:26041985

  15. A neuromorphic implementation of multiple spike-timing synaptic plasticity rules for large-scale neural networks.

    PubMed

    Wang, Runchun M; Hamilton, Tara J; Tapson, Jonathan C; van Schaik, André

    2015-01-01

    We present a neuromorphic implementation of multiple synaptic plasticity learning rules, which include both Spike Timing Dependent Plasticity (STDP) and Spike Timing Dependent Delay Plasticity (STDDP). We present a fully digital implementation as well as a mixed-signal implementation, both of which use a novel dynamic-assignment time-multiplexing approach and support up to 2(26) (64M) synaptic plasticity elements. Rather than implementing dedicated synapses for particular types of synaptic plasticity, we implemented a more generic synaptic plasticity adaptor array that is separate from the neurons in the neural network. Each adaptor performs synaptic plasticity according to the arrival times of the pre- and post-synaptic spikes assigned to it, and sends out a weighted or delayed pre-synaptic spike to the post-synaptic neuron in the neural network. This strategy provides great flexibility for building complex large-scale neural networks, as a neural network can be configured for multiple synaptic plasticity rules without changing its structure. We validate the proposed neuromorphic implementations with measurement results and illustrate that the circuits are capable of performing both STDP and STDDP. We argue that it is practical to scale the work presented here up to 2(36) (64G) synaptic adaptors on a current high-end FPGA platform.

  16. Learning and Memory, Part II: Molecular Mechanisms of Synaptic Plasticity

    ERIC Educational Resources Information Center

    Lombroso, Paul; Ogren, Marilee

    2009-01-01

    The molecular events that are responsible for strengthening synaptic connections and how these are linked to memory and learning are discussed. The laboratory preparations that allow the investigation of these events are also described.

  17. Presynaptic angiotensin II AT1 receptors enhance inhibitory and excitatory synaptic neurotransmission to motoneurons and other ventral horn neurons in neonatal rat spinal cord.

    PubMed

    Oz, Murat; Yang, Keun-Hang; O'donovan, Michael J; Renaud, Leo P

    2005-08-01

    In neonatal spinal cord, we previously reported that exogenous angiotensin II (ANG II) acts at postsynaptic AT1 receptors to depolarize neonatal rat spinal ventral horn neurons in vitro. This study evaluated an associated increase in synaptic activity. Patch clamp recordings revealed that 38/81 thoracolumbar (T7-L5) motoneurons responded to bath applied ANG II (0.3-1 microM; 30 s) with a prolonged (5-10 min) and reversible increase in spontaneous postsynaptic activity, selectively blockable with Losartan (n = 5) but not PD123319 (n = 5). ANG-II-induced events included both spontaneous inhibitory (IPSCs; n = 6) and excitatory postsynaptic currents (EPSCs; n = 5). While most ANG induced events were tetrodotoxin-sensitive, ANG induced a significant tetrodotoxin-resistant increase in frequency but not amplitude of miniature IPSCs (n = 7/13 cells) and EPSCs (n = 2/7 cells). In 35/77 unidentified neurons, ANG II also induced a tetrodotoxin-sensitive and prolonged increase in their spontaneous synaptic activity that featured both IPSCs (n = 5) and EPSCs (n = 4) when tested in the presence of selective amino acid receptor antagonists. When tested in the presence of tetrodotoxin, ANG II was noted to induce a significant increase in the frequency but not the amplitude of mIPSCs (n = 9) and mEPSCs (n = 8). ANG also increased spontaneous motor activity from isolated mouse lumbar ventral rootlets. Collectively, these observations support the existence of a wide pre- and postsynaptic distribution of ANG II AT1 receptors in neonatal ventral spinal cord that are capable of influencing both inhibitory and excitatory neurotransmission.

  18. Spike Train Auto-Structure Impacts Post-Synaptic Firing and Timing-Based Plasticity

    PubMed Central

    Scheller, Bertram; Castellano, Marta; Vicente, Raul; Pipa, Gordon

    2011-01-01

    Cortical neurons are typically driven by several thousand synapses. The precise spatiotemporal pattern formed by these inputs can modulate the response of a post-synaptic cell. In this work, we explore how the temporal structure of pre-synaptic inhibitory and excitatory inputs impact the post-synaptic firing of a conductance-based integrate and fire neuron. Both the excitatory and inhibitory input was modeled by renewal gamma processes with varying shape factors for modeling regular and temporally random Poisson activity. We demonstrate that the temporal structure of mutually independent inputs affects the post-synaptic firing, while the strength of the effect depends on the firing rates of both the excitatory and inhibitory inputs. In a second step, we explore the effect of temporal structure of mutually independent inputs on a simple version of Hebbian learning, i.e., hard bound spike-timing-dependent plasticity. We explore both the equilibrium weight distribution and the speed of the transient weight dynamics for different mutually independent gamma processes. We find that both the equilibrium distribution of the synaptic weights and the speed of synaptic changes are modulated by the temporal structure of the input. Finally, we highlight that the sensitivity of both the post-synaptic firing as well as the spike-timing-dependent plasticity on the auto-structure of the input of a neuron could be used to modulate the learning rate of synaptic modification. PMID:22203800

  19. Downregulation of caveolin-1 contributes to the synaptic plasticity deficit in the hippocampus of aged rats

    PubMed Central

    Liu, Yang; Liang, Zhanhua; Liu, Jing; Zou, Wei; Li, Xiaoyan; Wang, Yachen; An, Lijia

    2013-01-01

    Caveolin-1 is involved in the regulation of synaptic plasticity, but the relationship between its pression and cognitive function during aging remains controversial. To explore the relationship be-tween synaptic plasticity in the aging process and changes in learning and memory, we examined caveolin-1 expression in the hippocampus, cortex and cerebellum of rats at different ages. We also examined the relationship between the expression of caveolin-1 and synaptophysin, a marker of synaptic plasticity. Hippocampal caveolin-1 and synaptophysin expression in aged (22–24 month old) rats was significantly lower than that in young (1 month old) and adult (4 months old) rats. pression levels of both proteins were significantly greater in the cortex of aged rats than in that of young or adult rats, and levels were similar between the three age groups in the cerebellum. Linear regression analysis revealed that hippocampal expression of synaptophysin was associated with memory and learning abilities. Moreover, synaptophysin expression correlated positively with caveolin-1 expression in the hippocampus, cortex and cerebellum. These results confirm that caveolin-1 has a regulatory effect on synaptic plasticity, and suggest that the downregulation of hippocampal caveolin-1 expression causes a decrease in synaptic plasticity during physiological aging. PMID:25206583

  20. EEA1 restores homeostatic synaptic plasticity in hippocampal neurons from Rett syndrome mice.

    PubMed

    Xu, Xin; Pozzo-Miller, Lucas

    2017-08-15

    Rett syndrome is a neurodevelopmental disorder caused by loss-of-function mutations in MECP2, the gene encoding the transcriptional regulator methyl-CpG-binding protein 2 (MeCP2). Mecp2 deletion in mice results in an imbalance of excitation and inhibition in hippocampal neurons, which affects 'Hebbian' synaptic plasticity. We show that Mecp2-deficient neurons also lack homeostatic synaptic plasticity, likely due to reduced levels of EEA1, a protein involved in AMPA receptor endocytosis. Expression of EEA1 restored homeostatic synaptic plasticity in Mecp2-deficient neurons, providing novel targets of intervention in Rett syndrome. Rett syndrome is a neurodevelopmental disorder caused by loss-of-function mutations in MECP2, the gene encoding the transcriptional regulator methyl-CpG-binding protein 2 (MeCP2). Deletion of Mecp2 in mice results in an imbalance of synaptic excitation and inhibition in hippocampal pyramidal neurons, which affects 'Hebbian' long-term synaptic plasticity. Since the excitatory-inhibitory balance is maintained by homeostatic mechanisms, we examined the role of MeCP2 in homeostatic synaptic plasticity (HSP) at excitatory synapses. Negative feedback HSP, also known as synaptic scaling, maintains the global synaptic strength of individual neurons in response to sustained alterations in neuronal activity. Hippocampal neurons from Mecp2 knockout (KO) mice do not show the characteristic homeostatic scaling up of the amplitude of miniature excitatory postsynaptic currents (mEPSCs) and of synaptic levels of the GluA1 subunit of AMPA-type glutamate receptors after 48 h silencing with the Na(+) channel blocker tetrodotoxin. This deficit in HSP is bidirectional because Mecp2 KO neurons also failed to scale down mEPSC amplitudes and GluA1 synaptic levels after 48 h blockade of type A GABA receptor (GABAA R)-mediated inhibition with bicuculline. Consistent with the role of synaptic trafficking of AMPA-type of glutamate receptors in HSP, Mecp2 KO neurons

  1. Altered Synaptic Plasticity in Tourette's Syndrome and Its Relationship to Motor Skill Learning

    PubMed Central

    Ganos, Christos; Kahl, Ursula; Bäumer, Tobias; Münchau, Alexander

    2014-01-01

    Gilles de la Tourette syndrome is a neuropsychiatric disorder characterized by motor and phonic tics that can be considered motor responses to preceding inner urges. It has been shown that Tourette patients have inferior performance in some motor learning tasks and reduced synaptic plasticity induced by transcranial magnetic stimulation. However, it has not been investigated whether altered synaptic plasticity is directly linked to impaired motor skill acquisition in Tourette patients. In this study, cortical plasticity was assessed by measuring motor-evoked potentials before and after paired associative stimulation in 14 Tourette patients (13 male; age 18–39) and 15 healthy controls (12 male; age 18–33). Tic and urge severity were assessed using the Yale Global Tic Severity Scale and the Premonitory Urges for Tics Scale. Motor learning was assessed 45 minutes after inducing synaptic plasticity and 9 months later, using the rotary pursuit task. On average, long-term potentiation-like effects in response to the paired associative stimulation were present in healthy controls but not in patients. In Tourette patients, long-term potentiation-like effects were associated with more and long-term depression-like effects with less severe urges and tics. While motor learning did not differ between patients and healthy controls 45 minutes after inducing synaptic plasticity, the learning curve of the healthy controls started at a significantly higher level than the Tourette patients' 9 months later. Induced synaptic plasticity correlated positively with motor skills in healthy controls 9 months later. The present study confirms previously found long-term improvement in motor performance after paired associative stimulation in healthy controls but not in Tourette patients. Tourette patients did not show long-term potentiation in response to PAS and also showed reduced levels of motor skill consolidation after 9 months compared to healthy controls. Moreover, synaptic

  2. GRASP1 Regulates Synaptic Plasticity and Learning through Endosomal Recycling of AMPA Receptors.

    PubMed

    Chiu, Shu-Ling; Diering, Graham Hugh; Ye, Bing; Takamiya, Kogo; Chen, Chih-Ming; Jiang, Yuwu; Niranjan, Tejasvi; Schwartz, Charles E; Wang, Tao; Huganir, Richard L

    2017-03-22

    Learning depends on experience-dependent modification of synaptic efficacy and neuronal connectivity in the brain. We provide direct evidence for physiological roles of the recycling endosome protein GRASP1 in glutamatergic synapse function and animal behavior. Mice lacking GRASP1 showed abnormal excitatory synapse number, synaptic plasticity, and hippocampal-dependent learning and memory due to a failure in learning-induced synaptic AMPAR incorporation. We identified two GRASP1 point mutations from intellectual disability (ID) patients that showed convergent disruptive effects on AMPAR recycling and glutamate uncaging-induced structural and functional plasticity. Wild-type GRASP1, but not ID mutants, rescued spine loss in hippocampal CA1 neurons in Grasp1 knockout mice. Together, these results demonstrate a requirement for normal recycling endosome function in AMPAR-dependent synaptic function and neuronal connectivity in vivo, and suggest a potential role for GRASP1 in the pathophysiology of human cognitive disorders.

  3. Systems biology of synaptic plasticity: a review on N-methyl-D-aspartate receptor mediated biochemical pathways and related mathematical models.

    PubMed

    He, Y; Kulasiri, D; Samarasinghe, S

    2014-08-01

    Synaptic plasticity, an emergent property of synaptic networks, has shown strong correlation to one of the essential functions of the brain, memory formation. Through understanding synaptic plasticity, we hope to discover the modulators and mechanisms that trigger memory formation. In this paper, we first review the well understood modulators and mechanisms underlying N-methyl-D-aspartate receptor dependent synaptic plasticity, a major form of synaptic plasticity in hippocampus, and then comment on the key mathematical modelling approaches available in the literature to understand synaptic plasticity as the integration of the established functionalities of synaptic components.

  4. Differential effects of excitatory and inhibitory plasticity on synaptically-driven neuronal Input-Output functions

    PubMed Central

    Carvalho, Tiago P.; Buonomano, Dean V.

    2009-01-01

    Ultimately, whether or not a neuron produces a spike determines its contribution to local computations. In response to brief stimuli the probability a neuron will fire can be described by its input-output function, which depends on the net balance and timing of excitatory and inhibitory currents. While excitatory and inhibitory synapses are plastic, most studies examine plasticity of subthreshold events. Thus, the effects of concerted regulation of excitatory and inhibitory synaptic strength on neuronal input-output functions are not well understood. Here, theoretical analyses reveal that excitatory synaptic strength controls the threshold of the neuronal input-output function, while inhibitory plasticity alters the threshold and gain. Experimentally, changes in the balance of excitation and inhibition in CA1 pyramidal neurons also altered their input-output function as predicted by the model. These results support the existence of two functional modes of plasticity that can be used to optimize information processing: threshold and gain plasticity. PMID:19285473

  5. GABAergic synaptic plasticity during a developmentally regulated sleep-like state in C. elegans.

    PubMed

    Dabbish, Nooreen S; Raizen, David M

    2011-11-02

    Approximately one-fourth of the neurons in Caenorhabditis elegans adults are born during larval development, indicating tremendous plasticity in larval nervous system structure. Larval development shows cyclical expression of sleep-like quiescent behavior during lethargus periods, which occur at larval stage transitions. We studied plasticity at the neuromuscular junction during lethargus using the acetylcholinesterase inhibitor aldicarb. The rate of animal contraction when exposed to aldicarb is controlled by the balance between excitatory cholinergic and inhibitory GABAergic input on the muscle. During lethargus, there is an accelerated rate of contraction on aldicarb. Mutant analysis and optogenetic studies reveal that GABAergic synaptic transmission is reduced during lethargus. Worms in lethargus show partial resistance to GABA(A) receptor agonists, indicating that postsynaptic mechanisms contribute to lethargus-dependent plasticity. Using genetic manipulations that separate the quiescent state from the developmental stage, we show that the synaptic plasticity is dependent on developmental time and not on the behavioral state of the animal. We propose that the synaptic plasticity regulated by a developmental clock in C. elegans is analogous to synaptic plasticity regulated by the circadian clock in other species.

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

    PubMed

    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.

  7. 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

  8. In vivo BDNF modulation of adult functional and morphological synaptic plasticity at hippocampal mossy fibers.

    PubMed

    Gómez-Palacio-Schjetnan, Andrea; Escobar, Martha L

    2008-11-07

    Brain-derived neurotrophic factor (BDNF) has been proposed as a key regulator and mediator of long-term synaptic modifications related to learning and memory maintenance. Our previous studies show that application of high-frequency stimulation (HFS) sufficient to elicit LTP at the dentate gyrus (DG)-CA3 pathway produces mossy fiber structural modifications 7 days after tetanic stimulation. In the present study, we show that acute intrahippocampal microinfusion of BDNF induces a lasting potentiation of synaptic efficacy in the DG-CA3 projection of anesthetized adult rats. Furthermore, we show that BDNF functional modifications in synaptic efficacy are accompanied by a presynaptic structural long-lasting reorganization at the hippocampal mossy fiber pathway. These findings support the idea that BDNF plays an important role as synaptic messenger of activity-dependent synaptic plasticity in the adult mammalian brain, in vivo.

  9. Synaptic transmission and plasticity require AMPA receptor anchoring via its N-terminal domain.

    PubMed

    Watson, Jake F; Ho, Hinze; Greger, Ingo H

    2017-03-14

    AMPA-type glutamate receptors (AMPARs) mediate fast excitatory neurotransmission and are selectively recruited during activity-dependent plasticity to increase synaptic strength. A prerequisite for faithful signal transmission is the positioning and clustering of AMPARs at postsynaptic sites. The mechanisms underlying this positioning have largely been ascribed to the receptor cytoplasmic C-termini and to AMPAR-associated auxiliary subunits, both interacting with the postsynaptic scaffold. Here, using mouse organotypic hippocampal slices, we show that the extracellular AMPAR N-terminal domain (NTD), which projects midway into the synaptic cleft, plays a fundamental role in this process. This highly sequence-diverse domain mediates synaptic anchoring in a subunit-selective manner. Receptors lacking the NTD exhibit increased mobility in synapses, depress synaptic transmission and are unable to sustain long-term potentiation (LTP). Thus, synaptic transmission and the expression of LTP are dependent upon an AMPAR anchoring mechanism that is driven by the NTD.

  10. Modelling the molecular mechanisms of synaptic plasticity using systems biology approaches.

    PubMed

    Kotaleski, Jeanette Hellgren; Blackwell, Kim T

    2010-04-01

    Synaptic plasticity is thought to underlie learning and memory, but the complexity of the interactions between the ion channels, enzymes and genes that are involved in synaptic plasticity impedes a deep understanding of this phenomenon. Computer modelling has been used to investigate the information processing that is performed by the signalling pathways involved in synaptic plasticity in principal neurons of the hippocampus, striatum and cerebellum. In the past few years, new software developments that combine computational neuroscience techniques with systems biology techniques have allowed large-scale, kinetic models of the molecular mechanisms underlying long-term potentiation and long-term depression. We highlight important advancements produced by these quantitative modelling efforts and introduce promising approaches that use advancements in live-cell imaging.

  11. Autoregulatory and paracrine control of synaptic and behavioral plasticity by octopaminergic signaling.

    PubMed

    Koon, Alex C; Ashley, James; Barria, Romina; DasGupta, Shamik; Brain, Ruth; Waddell, Scott; Alkema, Mark J; Budnik, Vivian

    2011-02-01

    Adrenergic signaling has important roles in synaptic plasticity and metaplasticity. However, the underlying mechanisms of these functions remain poorly understood. We investigated the role of octopamine, the invertebrate counterpart of adrenaline and noradrenaline, in synaptic and behavioral plasticity in Drosophila. We found that an increase in locomotor speed induced by food deprivation was accompanied by an activity- and octopamine-dependent extension of octopaminergic arbors and that the formation and maintenance of these arbors required electrical activity. Growth of octopaminergic arbors was controlled by a cAMP- and CREB-dependent positive-feedback mechanism that required Octβ2R octopamine autoreceptors. Notably, this autoregulation was necessary for the locomotor response. In addition, octopamine neurons regulated the expansion of excitatory glutamatergic neuromuscular arbors through Octβ2Rs on glutamatergic motor neurons. Our results provide a mechanism for global regulation of excitatory synapses, presumably to maintain synaptic and behavioral plasticity in a dynamic range.

  12. Learning, AMPA receptor mobility and synaptic plasticity depend on n-cofilin-mediated actin dynamics

    PubMed Central

    Rust, Marco B; Gurniak, Christine B; Renner, Marianne; Vara, Hugo; Morando, Laura; Görlich, Andreas; Sassoè-Pognetto, Marco; Banchaabouchi, Mumna Al; Giustetto, Maurizio; Triller, Antoine; Choquet, Daniel; Witke, Walter

    2010-01-01

    Neuronal plasticity is an important process for learning, memory and complex behaviour. Rapid remodelling of the actin cytoskeleton in the postsynaptic compartment is thought to have an important function for synaptic plasticity. However, the actin-binding proteins involved and the molecular mechanisms that in vivo link actin dynamics to postsynaptic physiology are not well understood. Here, we show that the actin filament depolymerizing protein n-cofilin is controlling dendritic spine morphology and postsynaptic parameters such as late long-term potentiation and long-term depression. Loss of n-cofilin-mediated synaptic actin dynamics in the forebrain specifically leads to impairment of all types of associative learning, whereas exploratory learning is not affected. We provide evidence for a novel function of n-cofilin function in synaptic plasticity and in the control of extrasynaptic excitatory AMPA receptors diffusion. These results suggest a critical function of actin dynamics in associative learning and postsynaptic receptor availability. PMID:20407421

  13. A novel synaptic plasticity rule explains homeostasis of neuromuscular transmission

    PubMed Central

    Ouanounou, Gilles; Baux, Gérard; Bal, Thierry

    2016-01-01

    Excitability differs among muscle fibers and undergoes continuous changes during development and growth, yet the neuromuscular synapse maintains a remarkable fidelity of execution. Here we show in two evolutionarily distant vertebrates (Xenopus laevis cell culture and mouse nerve-muscle ex-vivo) that the skeletal muscle cell constantly senses, through two identified calcium signals, synaptic events and their efficacy in eliciting spikes. These sensors trigger retrograde signal(s) that control presynaptic neurotransmitter release, resulting in synaptic potentiation or depression. In the absence of spikes, synaptic events trigger potentiation. Once the synapse is sufficiently strong to initiate spiking, the occurrence of these spikes activates a negative retrograde feedback. These opposing signals dynamically balance the synapse in order to continuously adjust neurotransmitter release to a level matching current muscle cell excitability. DOI: http://dx.doi.org/10.7554/eLife.12190.001 PMID:27138195

  14. Probabilistic inference of short-term synaptic plasticity in neocortical microcircuits

    PubMed Central

    Costa, Rui P.; Sjöström, P. Jesper; van Rossum, Mark C. W.

    2013-01-01

    Short-term synaptic plasticity is highly diverse across brain area, cortical layer, cell type, and developmental stage. Since short-term plasticity (STP) strongly shapes neural dynamics, this diversity suggests a specific and essential role in neural information processing. Therefore, a correct characterization of short-term synaptic plasticity is an important step towards understanding and modeling neural systems. Phenomenological models have been developed, but they are usually fitted to experimental data using least-mean-square methods. We demonstrate that for typical synaptic dynamics such fitting may give unreliable results. As a solution, we introduce a Bayesian formulation, which yields the posterior distribution over the model parameters given the data. First, we show that common STP protocols yield broad distributions over some model parameters. Using our result we propose a experimental protocol to more accurately determine synaptic dynamics parameters. Next, we infer the model parameters using experimental data from three different neocortical excitatory connection types. This reveals connection-specific distributions, which we use to classify synaptic dynamics. Our approach to demarcate connection-specific synaptic dynamics is an important improvement on the state of the art and reveals novel features from existing data. PMID:23761760

  15. Pre- and postsynaptic twists in BDNF secretion and action in synaptic plasticity.

    PubMed

    Edelmann, Elke; Lessmann, Volkmar; Brigadski, Tanja

    2014-01-01

    Overwhelming evidence collected since the early 1990's strongly supports the notion that BDNF is among the key regulators of synaptic plasticity in many areas of the mammalian central nervous system. Still, due to the extremely low expression levels of endogenous BDNF in most brain areas, surprisingly little data i) pinpointing pre- and postsynaptic release sites, ii) unraveling the time course of release, and iii) elucidating the physiological levels of synaptic activity driving this secretion are available. Likewise, our knowledge regarding pre- and postsynaptic effects of endogenous BDNF at the single cell level in mediating long-term potentiation still is sparse. Thus, our review will discuss the data currently available regarding synaptic BDNF secretion in response to physiologically relevant levels of activity, and will discuss how endogenously secreted BDNF affects synaptic plasticity, giving a special focus on spike timing-dependent types of LTP and on mossy fiber LTP. We will attempt to open up perspectives how the remaining challenging questions regarding synaptic BDNF release and action might be addressed by future experiments. This article is part of the Special Issue entitled 'BDNF Regulation of Synaptic Structure, Function, and Plasticity'.

  16. Impairments of Synaptic Plasticity in Aged Animals and in Animal Models of Alzheimer's Disease

    PubMed Central

    Balietti, Marta; Tamagnini, Francesco; Fattoretti, Patrizia; Burattini, Costanza; Casoli, Tiziana; Platano, Daniela; Lattanzio, Fabrizia

    2012-01-01

    Abstract Aging is associated with a gradual decline in cognitive functions, and more dramatic cognitive impairments occur in patients affected by Alzheimer's disease (AD). Electrophysiological and molecular studies performed in aged animals and in animal models of AD have shown that cognitive decline is associated with significant modifications in synaptic plasticity (i.e., activity-dependent changes in synaptic strength) and have elucidated some of the cellular mechanisms underlying this process. Morphological studies have revealed a correlation between the quality of memory performance and the extent of structural changes of synaptic contacts occurring during memory consolidation. We briefly review recent experimental evidence here. PMID:22533439

  17. Factors Influencing Short-term Synaptic Plasticity in the Avian Cochlear Nucleus Magnocellularis

    PubMed Central

    Sanchez, Jason Tait; Quinones, Karla; Otto-Meyer, Sebastian

    2015-01-01

    Defined as reduced neural responses during high rates of activity, synaptic depression is a form of short-term plasticity important for the temporal filtering of sound. In the avian cochlear nucleus magnocellularis (NM), an auditory brainstem structure, mechanisms regulating short-term synaptic depression include pre-, post-, and extrasynaptic factors. Using varied paired-pulse stimulus intervals, we found that the time course of synaptic depression lasts up to four seconds at late-developing NM synapses. Synaptic depression was largely reliant on exogenous Ca2+-dependent probability of presynaptic neurotransmitter release, and to a lesser extent, on the desensitization of postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptor (AMPA-R). Interestingly, although extrasynaptic glutamate clearance did not play a significant role in regulating synaptic depression, blocking glutamate clearance at early-developing synapses altered synaptic dynamics, changing responses from depression to facilitation. These results suggest a developmental shift in the relative reliance on pre-, post-, and extrasynaptic factors in regulating short-term synaptic plasticity in NM. PMID:26527054

  18. Learning structure of sensory inputs with synaptic plasticity leads to interference

    PubMed Central

    Chrol-Cannon, Joseph; Jin, Yaochu

    2015-01-01

    Synaptic plasticity is often explored as a form of unsupervised adaptation in cortical microcircuits to learn the structure of complex sensory inputs and thereby improve performance of classification and prediction. The question of whether the specific structure of the input patterns is encoded in the structure of neural networks has been largely neglected. Existing studies that have analyzed input-specific structural adaptation have used simplified, synthetic inputs in contrast to complex and noisy patterns found in real-world sensory data. In this work, input-specific structural changes are analyzed for three empirically derived models of plasticity applied to three temporal sensory classification tasks that include complex, real-world visual and auditory data. Two forms of spike-timing dependent plasticity (STDP) and the Bienenstock-Cooper-Munro (BCM) plasticity rule are used to adapt the recurrent network structure during the training process before performance is tested on the pattern recognition tasks. It is shown that synaptic adaptation is highly sensitive to specific classes of input pattern. However, plasticity does not improve the performance on sensory pattern recognition tasks, partly due to synaptic interference between consecutively presented input samples. The changes in synaptic strength produced by one stimulus are reversed by the presentation of another, thus largely preventing input-specific synaptic changes from being retained in the structure of the network. To solve the problem of interference, we suggest that models of plasticity be extended to restrict neural activity and synaptic modification to a subset of the neural circuit, which is increasingly found to be the case in experimental neuroscience. PMID:26300769

  19. Lovastatin improves impaired synaptic plasticity and phasic alertness in patients with neurofibromatosis type 1.

    PubMed

    Mainberger, Florian; Jung, Nikolai H; Zenker, Martin; Wahlländer, Ute; Freudenberg, Leonie; Langer, Susanne; Berweck, Steffen; Winkler, Tobias; Straube, Andreas; Heinen, Florian; Granström, Sofia; Mautner, Victor-Felix; Lidzba, Karen; Mall, Volker

    2013-10-02

    Neurofibromatosis type 1 (NF1) is one of the most common genetic disorders causing learning disabilities by mutations in the neurofibromin gene, an important inhibitor of the RAS pathway. In a mouse model of NF1, a loss of function mutation of the neurofibromin gene resulted in increased gamma aminobutyric acid (GABA)-mediated inhibition which led to decreased synaptic plasticity and deficits in attentional performance. Most importantly, these defictis were normalized by lovastatin. This placebo-controlled, double blind, randomized study aimed to investigate synaptic plasticity and cognition in humans with NF1 and tried to answer the question whether potential deficits may be rescued by lovastatin. In NF1 patients (n = 11; 19-44 years) and healthy controls (HC; n = 11; 19-31 years) paired pulse transcranial magnetic stimulation (TMS) was used to study intracortical inhibition (paired pulse) and synaptic plasticity (paired associative stimulation). On behavioural level the Test of Attentional Performance (TAP) was used. To study the effect of 200 mg lovastatin for 4 days on all these parameters, a placebo-controlled, double blind, randomized trial was performed. In patients with NF1, lovastatin revealed significant decrease of intracortical inhibition, significant increase of synaptic plasticity as well as significant increase of phasic alertness. Compared to HC, patients with NF1 exposed increased intracortical inhibition, impaired synaptic plasticity and deficits in phasic alertness. This study demonstrates, for the first time, a link between a pathological RAS pathway activity, intracortical inhibition and impaired synaptic plasticity and its rescue by lovastatin in humans. Our findings revealed mechanisms of attention disorders in humans with NF1 and support the idea of a potential clinical benefit of lovastatin as a therapeutic option.

  20. Lovastatin improves impaired synaptic plasticity and phasic alertness in patients with neurofibromatosis type 1

    PubMed Central

    2013-01-01

    Background Neurofibromatosis type 1 (NF1) is one of the most common genetic disorders causing learning disabilities by mutations in the neurofibromin gene, an important inhibitor of the RAS pathway. In a mouse model of NF1, a loss of function mutation of the neurofibromin gene resulted in increased gamma aminobutyric acid (GABA)-mediated inhibition which led to decreased synaptic plasticity and deficits in attentional performance. Most importantly, these defictis were normalized by lovastatin. This placebo-controlled, double blind, randomized study aimed to investigate synaptic plasticity and cognition in humans with NF1 and tried to answer the question whether potential deficits may be rescued by lovastatin. Methods In NF1 patients (n = 11; 19–44 years) and healthy controls (HC; n = 11; 19–31 years) paired pulse transcranial magnetic stimulation (TMS) was used to study intracortical inhibition (paired pulse) and synaptic plasticity (paired associative stimulation). On behavioural level the Test of Attentional Performance (TAP) was used. To study the effect of 200 mg lovastatin for 4 days on all these parameters, a placebo-controlled, double blind, randomized trial was performed. Results In patients with NF1, lovastatin revealed significant decrease of intracortical inhibition, significant increase of synaptic plasticity as well as significant increase of phasic alertness. Compared to HC, patients with NF1 exposed increased intracortical inhibition, impaired synaptic plasticity and deficits in phasic alertness. Conclusions This study demonstrates, for the first time, a link between a pathological RAS pathway activity, intracortical inhibition and impaired synaptic plasticity and its rescue by lovastatin in humans. Our findings revealed mechanisms of attention disorders in humans with NF1 and support the idea of a potential clinical benefit of lovastatin as a therapeutic option. PMID:24088225

  1. Electrochemical-reaction-induced synaptic plasticity in MoOx-based solid state electrochemical cells.

    PubMed

    Yang, Chuan-Sen; Shang, Da-Shan; Chai, Yi-Sheng; Yan, Li-Qin; Shen, Bao-Gen; Sun, Young

    2017-02-08

    Solid state electrochemical cells with synaptic functions have important applications in building smart-terminal networks. Here, the essential synaptic functions including potentiation and depression of synaptic weight, transition from short- to long-term plasticity, spike-rate-dependent plasticity, and spike-timing-dependent plasticity behavior were successfully realized in an Ag/MoOx/fluorine-doped tin oxide (FTO) cell with continual resistance switching. The synaptic plasticity underlying these functions was controlled by tuning the excitatory post-synaptic current (EPSC) decay, which is determined by the applied voltage pulse number, width, frequency, and intervals between the pre- and post-spikes. The physical mechanism of the artificial synapse operation is attributed to the interfacial electrochemical reaction processes of the MoOx films with the adsorbed water, where protons generated by water decomposition under an electric field diffused into the MoOx films and intercalated into the lattice, leading to the short- and long-term retention of cell resistance, respectively. These results indicate the possibility of achieving advanced artificial synapses with solid state electrochemical cells and will contribute to the development of smart-terminal networking systems.

  2. Reelin supplementation enhances cognitive ability, synaptic plasticity, and dendritic spine density

    PubMed Central

    Rogers, Justin T.; Rusiana, Ian; Trotter, Justin; Zhao, Lisa; Donaldson, Erika; Pak, Daniel T.S.; Babus, Lenard W.; Peters, Melinda; Banko, Jessica L.; Chavis, Pascale; Rebeck, G. William; Hoe, Hyang-Sook; Weeber, Edwin J.

    2011-01-01

    Apolipoprotein receptors belong to an evolutionarily conserved surface receptor family that has intimate roles in the modulation of synaptic plasticity and is necessary for proper hippocampal-dependent memory formation. The known lipoprotein receptor ligand Reelin is important for normal synaptic plasticity, dendritic morphology, and cognitive function; however, the in vivo effect of enhanced Reelin signaling on cognitive function and synaptic plasticity in wild-type mice is unknown. The present studies test the hypothesis that in vivo enhancement of Reelin signaling can alter synaptic plasticity and ultimately influence processes of learning and memory. Purified recombinant Reelin was injected bilaterally into the ventricles of wild-type mice. We demonstrate that a single in vivo injection of Reelin increased activation of adaptor protein Disabled-1 and cAMP-response element binding protein after 15 min. These changes correlated with increased dendritic spine density, increased hippocampal CA1 long-term potentiation (LTP), and enhanced performance in associative and spatial learning and memory. The present study suggests that an acute elevation of in vivo Reelin can have long-term effects on synaptic function and cognitive ability in wild-type mice. PMID:21852430

  3. Intracerebroventricular administration of ouabain alters synaptic plasticity and dopamine release in rat medial prefrontal cortex.

    PubMed

    Sui, Li; Song, Xiao-Jin; Ren, Jie; Ju, Li-Hua; Wang, Yan

    2013-08-01

    Intracerebroventricular (ICV) administration of ouabain, a specific Na-K-ATPase inhibitor, in rats mimics the manic phenotypes of bipolar disorder and thus has been proposed as one of the best animal models of mania. Bipolar mania has been known to be associated with dysfunctions of medial prefrontal cortex (mPFC), a brain area critically involved in mental functions; however, the exact mechanism underlying these dysfunctions is not yet clear. The present study investigated synaptic transmission, synaptic plasticity, and dopamine release in Sprague-Dawley rat mPFC following ICV administration of ouabain (5 μl of 1 mM ouabain). The electrophysiological results demonstrated that ouabain depressed the short- and the long-term synaptic plasticity, represented by paired-pulse facilitation and long-term potentiation, respectively, in the mPFC. These ouabain-induced alterations in synaptic plasticity can be prevented by pre-treatment with lithium (intraperitoneal injection of 47.5 mg/kg lithium, twice a day, 7 days), which acts as an effective mood stabilizer in preventing mania. The electrochemical results demonstrated that ICV administration of ouabain enhanced dopamine release in the mPFC, which did not be affected by pre-treatment with lithium. These findings suggested that alterations in synaptic plasticity and dopamine release in the mPFC might underlie the dysfunctions of mPFC accompanied with ouabain administration-induced bipolar mania.

  4. Chondroitin Sulfate Induces Depression of Synaptic Transmission and Modulation of Neuronal Plasticity in Rat Hippocampal Slices.

    PubMed

    Albiñana, Elisa; Gutierrez-Luengo, Javier; Hernández-Juarez, Natalia; Baraibar, Andrés M; Montell, Eulalia; Vergés, Josep; García, Antonio G; Hernández-Guijo, Jesus M

    2015-01-01

    It is currently known that in CNS the extracellular matrix is involved in synaptic stabilization and limitation of synaptic plasticity. However, it has been reported that the treatment with chondroitinase following injury allows the formation of new synapses and increased plasticity and functional recovery. So, we hypothesize that some components of extracellular matrix may modulate synaptic transmission. To test this hypothesis we evaluated the effects of chondroitin sulphate (CS) on excitatory synaptic transmission, cellular excitability, and neuronal plasticity using extracellular recordings in the CA1 area of rat hippocampal slices. CS caused a reversible depression of evoked field excitatory postsynaptic potentials in a concentration-dependent manner. CS also reduced the population spike amplitude evoked after orthodromic stimulation but not when the population spikes were antidromically evoked; in this last case a potentiation was observed. CS also enhanced paired-pulse facilitation and long-term potentiation. Our study provides evidence that CS, a major component of the brain perineuronal net and extracellular matrix, has a function beyond the structural one, namely, the modulation of synaptic transmission and neuronal plasticity in the hippocampus.

  5. Dynamic Control of Synaptic Adhesion and Organizing Molecules in Synaptic Plasticity

    PubMed Central

    2017-01-01

    Synapses play a critical role in establishing and maintaining neural circuits, permitting targeted information transfer throughout the brain. A large portfolio of synaptic adhesion/organizing molecules (SAMs) exists in the mammalian brain involved in synapse development and maintenance. SAMs bind protein partners, forming trans-complexes spanning the synaptic cleft or cis-complexes attached to the same synaptic membrane. SAMs play key roles in cell adhesion and in organizing protein interaction networks; they can also provide mechanisms of recognition, generate scaffolds onto which partners can dock, and likely take part in signaling processes as well. SAMs are regulated through a portfolio of different mechanisms that affect their protein levels, precise localization, stability, and the availability of their partners at synapses. Interaction of SAMs with their partners can further be strengthened or weakened through alternative splicing, competing protein partners, ectodomain shedding, or astrocytically secreted factors. Given that numerous SAMs appear altered by synaptic activity, in vivo, these molecules may be used to dynamically scale up or scale down synaptic communication. Many SAMs, including neurexins, neuroligins, cadherins, and contactins, are now implicated in neuropsychiatric and neurodevelopmental diseases, such as autism spectrum disorder, schizophrenia, and bipolar disorder and studying their molecular mechanisms holds promise for developing novel therapeutics. PMID:28255461

  6. Dynamic Control of Synaptic Adhesion and Organizing Molecules in Synaptic Plasticity

    SciTech Connect

    Rudenko, Gabby

    2017-01-01

    Synapses play a critical role in establishing and maintaining neural circuits, permitting targeted information transfer throughout the brain. A large portfolio of synaptic adhesion/organizing molecules (SAMs) exists in the mammalian brain involved in synapse development and maintenance. SAMs bind protein partners, formingtrans-complexes spanning the synaptic cleft orcis-complexes attached to the same synaptic membrane. SAMs play key roles in cell adhesion and in organizing protein interaction networks; they can also provide mechanisms of recognition, generate scaffolds onto which partners can dock, and likely take part in signaling processes as well. SAMs are regulated through a portfolio of different mechanisms that affect their protein levels, precise localization, stability, and the availability of their partners at synapses. Interaction of SAMs with their partners can further be strengthened or weakened through alternative splicing, competing protein partners, ectodomain shedding, or astrocytically secreted factors. Given that numerous SAMs appear altered by synaptic activity, in vivo, these molecules may be used to dynamically scale up or scale down synaptic communication. Many SAMs, including neurexins, neuroligins, cadherins, and contactins, are now implicated in neuropsychiatric and neurodevelopmental diseases, such as autism spectrum disorder, schizophrenia, and bipolar disorder and studying their molecular mechanisms holds promise for developing novel therapeutics.

  7. Dynamic Control of Synaptic Adhesion and Organizing Molecules in Synaptic Plasticity.

    PubMed

    Rudenko, Gabby

    2017-01-01

    Synapses play a critical role in establishing and maintaining neural circuits, permitting targeted information transfer throughout the brain. A large portfolio of synaptic adhesion/organizing molecules (SAMs) exists in the mammalian brain involved in synapse development and maintenance. SAMs bind protein partners, forming trans-complexes spanning the synaptic cleft or cis-complexes attached to the same synaptic membrane. SAMs play key roles in cell adhesion and in organizing protein interaction networks; they can also provide mechanisms of recognition, generate scaffolds onto which partners can dock, and likely take part in signaling processes as well. SAMs are regulated through a portfolio of different mechanisms that affect their protein levels, precise localization, stability, and the availability of their partners at synapses. Interaction of SAMs with their partners can further be strengthened or weakened through alternative splicing, competing protein partners, ectodomain shedding, or astrocytically secreted factors. Given that numerous SAMs appear altered by synaptic activity, in vivo, these molecules may be used to dynamically scale up or scale down synaptic communication. Many SAMs, including neurexins, neuroligins, cadherins, and contactins, are now implicated in neuropsychiatric and neurodevelopmental diseases, such as autism spectrum disorder, schizophrenia, and bipolar disorder and studying their molecular mechanisms holds promise for developing novel therapeutics.

  8. miRNAs in NMDA receptor-dependent synaptic plasticity and psychiatric disorders

    PubMed Central

    Shen, Hongmei; Li, Zheng

    2017-01-01

    The identification and functional delineation of miRNAs (a class of small non-coding RNAs) have added a new layer of complexity to our understanding of the molecular mechanisms underlying synaptic plasticity. Genome-wide association studies in conjunction with investigations in cellular and animal models, moreover, provide evidence that miRNAs are involved in psychiatric disorders. In the present review, we examine the current knowledge about the roles played by miRNAs in NMDA (N-methyl-d-aspartate) receptor-dependent synaptic plasticity and psychiatric disorders. PMID:27252401

  9. All About Running: Synaptic Plasticity, Growth Factors and Adult Hippocampal Neurogenesis

    PubMed Central

    Vivar, Carmen; Potter, Michelle C.; van Praag, Henriette

    2015-01-01

    Accumulating evidence from animal and human research shows exercise benefits learning and memory, which may reduce the risk of neurodegenerative diseases, and could delay age-related cognitive decline. Exercise-induced improvements in learning and memory are correlated with enhanced adult hippocampal neurogenesis and increased activity-dependent synaptic plasticity. In this present chapter we will highlight the effects of physical activity on cognition in rodents, as well as on dentate gyrus (DG) neurogenesis, synaptic plasticity, spine density, neurotransmission and growth factors, in particular brain-derived nerve growth factor (BDNF). PMID:22847651

  10. Spike-timing-dependent synaptic plasticity depends on dendritic location

    NASA Astrophysics Data System (ADS)

    Froemke, Robert C.; Poo, Mu-ming; Dan, Yang

    2005-03-01

    In the neocortex, each neuron receives thousands of synaptic inputs distributed across an extensive dendritic tree. Although postsynaptic processing of each input is known to depend on its dendritic location, it is unclear whether activity-dependent synaptic modification is also location-dependent. Here we report that both the magnitude and the temporal specificity of spike-timing-dependent synaptic modification vary along the apical dendrite of rat cortical layer 2/3 pyramidal neurons. At the distal dendrite, the magnitude of long-term potentiation is smaller, and the window of pre-/postsynaptic spike interval for long-term depression (LTD) is broader. The spike-timing window for LTD correlates with the window of action potential-induced suppression of NMDA (N-methyl-D-aspartate) receptors; this correlation applies to both their dendritic location-dependence and pharmacological properties. Presynaptic stimulation with partial blockade of NMDA receptors induced LTD and occluded further induction of spike-timing-dependent LTD, suggesting that NMDA receptor suppression underlies LTD induction. Computer simulation studies showed that the dendritic inhomogeneity of spike-timing-dependent synaptic modification leads to differential input selection at distal and proximal dendrites according to the temporal characteristics of presynaptic spike trains. Such location-dependent tuning of inputs, together with the dendritic heterogeneity of postsynaptic processing, could enhance the computational capacity of cortical pyramidal neurons.

  11. 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

  12. Hippocampal Testosterone Relates to Reference Memory Performance and Synaptic Plasticity in Male Rats

    PubMed Central

    Schulz, Kristina; Korz, Volker

    2010-01-01

    Steroids are important neuromodulators influencing cognitive performance and synaptic plasticity. While the majority of literature concerns adrenal- and gonadectomized animals, very little is known about the “natural” endogenous release of hormones during learning. Therefore, we measured blood and brain (hippocampus, prefrontal cortex) testosterone, estradiol, and corticosterone concentrations of intact male rats undergoing a spatial learning paradigm which is known to reinforce hippocampal plasticity. We found significant modulations of all investigated hormones over the training course. Corticosterone and testosterone were correlated manifold with behavior, while estradiol expressed fewer correlations. In the recall session, testosterone was tightly coupled to reference memory (RM) performance, which is crucial for reinforcement of synaptic plasticity in the dentate gyrus. Intriguingly, prefrontal cortex and hippocampal levels related differentially to RM performance. Correlations of testosterone and corticosterone switched from unspecific activity to specific cognitive functions over training. Correspondingly, exogenous application of testosterone revealed different effects on synaptic and neuronal plasticity in trained versus untrained animals. While hippocampal long-term potentiation (LTP) of the field excitatory postsynaptic potential (fEPSP) was prolonged in untrained rats, both the fEPSP- and the population spike amplitude (PSA)-LTP was impaired in trained rats. Behavioral performance was unaffected, but correlations of hippocampal field potentials with behavior were decoupled in treated rats. The data provide important evidence that besides adrenal, also gonadal steroids play a mechanistic role in linking synaptic plasticity to cognitive performance. PMID:21188275

  13. Dietary curcumin counteracts the outcome of traumatic brain injury on oxidative stress, synaptic plasticity, and cognition.

    PubMed

    Wu, Aiguo; Ying, Zhe; Gomez-Pinilla, Fernando

    2006-02-01

    The pervasive action of oxidative stress on neuronal function and plasticity after traumatic brain injury (TBI) is becoming increasingly recognized. Here, we evaluated the capacity of the powerful antioxidant curry spice curcumin ingested in the diet to counteract the oxidative damage encountered in the injured brain. In addition, we have examined the possibility that dietary curcumin may favor the injured brain by interacting with molecular mechanisms that maintain synaptic plasticity and cognition. The analysis was focused on the BDNF system based on its action on synaptic plasticity and cognition by modulating synapsin I and CREB. Rats were exposed to a regular diet or a diet high in saturated fat, with or without 500 ppm curcumin for 4 weeks (n = 8/group), before a mild fluid percussion injury (FPI) was performed. The high-fat diet has been shown to exacerbate the effects of TBI on synaptic plasticity and cognitive function. Supplementation of curcumin in the diet dramatically reduced oxidative damage and normalized levels of BDNF, synapsin I, and CREB that had been altered after TBI. Furthermore, curcumin supplementation counteracted the cognitive impairment caused by TBI. These results are in agreement with previous evidence, showing that oxidative stress can affect the injured brain by acting through the BDNF system to affect synaptic plasticity and cognition. The fact that oxidative stress is an intrinsic component of the neurological sequel of TBI and other insults indicates that dietary antioxidant therapy is a realistic approach to promote protective mechanisms in the injured brain.

  14. Fear Extinction as a Model for Synaptic Plasticity in Major Depressive Disorder

    PubMed Central

    Feige, Bernd; Blechert, Jens; Normann, Claus; Nissen, Christoph

    2014-01-01

    Background The neuroplasticity hypothesis of major depressive disorder proposes that a dysfunction of synaptic plasticity represents a basic pathomechanism of the disorder. Animal models of depression indicate enhanced plasticity in a ventral emotional network, comprising the amygdala. Here, we investigated fear extinction learning as a non-invasive probe for amygdala-dependent synaptic plasticity in patients with major depressive disorder and healthy controls. Methods Differential fear conditioning was measured in 37 inpatients with severe unipolar depression (International Classification of Diseases, 10th revision, criteria) and 40 healthy controls. The eye-blink startle response, a subcortical output signal that is modulated by local synaptic plasticity in the amygdala in fear acquisition and extinction learning, was recorded as the primary outcome parameter. Results After robust and similar fear acquisition in both groups, patients with major depressive disorder showed significantly enhanced fear extinction learning in comparison to healthy controls, as indicated by startle responses to conditioned stimuli. The strength of extinction learning was positively correlated with the total illness duration. Conclusions The finding of enhanced fear extinction learning in major depressive disorder is consistent with the concept that the disorder is characterized by enhanced synaptic plasticity in the amygdala and the ventral emotional network. Clinically, the observation emphasizes the potential of successful extinction learning, the basis of exposure therapy, in anxiety-related disorders despite the frequent comorbidity of major depressive disorder. PMID:25545818

  15. Brain Deletion of Insulin Receptor Substrate 2 Disrupts Hippocampal Synaptic Plasticity and Metaplasticity

    PubMed Central

    Costello, Derek A.; Claret, Marc; Al-Qassab, Hind; Plattner, Florian; Irvine, Elaine E.; Choudhury, Agharul I.; Giese, K. Peter; Withers, Dominic J.; Pedarzani, Paola

    2012-01-01

    Objective Diabetes mellitus is associated with cognitive deficits and an increased risk of dementia, particularly in the elderly. These deficits and the corresponding neurophysiological structural and functional alterations are linked to both metabolic and vascular changes, related to chronic hyperglycaemia, but probably also defects in insulin action in the brain. To elucidate the specific role of brain insulin signalling in neuronal functions that are relevant for cognitive processes we have investigated the behaviour of neurons and synaptic plasticity in the hippocampus of mice lacking the insulin receptor substrate protein 2 (IRS-2). Research Design and Methods To study neuronal function and synaptic plasticity in the absence of confounding factors such as hyperglycaemia, we used a mouse model with a central nervous system- (CNS)-restricted deletion of IRS-2 (NesCreIrs2KO). Results We report a deficit in NMDA receptor-dependent synaptic plasticity in the hippocampus of NesCreIrs2KO mice, with a concomitant loss of metaplasticity, the modulation of synaptic plasticity by the previous activity of a synapse. These plasticity changes are associated with reduced basal phosphorylation of the NMDA receptor subunit NR1 and of downstream targets of the PI3K pathway, the protein kinases Akt and GSK-3β. Conclusions These findings reveal molecular and cellular mechanisms that might underlie cognitive deficits linked to specific defects of neuronal insulin signalling. PMID:22383997

  16. Coexistence of Multiple Types of Synaptic Plasticity in Individual Hippocampal CA1 Pyramidal Neurons

    PubMed Central

    Edelmann, Elke; Cepeda-Prado, Efrain; Leßmann, Volkmar

    2017-01-01

    Understanding learning and memory mechanisms is an important goal in neuroscience. To gain insights into the underlying cellular mechanisms for memory formation, synaptic plasticity processes are studied with various techniques in different brain regions. A valid model to scrutinize different ways to enhance or decrease synaptic transmission is recording of long-term potentiation (LTP) or long-term depression (LTD). At the single cell level, spike timing-dependent plasticity (STDP) protocols have emerged as a powerful tool to investigate synaptic plasticity with stimulation paradigms that also likely occur during memory formation in vivo. Such kind of plasticity can be induced by different STDP paradigms with multiple repeat numbers and stimulation patterns. They subsequently recruit or activate different molecular pathways and neuromodulators for induction and expression of STDP. Dopamine (DA) and brain-derived neurotrophic factor (BDNF) have been recently shown to be important modulators for hippocampal STDP at Schaffer collateral (SC)-CA1 synapses and are activated exclusively by distinguishable STDP paradigms. Distinct types of parallel synaptic plasticity in a given neuron depend on specific subcellular molecular prerequisites. Since the basal and apical dendrites of CA1 pyramidal neurons are known to be heterogeneous, and distance-dependent dendritic gradients for specific receptors and ion channels are described, the dendrites might provide domain specific locations for multiple types of synaptic plasticity in the same neuron. In addition to the distinct signaling and expression mechanisms of various types of LTP and LTD, activation of these different types of plasticity might depend on background brain activity states. In this article, we will discuss some ideas why multiple forms of synaptic plasticity can simultaneously and independently coexist and can contribute so effectively to increasing the efficacy of memory storage and processing capacity of the

  17. Maladaptive Synaptic Plasticity in L-DOPA-Induced Dyskinesia

    PubMed Central

    Wang, Qiang; Zhang, Wangming

    2016-01-01

    The emergence of L-DOPA-induced dyskinesia (LID) in patients with Parkinson disease (PD) could be due to maladaptive plasticity of corticostriatal synapses in response to L-DOPA treatment. A series of recent studies has revealed that LID is associated with marked morphological plasticity of striatal dendritic spines, particularly cell type-specific structural plasticity of medium spiny neurons (MSNs) in the striatum. In addition, evidence demonstrating the occurrence of plastic adaptations, including aberrant morphological and functional features, in multiple components of cortico-basal ganglionic circuitry, such as primary motor cortex (M1) and basal ganglia (BG) output nuclei. These adaptations have been implicated in the pathophysiology of LID. Here, we briefly review recent studies that have addressed maladaptive plastic changes within the cortico-BG loop in dyskinetic animal models of PD and patients with PD. PMID:28066191

  18. A spaceflight study of synaptic plasticity in adult rat vestibular maculas

    NASA Technical Reports Server (NTRS)

    Ross, M. D.

    1994-01-01

    Behavioral signs of vestibular perturbation in altered gravity have not been well correlated with structural modifications in neurovestibular centers. This ultrastructural research investigated synaptic plasticity in hair cells of adult rat utricular maculas exposed to microgravity for nine days on a space shuttle. The hypothesis was that synaptic plasticity would be more evident in type II hair cells because they are part of a distributed modifying macular circuitry. All rats were shared with other investigators and were subjected to treatments unrelated to this experiment. Maculas were obtained from flight and control rats after shuttle return (R + 0) and nine days post-flight (R + 9). R + 9 rats had chromodacryorrhea, a sign of acute stress. Tissues were prepared for ultrastructural study by conventional methods. Ribbon synapses were counted in fifty serial sections from medial utricular macular regions of three rats of each flight and control group. Counts in fifty additional consecutive sections from one sample in each group established method reliability. All synapses were photographed and located to specific cells on mosaics of entire sections. Pooled data were analyzed statistically. Flown rats showed abnormal posture and movement at R + 0. They had statistically significant increases in total ribbon synapses and in sphere-like ribbons in both kinds of hair cells; in type II cells, pairs of synapses nearly doubled and clusters of 3 to 6 synapses increased twelve-fold. At R + 9, behavioral signs were normal. However, synapse counts remained high in both kinds of hair cells of flight maculas and were elevated in control type II cells. Only counts in type I cells showed statistically significant differences at R + 9. High synaptic counts at R + 9 may have resulted from stress due to experimental treatments. The results nevertheless demonstrate that adult maculas retain the potential for synaptic plasticity. Type II cells exhibited more synaptic plasticity, but

  19. A spaceflight study of synaptic plasticity in adult rat vestibular maculas

    NASA Technical Reports Server (NTRS)

    Ross, M. D.

    1994-01-01

    Behavioral signs of vestibular perturbation in altered gravity have not been well correlated with structural modifications in neurovestibular centers. This ultrastructural research investigated synaptic plasticity in hair cells of adult rat utricular maculas exposed to microgravity for nine days on a space shuttle. The hypothesis was that synaptic plasticity would be more evident in type II hair cells because they are part of a distributed modifying macular circuitry. All rats were shared with other investigators and were subjected to treatments unrelated to this experiment. Maculas were obtained from flight and control rats after shuttle return (R + 0) and nine days post-flight (R + 9). R + 9 rats had chromodacryorrhea, a sign of acute stress. Tissues were prepared for ultrastructural study by conventional methods. Ribbon synapses were counted in fifty serial sections from medial utricular macular regions of three rats of each flight and control group. Counts in fifty additional consecutive sections from one sample in each group established method reliability. All synapses were photographed and located to specific cells on mosaics of entire sections. Pooled data were analyzed statistically. Flown rats showed abnormal posture and movement at R + 0. They had statistically significant increases in total ribbon synapses and in sphere-like ribbons in both kinds of hair cells; in type II cells, pairs of synapses nearly doubled and clusters of 3 to 6 synapses increased twelve-fold. At R + 9, behavioral signs were normal. However, synapse counts remained high in both kinds of hair cells of flight maculas and were elevated in control type II cells. Only counts in type I cells showed statistically significant differences at R + 9. High synaptic counts at R + 9 may have resulted from stress due to experimental treatments. The results nevertheless demonstrate that adult maculas retain the potential for synaptic plasticity. Type II cells exhibited more synaptic plasticity, but

  20. Learning of Precise Spike Times with Homeostatic Membrane Potential Dependent Synaptic Plasticity

    PubMed Central

    Albers, Christian; Westkott, Maren; Pawelzik, Klaus

    2016-01-01

    Precise spatio-temporal patterns of neuronal action potentials underly e.g. sensory representations and control of muscle activities. However, it is not known how the synaptic efficacies in the neuronal networks of the brain adapt such that they can reliably generate spikes at specific points in time. Existing activity-dependent plasticity rules like Spike-Timing-Dependent Plasticity are agnostic to the goal of learning spike times. On the other hand, the existing formal and supervised learning algorithms perform a temporally precise comparison of projected activity with the target, but there is no known biologically plausible implementation of this comparison. Here, we propose a simple and local unsupervised synaptic plasticity mechanism that is derived from the requirement of a balanced membrane potential. Since the relevant signal for synaptic change is the postsynaptic voltage rather than spike times, we call the plasticity rule Membrane Potential Dependent Plasticity (MPDP). Combining our plasticity mechanism with spike after-hyperpolarization causes a sensitivity of synaptic change to pre- and postsynaptic spike times which can reproduce Hebbian spike timing dependent plasticity for inhibitory synapses as was found in experiments. In addition, the sensitivity of MPDP to the time course of the voltage when generating a spike allows MPDP to distinguish between weak (spurious) and strong (teacher) spikes, which therefore provides a neuronal basis for the comparison of actual and target activity. For spatio-temporal input spike patterns our conceptually simple plasticity rule achieves a surprisingly high storage capacity for spike associations. The sensitivity of the MPDP to the subthreshold membrane potential during training allows robust memory retrieval after learning even in the presence of activity corrupted by noise. We propose that MPDP represents a biophysically plausible mechanism to learn temporal target activity patterns. PMID:26900845

  1. The APP Intracellular Domain Is Required for Normal Synaptic Morphology, Synaptic Plasticity, and Hippocampus-Dependent Behavior.

    PubMed

    Klevanski, Maja; Herrmann, Ulrike; Weyer, Sascha W; Fol, Romain; Cartier, Nathalie; Wolfer, David P; Caldwell, John H; Korte, Martin; Müller, Ulrike C

    2015-12-09

    The amyloid precursor protein family (APP/APLPs) has essential roles for neuromuscular synapse development and for the formation and plasticity of synapses within the CNS. Despite this, it has remained unclear whether APP mediates its functions primarily as a cell surface adhesion and signaling molecule or via its numerous proteolytic cleavage products. To address these questions, we followed a genetic approach and used APPΔCT15 knockin mice lacking the last 15 amino acids of APP, including the highly conserved YENPTY protein interaction motif. To circumvent functional compensation by the closely related APLP2, these mice were bred to an APLP2-KO background to generate APPΔCT15-DM double mutants. These APPΔCT15-DM mice were partially viable and displayed defects in neuromuscular synapse morphology and function with impairments in the ability to sustain transmitter release that resulted in muscular weakness. In the CNS, we demonstrate pronounced synaptic deficits including impairments in LTP that were associated with deficits in spatial learning and memory. Thus, the APP-CT15 domain provides essential physiological functions, likely via recruitment of specific interactors. Together with the well-established role of APPsα for synaptic plasticity, this shows that multiple domains of APP, including the conserved C-terminus, mediate signals required for normal PNS and CNS physiology. In addition, we demonstrate that lack of the APP-CT15 domain strongly impairs Aβ generation in vivo, establishing the APP C-terminus as a target for Aβ-lowering strategies. Synaptic dysfunction and cognitive decline are early hallmark features of Alzheimer's disease. Thus, it is essential to elucidate the in vivo function(s) of APP at the synapse. At present, it is unknown whether APP family proteins function as cell surface receptors, or mainly via shedding of their secreted ectodomains, such as neurotrophic APPsα. Here, to dissect APP functional domains, we used APP mutant mice

  2. Wnts in adult brain: from synaptic plasticity to cognitive deficiencies

    PubMed Central

    Oliva, Carolina A.; Vargas, Jessica Y.; Inestrosa, Nibaldo C.

    2013-01-01

    During development of the central nervous system the Wnt signaling pathway has been implicated in a wide spectrum of physiological processes, including neuronal connectivity and synapse formation. Wnt proteins and components of the Wnt pathway are expressed in the brain since early development to the adult life, however, little is known about its role in mature synapses. Here, we review evidences indicating that Wnt proteins participate in the remodeling of pre- and post-synaptic regions, thus modulating synaptic function. We include the most recent data in the literature showing that Wnts are constantly released in the brain to maintain the basal neural activity. Also, we review the evidences that involve components of the Wnt pathway in the development of neurological and mental disorders, including a special emphasis on in vivo studies that relate behavioral abnormalities to deficiencies in Wnt signaling. Finally, we include the evidences that support a neuroprotective role of Wnt proteins in Alzheimer’s disease. We postulate that deregulation in Wnt signaling might have a fundamental role in the origin of neurological diseases, by altering the synaptic function at stages where the phenotype is not yet established but when the cognitive decline starts. PMID:24348327

  3. Wnts in adult brain: from synaptic plasticity to cognitive deficiencies.

    PubMed

    Oliva, Carolina A; Vargas, Jessica Y; Inestrosa, Nibaldo C

    2013-12-03

    During development of the central nervous system the Wnt signaling pathway has been implicated in a wide spectrum of physiological processes, including neuronal connectivity and synapse formation. Wnt proteins and components of the Wnt pathway are expressed in the brain since early development to the adult life, however, little is known about its role in mature synapses. Here, we review evidences indicating that Wnt proteins participate in the remodeling of pre- and post-synaptic regions, thus modulating synaptic function. We include the most recent data in the literature showing that Wnts are constantly released in the brain to maintain the basal neural activity. Also, we review the evidences that involve components of the Wnt pathway in the development of neurological and mental disorders, including a special emphasis on in vivo studies that relate behavioral abnormalities to deficiencies in Wnt signaling. Finally, we include the evidences that support a neuroprotective role of Wnt proteins in Alzheimer's disease. We postulate that deregulation in Wnt signaling might have a fundamental role in the origin of neurological diseases, by altering the synaptic function at stages where the phenotype is not yet established but when the cognitive decline starts.

  4. Functional diversity on synaptic plasticity mediated by endocannabinoids

    PubMed Central

    Cachope, Roger

    2012-01-01

    Endocannabinoids (eCBs) act as modulators of synaptic transmission through activation of a number of receptors, including, but not limited to, cannabinoid receptor 1 (CB1). eCBs share CB1 receptors as a common target with Δ9-tetrahydrocannabinol (THC), the main psychoactive ingredient in marijuana. Although THC has been used for recreational and medicinal purposes for thousands of years, little was known about its effects at the cellular level or on neuronal circuits. Identification of CB1 receptors and the subsequent development of its specific ligands has therefore enhanced our ability to study and bring together a substantial amount of knowledge regarding how marijuana and eCBs modify interneuronal communication. To date, the eCB system, composed of cannabinoid receptors, ligands and the relevant enzymes, is recognized as the best-described retrograde signalling system in the brain. Its impact on synaptic transmission is widespread and more diverse than initially thought. The aim of this review is to succinctly present the most common forms of eCB-mediated modulation of synaptic transmission, while also illustrating the multiplicity of effects resulting from specializations of this signalling system at the circuital level. PMID:23108543

  5. Dietary cholesterol alters memory and synaptic structural plasticity in young rat brain.

    PubMed

    Ya, Bai-liu; Liu, Wen-yan; Ge, Feng; Zhang, Yan-xia; Zhu, Bao-liang; Bai, Bo

    2013-08-01

    Cholesterol plays an important role in synaptic plasticity, learning and memory. To better explore how dietary cholesterol contributes to learning and memory and the related changes in synaptic structural plasticity, rats were categorized into a regular diet (RD) group and a cholesterol-enriched diet (CD) group, and were fed with respective diet for 2 months. Dietary cholesterol impacts on learning and memory, hippocampal synaptic ultrastructure, expression levels of postsynaptic density-95 (PSD-95), synaptophysin (SYP) and cannabinoid receptor type 1 (CB1R) were investigated. We found CD rats had better performances in learning and memory using Morris water maze and object recognition test than RD rats. The memory improvement was accompanied with alterations of synaptic ultrastructure in the CA1 area of the hippocampus evaluated by electron microscopy, enhanced immunoreactivity of SYP, a presynaptic marker in hippocampus detected by immunocytochemistry, as well as increased levels of PSD-95, SYP and decreased level of CB1R in brains of CD rats determined by Western blot. Taken together, the results suggest that the improvement of learning and memory abilities of the young adult rats induced by dietary cholesterol may be linked with changes in synaptic structural plasticity in the brain.

  6. A role for synaptic plasticity in the adolescent development of executive function

    PubMed Central

    Selemon, L D

    2013-01-01

    Adolescent brain maturation is characterized by the emergence of executive function mediated by the prefrontal cortex, e.g., goal planning, inhibition of impulsive behavior and set shifting. Synaptic pruning of excitatory contacts is the signature morphologic event of late brain maturation during adolescence. Mounting evidence suggests that glutamate receptor-mediated synaptic plasticity, in particular long term depression (LTD), is important for elimination of synaptic contacts in brain development. This review examines the possibility (1) that LTD mechanisms are enhanced in the prefrontal cortex during adolescence due to ongoing synaptic pruning in this late developing cortex and (2) that enhanced synaptic plasticity in the prefrontal cortex represents a key molecular substrate underlying the critical period for maturation of executive function. Molecular sites of interaction between environmental factors, such as alcohol and stress, and glutamate receptor mediated plasticity are considered. The accentuated negative impact of these factors during adolescence may be due in part to interference with LTD mechanisms that refine prefrontal cortical circuitry and when disrupted derail normal maturation of executive function. Diminished prefrontal cortical control over risk-taking behavior could further exacerbate negative outcomes associated with these behaviors, as for example addiction and depression. Greater insight into the neurobiology of the adolescent brain is needed to fully understand the molecular basis for heightened vulnerability during adolescence to the injurious effects of substance abuse and stress. PMID:23462989

  7. Learning the structure of correlated synaptic subgroups using stable and competitive spike-timing-dependent plasticity.

    PubMed

    Meffin, H; Besson, J; Burkitt, A N; Grayden, D B

    2006-04-01

    Synaptic plasticity must be both competitive and stable if ongoing learning of the structure of neural inputs is to occur. In this paper, a wide class of spike-timing-dependent plasticity (STDP) models is identified that have both of these desirable properties in the case in which the input consists of subgroups of synapses that are correlated within the subgroup through the occurrence of simultaneous input spikes. The process of synaptic structure formation is studied, illustrating one particular class of these models. When the learning rate is small, multiple alternative synaptic structures are possible given the same inputs, with the outcome depending on the initial weight configuration. For large learning rates, the synaptic structure does not stabilize, resulting in neurons without consistent response properties. For learning rates in between, a unique and stable synaptic structure typically forms. When this synaptic structure exhibits a bimodal distribution, the neuron will respond selectively to one or more of the subgroups. The robustness with which this selectivity develops during learning is largely determined by the ratio of the subgroup correlation strength to the number of subgroups. The fraction of potentiated subgroups is primarily determined by the balance between potentiation and depression.

  8. Elements of a neurobiological theory of hippocampal function: the role of synaptic plasticity, synaptic tagging and schemas.

    PubMed

    Morris, R G M

    2006-06-01

    The 2004 EJN Lecture was an attempt to lay out further aspects of a developing neurobiological theory of hippocampal function [Morris, R.G.M., Moser, E.I., Riedel, G., Martin, S.J., Sandin, J., Day, M. & O'Carroll, C. (2003) Phil. Trans. R. Soc. Lond. B Biol. Sci., 358, 773-786.] These are that (i) activity-dependent synaptic plasticity plays a key role in the automatic encoding and initial storage of attended experience; (ii) the persistence of hippocampal synaptic potentiation over time can be influenced by other independent neural events happening closely in time, an idea with behavioural implications for memory; and (iii) that systems-level consolidation of memory traces within neocortex is guided both by hippocampal traces that have been subject to cellular consolidation and by the presence of organized schema in neocortex into which relevant newly encoded information might be stored. Hippocampal memory is associative and, to study it more effectively than with previous paradigms, a new learning task is described which is unusual in requiring the incidental encoding of flavour-place paired associates, with the readout of successful storage being successful recall of a place given the flavour with which it was paired. NMDA receptor-dependent synaptic plasticity is shown to be critical for the encoding and intermediate storage of memory traces in this task, while AMPA receptor-mediated fast synaptic transmission is necessary for memory retrieval. Typically, these rapidly encoded traces decay quite rapidly over time. Synaptic potentiation also decays rapidly, but can be rendered more persistent by a process of cellular consolidation in which synaptic tagging and capture play a key part in determining whether or not it will be persistent. Synaptic tags set at the time of an event, even many trivial events, can capture the products of the synthesis of plasticity proteins set in train by events before, during or even after an event to be remembered. Tag

  9. Exosomes neutralize synaptic-plasticity-disrupting activity of Aβ assemblies in vivo

    PubMed Central

    2013-01-01

    Background Exosomes, small extracellular vesicles of endosomal origin, have been suggested to be involved in both the metabolism and aggregation of Alzheimer’s disease (AD)-associated amyloid β-protein (Aβ). Despite their ubiquitous presence and the inclusion of components which can potentially interact with Aβ, the role of exosomes in regulating synaptic dysfunction induced by Aβ has not been explored. Results We here provide in vivo evidence that exosomes derived from N2a cells or human cerebrospinal fluid can abrogate the synaptic-plasticity-disrupting activity of both synthetic and AD brain-derived Aβ. Mechanistically, this effect involves sequestration of synaptotoxic Aβ assemblies by exosomal surface proteins such as PrPC rather than Aβ proteolysis. Conclusions These data suggest that exosomes can counteract the inhibitory action of Aβ, which contributes to perpetual capability for synaptic plasticity. PMID:24284042

  10. Developmental Synaptic Plasticity at the Thalamocortical Input to Barrel Cortex: Mechanisms and Roles

    PubMed Central

    Daw, Michael I.; Scott, Helen L.; Isaac, John T.R.

    2007-01-01

    The thalamocortical (TC) input to layer IV provides the major pathway for ascending sensory information to the mammalian sensory cortex. During development there is a dramatic refinement of this input that underlies the maturation of the topographical map in layer IV. Over the last ten years our understanding of the mechanisms of the developmental and experience-driven changes in synaptic function at TC synapses has been greatly advanced. Here we describe these studies that point to a key role for NMDA receptor-dependent synaptic plasticity, a role for kainate receptors and for a rapid maturation in GABAergic inhibition. The expression mechanisms of some of the forms of neonatal synaptic plasticity are novel and, in combination with other mechanisms, produce a layer IV circuit that exhibits functional properties necessary for mature sensory processing. PMID:17329121

  11. Transcriptional Control of Synaptic Plasticity by Transcription Factor NF-κB.

    PubMed

    Engelmann, Christian; Haenold, Ronny

    2016-01-01

    Activation of nuclear factor kappa B (NF-κB) transcription factors is required for the induction of synaptic plasticity and memory formation. All components of this signaling pathway are localized at synapses, and transcriptionally active NF-κB dimers move to the nucleus to translate synaptic signals into altered gene expression. Neuron-specific inhibition results in altered connectivity of excitatory and inhibitory synapses and functionally in selective learning deficits. Recent research on transgenic mice with impaired or hyperactivated NF-κB gave important insights into plasticity-related target gene expression that is regulated by NF-κB. In this minireview, we update the available data on the role of this transcription factor for learning and memory formation and comment on cross-sectional activation of NF-κB in the aged and diseased brain that may directly or indirectly affect κB-dependent transcription of synaptic genes.

  12. HDAC4 governs a transcriptional program essential for synaptic plasticity and memory.

    PubMed

    Sando, Richard; Gounko, Natalia; Pieraut, Simon; Liao, Lujian; Yates, John; Maximov, Anton

    2012-11-09

    Neuronal activity influences genes involved in circuit development and information processing. However, the molecular basis of this process remains poorly understood. We found that HDAC4, a histone deacetylase that shuttles between the nucleus and cytoplasm, controls a transcriptional program essential for synaptic plasticity and memory. The nuclear import of HDAC4 and its association with chromatin is negatively regulated by NMDA receptors. In the nucleus, HDAC4 represses genes encoding constituents of central synapses, thereby affecting synaptic architecture and strength. Furthermore, we show that a truncated form of HDAC4 encoded by an allele associated with mental retardation is a gain-of-function nuclear repressor that abolishes transcription and synaptic transmission despite the loss of the deacetylase domain. Accordingly, mice carrying a mutant that mimics this allele exhibit deficits in neurotransmission, spatial learning, and memory. These studies elucidate a mechanism of experience-dependent plasticity and define the biological role of HDAC4 in the brain.

  13. 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…

  14. SRC Inhibition Reduces NR2B Surface Expression and Synaptic Plasticity in the Amygdala

    ERIC Educational Resources Information Center

    Sinai, Laleh; Duffy, Steven; Roder, John C.

    2010-01-01

    The Src protein tyrosine kinase plays a central role in the regulation of N-methyl-d-aspartate receptor (NMDAR) activity by regulating NMDAR subunit 2B (NR2B) surface expression. In the amygdala, NMDA-dependent synaptic plasticity resulting from convergent somatosensory and auditory inputs contributes to emotional memory; however, the role of Src…

  15. Somato-dendritic Synaptic Plasticity and Error-backpropagation in Active Dendrites

    PubMed Central

    Schiess, Mathieu; Urbanczik, Robert; Senn, Walter

    2016-01-01

    In the last decade dendrites of cortical neurons have been shown to nonlinearly combine synaptic inputs by evoking local dendritic spikes. It has been suggested that these nonlinearities raise the computational power of a single neuron, making it comparable to a 2-layer network of point neurons. But how these nonlinearities can be incorporated into the synaptic plasticity to optimally support learning remains unclear. We present a theoretically derived synaptic plasticity rule for supervised and reinforcement learning that depends on the timing of the presynaptic, the dendritic and the postsynaptic spikes. For supervised learning, the rule can be seen as a biological version of the classical error-backpropagation algorithm applied to the dendritic case. When modulated by a delayed reward signal, the same plasticity is shown to maximize the expected reward in reinforcement learning for various coding scenarios. Our framework makes specific experimental predictions and highlights the unique advantage of active dendrites for implementing powerful synaptic plasticity rules that have access to downstream information via backpropagation of action potentials. PMID:26841235

  16. Environmental Enrichment Ameliorates Neonatal Sevoflurane Exposure-Induced Cognitive and Synaptic Plasticity Impairments.

    PubMed

    Ji, Mu-huo; Wang, Xing-ming; Sun, Xiao-ru; Zhang, Hui; Ju, Ling-sha; Qiu, Li-li; Yang, Jiao-jiao; Jia, Min; Wu, Jing; Yang, Jianjun

    2015-11-01

    Early exposure to sevoflurane, an inhalation anesthetic, induces neurodegeneration in the developing brain and subsequent long-term neurobehavioral abnormalities. Here, we investigated whether an enriched environment could mitigate neonatal sevoflurane exposure-induced long-term cognitive and synaptic plasticity impairments. Male C57BL/6 mice were exposed to 3 % sevoflurane 2 h daily for 3 days from postnatal day 6 (P6) to P8. The exposed mice were randomly allocated to an enriched environment for 2 h daily between P8 and P42 or to a standard environment. Their behavior and cognition were assessed using open field (P35) and fear conditioning tests (P41-P42). Hematoxylin-eosin staining was used to study morphological changes in pyramidal neurons of hippocampal CA1 and CA3 regions. Synaptic plasticity alternations were assessed using western blotting, Golgi staining, and electrophysiological recording. We found that sevoflurane-exposed mice housed in a standard environment exhibited a reduced freezing response in the contextual test, decreased number of dendritic spines on pyramidal neurons and synaptic plasticity-related proteins in the hippocampus, and impaired long-term potentiation. However, in an enriched environment, some of these abnormities induced by repeated sevoflurane exposure. In conclusion, neonatal sevoflurane exposure-induced cognitive and synaptic plasticity impairments are ameliorated by an enriched environment.

  17. Dopamine and Norepinephrine Receptors Participate in Methylphenidate Enhancement of In Vivo Hippocampal Synaptic Plasticity

    PubMed Central

    Jenson, Daniel; Yang, Kechun; Acevedo-Rodriguez, Alexandra; Levine, Amber; Broussard, John I.; Tang, Jianrong; Dani, John A.

    2014-01-01

    Attention-deficit hyperactive disorder (ADHD) is the most commonly studied and diagnosed psychiatric disorder in children. Methylphenidate (MPH, e.g., Ritalin) has been used to treat ADHD for over 50 years. It is the most commonly prescribed treatment for ADHD, and in the past decade it was the drug most commonly prescribed to teenagers. In addition, MPH has become one of the most widely abused drugs on college campuses. In this study, we examined the effects of MPH on hippocampal synaptic plasticity, which serves as a measurable quantification of memory mechanisms. Field potentials were recorded with permanently implanted electrodes in freely-moving mice to quantify MPH modulation of perforant path synaptic transmission onto granule cells of the dentate gyrus. Our hypothesis was that MPH affects hippocampal synaptic plasticity underlying learning because MPH boosts catecholamine signaling by blocking the dopamine and norepinephrine transporters (DAT and NET respectively). In vitro hippocampal slice experiments indicated MPH enhances perforant path plasticity, and this MPH enhancement arose from action via D1-type dopamine receptors and β-type adrenergic receptors. Similarly, MPH boosted in vivo initiation of long-term potentiation (LTP). While there was an effect via both dopamine and adrenergic receptors in vivo, LTP induction was more dependent on the MPH-induced action via D1-type dopamine receptors. Under biologically reasonable experimental conditions, MPH enhances hippocampal synaptic plasticity via catecholamine receptors. PMID:25445492

  18. Suppression of synaptic plasticity by fullerenol in rat hippocampus in vitro

    PubMed Central

    Wang, Xin-Xing; Zha, Ying-Ying; Yang, Bo; Chen, Lin; Wang, Ming

    2016-01-01

    Fullerenol, a water-soluble fullerene derivative, has attracted much attention due to its bioactive properties, including the antioxidative properties and free radical scavenging ability. Due to its superior nature, fullerenol represents a promising diagnostic, therapeutic, and protective agent. Therefore, elucidation of the possible side effects of fullerenol is important in determining its potential role. In the present study, we investigated the acute effects of 5 μM fullerenol on synaptic plasticity in hippocampal brain slices of rats. Incubation with fullerenol for 20 minutes significantly decreased the peak of paired-pulse facilitation and long-term potentiation, indicating that fullerenol suppresses the short- and long-term synaptic plasticity of region I of hippocampus. We found that fullerenol depressed the activity and the expression of nitric oxide (NO) synthase in hippocampus. In view of the important role of NO in synaptic plasticity, the inhibition of fullerenol on NO synthase may contribute to the suppression of synaptic plasticity. These findings may facilitate the evaluation of the side effects of fullerenol. PMID:27729790

  19. SRC Inhibition Reduces NR2B Surface Expression and Synaptic Plasticity in the Amygdala

    ERIC Educational Resources Information Center

    Sinai, Laleh; Duffy, Steven; Roder, John C.

    2010-01-01

    The Src protein tyrosine kinase plays a central role in the regulation of N-methyl-d-aspartate receptor (NMDAR) activity by regulating NMDAR subunit 2B (NR2B) surface expression. In the amygdala, NMDA-dependent synaptic plasticity resulting from convergent somatosensory and auditory inputs contributes to emotional memory; however, the role of Src…

  20. 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…

  1. Computational quest for understanding the role of astrocyte signaling in synaptic transmission and plasticity

    PubMed Central

    De Pittà, Maurizio; Volman, Vladislav; Berry, Hugues; Parpura, Vladimir; Volterra, Andrea; Ben-Jacob, Eshel

    2012-01-01

    The complexity of the signaling network that underlies astrocyte-synapse interactions may seem discouraging when tackled from a theoretical perspective. Computational modeling is challenged by the fact that many details remain hitherto unknown and conventional approaches to describe synaptic function are unsuitable to explain experimental observations when astrocytic signaling is taken into account. Supported by experimental evidence is the possibility that astrocytes perform genuine information processing by means of their calcium signaling and are players in the physiological setting of the basal tone of synaptic transmission. Here we consider the plausibility of this scenario from a theoretical perspective, focusing on the modulation of synaptic release probability by the astrocyte and its implications on synaptic plasticity. The analysis of the signaling pathways underlying such modulation refines our notion of tripartite synapse and has profound implications on our understanding of brain function. PMID:23267326

  2. The Synaptic Proteome during Development and Plasticity of the Mouse Visual Cortex*

    PubMed Central

    Dahlhaus, Martijn; Wan Li, Ka; van der Schors, Roel C.; Saiepour, M. Hadi; van Nierop, Pim; Heimel, J. Alexander; Hermans, Josephine M.; Loos, Maarten; Smit, August B.; Levelt, Christiaan N.

    2011-01-01

    During brain development, the neocortex shows periods of enhanced plasticity, which enables the acquisition of knowledge and skills that we use and build on in adult life. Key to persistent modifications of neuronal connectivity and plasticity of the neocortex are molecular changes occurring at the synapse. Here we used isobaric tag for relative and absolute quantification to measure levels of 467 synaptic proteins in a well-established model of plasticity in the mouse visual cortex and the regulation of its critical period. We found that inducing visual cortex plasticity by monocular deprivation during the critical period increased levels of kinases and proteins regulating the actin-cytoskeleton and endocytosis. Upon closure of the critical period with age, proteins associated with transmitter vesicle release and the tubulin- and septin-cytoskeletons increased, whereas actin-regulators decreased in line with augmented synapse stability and efficacy. Maintaining the visual cortex in a plastic state by dark rearing mice into adulthood only partially prevented these changes and increased levels of G-proteins and protein kinase A subunits. This suggests that in contrast to the general belief, dark rearing does not simply delay cortical development but may activate signaling pathways that specifically maintain or increase the plasticity potential of the visual cortex. Altogether, this study identified many novel candidate plasticity proteins and signaling pathways that mediate synaptic plasticity during critical developmental periods or restrict it in adulthood. PMID:21398567

  3. Effects of Selective Deafferentation on the Discharge Characteristics of Medial Rectus Motoneurons.

    PubMed

    Hernández, Rosendo G; Benítez-Temiño, Beatriz; Morado-Díaz, Camilo J; Davis-López de Carrizosa, María América; de la Cruz, Rosa R; Pastor, Angel M

    2017-09-20

    of Deiters (ATD) are a dual system that supports the firing of medial rectus motoneurons. We report the effect of sectioning the MLF or the ATD pathway on the firing of medial rectus motoneurons, as well as the plastic mechanisms by which one input compensates for the lack of the other. This work shows that while the effects of MLF transection are permanent, the ATD section produces transitory effects. A mechanism based on axonal sprouting and occupancy of the vacant synaptic space due to deafferentation is the base for the mechanism of compensation on the medial rectus motoneuron. Copyright © 2017 the authors 0270-6474/17/379172-17$15.00/0.

  4. Mapping the Consequences of Impaired Synaptic Plasticity in Schizophrenia through Development: An Integrative Model for Diverse Clinical Features.

    PubMed

    Forsyth, Jennifer K; Lewis, David A

    2017-10-01

    Schizophrenia is associated with alterations in sensory, motor, and cognitive functions that emerge before psychosis onset; identifying pathogenic processes that can account for this multi-faceted phenotype remains a challenge. Accumulating evidence suggests that synaptic plasticity is impaired in schizophrenia. Given the role of synaptic plasticity in learning, memory, and neural circuit maturation, impaired plasticity may underlie many features of the schizophrenia syndrome. Here, we summarize the neurobiology of synaptic plasticity, review evidence that plasticity is impaired in schizophrenia, and explore a framework in which impaired synaptic plasticity interacts with brain maturation to yield the emergence of sensory, motor, cognitive, and psychotic features at different times during development in schizophrenia. Key gaps in the literature and future directions for testing this framework are discussed. Copyright © 2017 Elsevier Ltd. All rights reserved.

  5. Two aspects of ASIC function: Synaptic plasticity and neuronal injury.

    PubMed

    Huang, Yan; Jiang, Nan; Li, Jun; Ji, Yong-Hua; Xiong, Zhi-Gang; Zha, Xiang-ming

    2015-07-01

    Extracellular brain pH fluctuates in both physiological and disease conditions. The main postsynaptic proton receptor is the acid-sensing ion channels (ASICs). During the past decade, much progress has been made on protons, ASICs, and neurological disease. This review summarizes the recent progress on synaptic role of protons and our current understanding of how ASICs contribute to various types of neuronal injury in the brain. This article is part of the Special Issue entitled 'Acid-Sensing Ion Channels in the Nervous System'. Copyright © 2015 Elsevier Ltd. All rights reserved.

  6. New rules governing synaptic plasticity in core nucleus accumbens medium spiny neurons.

    PubMed

    Ji, Xincai; Martin, Gilles E

    2012-12-01

    The nucleus accumbens is a forebrain region responsible for drug reward and goal-directed behaviors. It has long been believed that drugs of abuse exert their addictive properties on behavior by altering the strength of synaptic communication over long periods of time. To date, attempts at understanding the relationship between drugs of abuse and synaptic plasticity have relied on the high-frequency long-term potentiation model of T.V. Bliss & T. Lømo [(1973) Journal of Physiology, 232, 331-356]. We examined synaptic plasticity using spike-timing-dependent plasticity, a stimulation paradigm that reflects more closely the in vivo firing patterns of mouse core nucleus accumbens medium spiny neurons and their afferents. In contrast to other brain regions, the same stimulation paradigm evoked bidirectional long-term plasticity. The magnitude of spike-timing-dependent long-term potentiation (tLTP) changed with the delay between action potentials and excitatory post-synaptic potentials, and frequency, whereas that of spike-timing-dependent long-term depression (tLTD) remained unchanged. We showed that tLTP depended on N-methyl-d-aspartate receptors, whereas tLTD relied on action potentials. Importantly, the intracellular calcium signaling pathways mobilised during tLTP and tLTD were different. Thus, calcium-induced calcium release underlies tLTD but not tLTP. Finally, we found that the firing pattern of a subset of medium spiny neurons was strongly inhibited by dopamine receptor agonists. Surprisingly, these neurons were exclusively associated with tLTP but not with tLTD. Taken together, these data point to the existence of two subgroups of medium spiny neurons with distinct properties, each displaying unique abilities to undergo synaptic plasticity.

  7. Microglia: a new frontier for synaptic plasticity, learning and memory, and neurodegenerative disease research.

    PubMed

    Morris, Gary P; Clark, Ian A; Zinn, Raphael; Vissel, Bryce

    2013-10-01

    We focus on emerging roles for microglia in synaptic plasticity, cognition and disease. We outline evidence that ramified microglia, traditionally thought to be functionally "resting" (i.e. quiescent) in the normal brain, in fact are highly dynamic and plastic. Ramified microglia continually and rapidly extend processes, contact synapses in an activity and experience dependent manner, and play a functionally dynamic role in synaptic plasticity, possibly through release of cytokines and growth factors. Ramified microglial also contribute to structural plasticity through the elimination of synapses via phagocytic mechanisms, which is necessary for normal cognition. Microglia have numerous mechanisms to monitor neuronal activity and numerous mechanisms also exist to prevent them transitioning to an activated state, which involves retraction of their surveying processes. Based on the evidence, we suggest that maintaining the ramified state of microglia is essential for normal synaptic and structural plasticity that supports cognition. Further, we propose that change of their ramified morphology and function, as occurs in inflammation associated with numerous neurological disorders such as Alzheimer's and Parkinson's disease, disrupts their intricate and essential synaptic functions. In turn altered microglia function could cause synaptic dysfunction and excess synapse loss early in disease, initiating a range of pathologies that follow. We conclude that the future of learning and memory research depends on an understanding of the role of non-neuronal cells and that this should include using sophisticated molecular, cellular, physiological and behavioural approaches combined with imaging to causally link the role of microglia to brain function and disease including Alzheimer's and Parkinson's disease and other neuropsychiatric disorders. Copyright © 2013 Elsevier Inc. All rights reserved.

  8. Adenosine A2A Receptors in the Amygdala Control Synaptic Plasticity and Contextual Fear Memory.

    PubMed

    Simões, Ana Patrícia; Machado, Nuno J; Gonçalves, Nélio; Kaster, Manuella P; Simões, Ana T; Nunes, Ana; Pereira de Almeida, Luís; Goosens, Ki Ann; Rial, Daniel; Cunha, Rodrigo A

    2016-11-01

    The consumption of caffeine modulates working and reference memory through the antagonism of adenosine A2A receptors (A2ARs) controlling synaptic plasticity processes in hippocampal excitatory synapses. Fear memory essentially involves plastic changes in amygdala circuits. However, it is unknown if A2ARs in the amygdala regulate synaptic plasticity and fear memory. We report that A2ARs in the amygdala are enriched in synapses and located to glutamatergic synapses, where they selectively control synaptic plasticity rather than synaptic transmission at a major afferent pathway to the amygdala. Notably, the downregulation of A2ARs selectively in the basolateral complex of the amygdala, using a lentivirus with a silencing shRNA (small hairpin RNA targeting A2AR (shA2AR)), impaired fear acquisition as well as Pavlovian fear retrieval. This is probably associated with the upregulation and gain of function of A2ARs in the amygdala after fear acquisition. The importance of A2ARs to control fear memory was further confirmed by the ability of SCH58261 (0.1 mg/kg; A2AR antagonist), caffeine (5 mg/kg), but not DPCPX (0.5 mg/kg; A1R antagonist), treatment for 7 days before fear conditioning onwards, to attenuate the retrieval of context fear after 24-48 h and after 7-8 days. These results demonstrate that amygdala A2ARs control fear memory and the underlying process of synaptic plasticity in this brain region. This provides a neurophysiological basis for the association between A2AR polymorphisms and phobia or panic attacks in humans and prompts a therapeutic interest in A2ARs to manage fear-related pathologies.

  9. New Rules Governing Synaptic Plasticity In Core Nucleus Accumbens Medium Spiny Neurons

    PubMed Central

    Ji, Xincai; Martin, Gilles E.

    2012-01-01

    The nucleus accumbens is a forebrain region responsible for drug reward and goal directed behaviors. It has long been believed that drugs of abuse exert their addictive properties on behavior by altering the strength of synaptic communication over long periods of time. To date, attempts at understanding the relationship between drugs of abuse and synaptic plasticity have relied on the high-frequency long-term potentiation model of Bliss and LØmo (1973). We examined synaptic plasticity using spike-timing-dependent plasticity, a stimulation paradigm that reflects more closely in vivo firing patterns of core NAcc medium spiny neurons and their afferents. In contrast to other brain regions, the same stimulation paradigm evoked bidirectional long-term plasticity. Long-term potentiation (tLTP) magnitude changed with delay between action potentials (APs) and excitatory post-synaptic potentials (EPSPs), and frequency, while that of long-term depression (tLTD) remained unchanged. We showed that tLTP depended on NMDA receptors, whereas tLTD relied on action potentials. Importantly, intracellular calcium signaling pathways mobilized during tLTP and tLTD were different. Thus, calcium-induced calcium release underlies tLTD but not tLTP. Finally, we found that the firing pattern of a subset of MSNs was strongly inhibited by dopamine receptor agonists. Surprisingly, these neurons were exclusively associated with tLTP but not with tLTD. Taken together, these data point to the existence of two subgroups of MSNs with distinct properties, each displaying unique abilities to undergo synaptic plasticity. PMID:23013293

  10. ATP from synaptic terminals and astrocytes regulates NMDA receptors and synaptic plasticity through PSD-95 multi-protein complex

    PubMed Central

    Lalo, U.; Palygin, O.; Verkhratsky, A.; Grant, S. G. N.; Pankratov, Y.

    2016-01-01

    Recent studies highlighted the importance of astrocyte-secreted molecules, such as ATP, for the slow modulation of synaptic transmission in central neurones. Biophysical mechanisms underlying the impact of gliotransmitters on the strength of individual synapse remain, however, unclear. Here we show that purinergic P2X receptors can bring significant contribution to the signalling in the individual synaptic boutons. ATP released from astrocytes facilitates a recruitment of P2X receptors into excitatory synapses by Ca2+-dependent mechanism. P2X receptors, co-localized with NMDA receptors in the excitatory synapses, can be activated by ATP co-released with glutamate from pre-synaptic terminals and by glia-derived ATP. An activation of P2X receptors in turn leads to down-regulation of postsynaptic NMDA receptors via Ca2+-dependent de-phosphorylation and interaction with PSD-95 multi-protein complex. Genetic deletion of the PSD-95 or P2X4 receptors obliterated ATP-mediated down-regulation of NMDA receptors. Impairment of purinergic modulation of NMDA receptors in the PSD-95 mutants dramatically decreased the threshold of LTP induction and increased the net magnitude of LTP. Our findings show that synergistic action of glia- and neurone-derived ATP can pre-modulate efficacy of excitatory synapses and thereby can have an important role in the glia-neuron communications and brain meta-plasticity. PMID:27640997

  11. Stable learning of functional maps in self-organizing spiking neural networks with continuous synaptic plasticity

    PubMed Central

    Srinivasa, Narayan; Jiang, Qin

    2013-01-01

    This study describes a spiking model that self-organizes for stable formation and maintenance of orientation and ocular dominance maps in the visual cortex (V1). This self-organization process simulates three development phases: an early experience-independent phase, a late experience-independent phase and a subsequent refinement phase during which experience acts to shape the map properties. The ocular dominance maps that emerge accommodate the two sets of monocular inputs that arise from the lateral geniculate nucleus (LGN) to layer 4 of V1. The orientation selectivity maps that emerge feature well-developed iso-orientation domains and fractures. During the last two phases of development the orientation preferences at some locations appear to rotate continuously through ±180° along circular paths and referred to as pinwheel-like patterns but without any corresponding point discontinuities in the orientation gradient maps. The formation of these functional maps is driven by balanced excitatory and inhibitory currents that are established via synaptic plasticity based on spike timing for both excitatory and inhibitory synapses. The stability and maintenance of the formed maps with continuous synaptic plasticity is enabled by homeostasis caused by inhibitory plasticity. However, a prolonged exposure to repeated stimuli does alter the formed maps over time due to plasticity. The results from this study suggest that continuous synaptic plasticity in both excitatory neurons and interneurons could play a critical role in the formation, stability, and maintenance of functional maps in the cortex. PMID:23450808

  12. Multiple forms of long-term synaptic plasticity at hippocampal mossy fiber synapses on interneurons.

    PubMed

    Galván, Emilio J; Cosgrove, Kathleen E; Barrionuevo, Germán

    2011-04-01

    The hippocampal mossy fiber (MF) pathway originates from the dentate gyrus granule cells and provides a powerful excitatory synaptic drive to neurons in the dentate gyrus hilus and area CA3. Much of the early work on the MF pathway focused on its electrophysiological properties, and ability to drive CA3 pyramidal cell activity. Over the last ten years, however, a new focus on the synaptic interaction between granule cells and inhibitory interneurons has emerged. These data have revealed an immense heterogeneity of long-term plasticity at MF synapses on various interneuron targets. Interestingly, these studies also indicate that the mechanisms of MF long-term plasticity in some interneuron subtypes may be more similar to pyramidal cells than previously appreciated. In this review, we first define the synapse types at each of the interneuron targets based on the receptors present. We then describe the different forms of long-term plasticity observed, and the mechanisms underlying each form as they are currently understood. Finally we highlight various open questions surrounding MF long-term plasticity in interneurons, focusing specifically on the induction and maintenance of LTP, and what the functional impact of persistent changes in efficacy at MF-interneuron synapses might be on the emergent properties of the inhibitory network dynamics in area CA3. This article is part of a Special Issue entitled 'Synaptic Plasticity & Interneurons'.

  13. Stable learning of functional maps in self-organizing spiking neural networks with continuous synaptic plasticity.

    PubMed

    Srinivasa, Narayan; Jiang, Qin

    2013-01-01

    This study describes a spiking model that self-organizes for stable formation and maintenance of orientation and ocular dominance maps in the visual cortex (V1). This self-organization process simulates three development phases: an early experience-independent phase, a late experience-independent phase and a subsequent refinement phase during which experience acts to shape the map properties. The ocular dominance maps that emerge accommodate the two sets of monocular inputs that arise from the lateral geniculate nucleus (LGN) to layer 4 of V1. The orientation selectivity maps that emerge feature well-developed iso-orientation domains and fractures. During the last two phases of development the orientation preferences at some locations appear to rotate continuously through ±180° along circular paths and referred to as pinwheel-like patterns but without any corresponding point discontinuities in the orientation gradient maps. The formation of these functional maps is driven by balanced excitatory and inhibitory currents that are established via synaptic plasticity based on spike timing for both excitatory and inhibitory synapses. The stability and maintenance of the formed maps with continuous synaptic plasticity is enabled by homeostasis caused by inhibitory plasticity. However, a prolonged exposure to repeated stimuli does alter the formed maps over time due to plasticity. The results from this study suggest that continuous synaptic plasticity in both excitatory neurons and interneurons could play a critical role in the formation, stability, and maintenance of functional maps in the cortex.

  14. Presynaptic NMDA Receptors: Newly Appreciated Roles in Cortical Synaptic Function and Plasticity

    PubMed Central

    Corlew, Rebekah; Brasier, Daniel J.; Feldman, Daniel E.; Philpot, Benjamin D.

    2009-01-01

    Many aspects of synaptic development, plasticity, and neurotransmission are critically influenced by NMDA-type glutamate receptors (NMDARs). Moreover, dysfunction of NMDARs has been implicated in a broad array of neurological disorders, including schizophrenia, stroke, epilepsy, and neuropathic pain. Classically, NMDARs were thought to be exclusively postsynaptic. However, substantial evidence in the last 10 years demonstrates that NMDARs also exist presynaptically, and that presynaptic NMDA receptors (preNMDARs) modulate synapse function and have critical roles in plasticity at many synapses. Here we review current knowledge of the role of preNMDARs in synaptic transmission and plasticity, focusing on the neocortex. We discuss the prevalence, function, and development of these receptors, and their potential modification by experience and in brain pathology. PMID:19029059

  15. Retrograde response in axotomized motoneurons: nitric oxide as a key player in triggering reversion toward a dedifferentiated phenotype.

    PubMed

    González-Forero, D; Moreno-López, B

    2014-12-26

    The adult brain retains a considerable capacity to functionally reorganize its circuits, which mainly relies on the prevalence of three basic processes that confer plastic potential: synaptic plasticity, plastic changes in intrinsic excitability and, in certain central nervous system (CNS) regions, also neurogenesis. Experimental models of peripheral nerve injury have provided a useful paradigm for studying injury-induced mechanisms of central plasticity. In particular, axotomy of somatic motoneurons triggers a robust retrograde reaction in the CNS, characterized by the expression of plastic changes affecting motoneurons, their synaptic inputs and surrounding glia. Axotomized motoneurons undergo a reprograming of their gene expression and biosynthetic machineries which produce cell components required for axonal regrowth and lead them to resume a functionally dedifferentiated phenotype characterized by the removal of afferent synaptic contacts, atrophy of dendritic arbors and an enhanced somato-dendritic excitability. Although experimental research has provided valuable clues to unravel many basic aspects of this central response, we are still lacking detailed information on the cellular/molecular mechanisms underlying its expression. It becomes clear, however, that the state-switch must be orchestrated by motoneuron-derived signals produced under the direction of the re-activated growth program. Our group has identified the highly reactive gas nitric oxide (NO) as one of these signals, by providing robust evidence for its key role to induce synapse elimination and increases in intrinsic excitability following motor axon damage. We have elucidated operational principles of the NO-triggered downstream transduction pathways mediating each of these changes. Our findings further demonstrate that de novo NO synthesis is not only "necessary" but also "sufficient" to promote the expression of at least some of the features that reflect reversion toward a dedifferentiated

  16. Short-Term Synaptic Plasticity Regulation in Solution-Gated Indium-Gallium-Zinc-Oxide Electric-Double-Layer Transistors.

    PubMed

    Wan, Chang Jin; Liu, Yang Hui; Zhu, Li Qiang; Feng, Ping; Shi, Yi; Wan, Qing

    2016-04-20

    In the biological nervous system, synaptic plasticity regulation is based on the modulation of ionic fluxes, and such regulation was regarded as the fundamental mechanism underlying memory and learning. Inspired by such biological strategies, indium-gallium-zinc-oxide (IGZO) electric-double-layer (EDL) transistors gated by aqueous solutions were proposed for synaptic behavior emulations. Short-term synaptic plasticity, such as paired-pulse facilitation, high-pass filtering, and orientation tuning, was experimentally emulated in these EDL transistors. Most importantly, we found that such short-term synaptic plasticity can be effectively regulated by alcohol (ethyl alcohol) and salt (potassium chloride) additives. Our results suggest that solution gated oxide-based EDL transistors could act as the platforms for short-term synaptic plasticity emulation.

  17. Apolipoprotein E in Synaptic Plasticity and Alzheimer’s Disease: Potential Cellular and Molecular Mechanisms

    PubMed Central

    Kim, Jaekwang; Yoon, Hyejin; Basak, Jacob; Kim, Jungsu

    2014-01-01

    Alzheimer’s disease (AD) is clinically characterized with progressive memory loss and cognitive decline. Synaptic dysfunction is an early pathological feature that occurs prior to neurodegeneration and memory dysfunction. Mounting evidence suggests that aggregation of amyloid-β (Aβ) and hyperphosphorylated tau leads to synaptic deficits and neurodegeneration, thereby to memory loss. Among the established genetic risk factors for AD, the ɛ4 allele of apolipoprotein E (APOE) is the strongest genetic risk factor. We and others previously demonstrated that apoE regulates Aβ aggregation and clearance in an isoform-dependent manner. While the effect of apoE on Aβ may explain how apoE isoforms differentially affect AD pathogenesis, there are also other underexplored pathogenic mechanisms. They include differential effects of apoE on cerebral energy metabolism, neuroinflammation, neurovascular function, neurogenesis, and synaptic plasticity. ApoE is a major carrier of cholesterols that are required for neuronal activity and injury repair in the brain. Although there are a few conflicting findings and the underlying mechanism is still unclear, several lines of studies demonstrated that apoE4 leads to synaptic deficits and impairment in long-term potentiation, memory and cognition. In this review, we summarize current understanding of apoE function in the brain, with a particular emphasis on its role in synaptic plasticity and the underlying cellular and molecular mechanisms, involving low-density lipoprotein receptor-related protein 1 (LRP1), syndecan, and LRP8/ApoER2. PMID:25358504

  18. Activity- and age-dependent GABAergic synaptic plasticity in the developing rat hippocampus.

    PubMed

    Gubellini, P; Ben-Ari, Y; Gaïarsa, J L

    2001-12-01

    Activity-dependent plasticity of GABAergic synaptic transmission was investigated in rat hippocampal slices obtained between postnatal day (P) 0-15 using the whole-cell patch-clamp recording technique. Spontaneous GABA(A) receptor-mediated postsynaptic currents (sGABA(A)-PSCs) were isolated in the presence of ionotropic glutamate receptor antagonists. A conditioning protocol relevant to the physiological condition, consisting of repetitive depolarizing pulses (DPs) at 0.1 Hz, was able to induce long-lasting changes in both frequency and amplitude of sGABA(A)-PSCs between P0 and P8. Starting from P12, DPs were unable to induce any form of synaptic plasticity. The effects of DPs were tightly keyed to the frequency at which they were delivered. When delivered at a lower (0.05 Hz) or higher (1 Hz) frequency, DPs failed to induce any long-lasting change in the frequency or amplitude of sGABA(A)-PSCs. In two cases, DPs were able to activate sGABA(A)-PSCs in previously synaptically silent cells at P0-1. These results show that long-term changes in GABAergic synaptic activity can be induced during a restricted period of development by a conditioning protocol relevant to the physiological condition. It is suggested that such activity-induced modifications may represent a physiological mechanism for the functional maturation of GABAergic synaptic transmission.

  19. Bidirectional synaptic structural plasticity after chronic cocaine administration occurs through Rap1 small GTPase signaling

    PubMed Central

    Cahill, Michael E.; Bagot, Rosemary C.; Gancarz, Amy M.; Walker, Deena M.; Sun, HaoSheng; Wang, Zi-Jun; Heller, Elizabeth A.; Feng, Jian; Kennedy, Pamela J.; Koo, Ja Wook; Cates, Hannah M.; Neve, Rachael L.; Shen, Li; Dietz, David M.

    2016-01-01

    Summary Dendritic spines are the sites of most excitatory synapses in the CNS, and opposing alterations in the synaptic structure of medium spiny neurons (MSNs) of the nucleus accumbens, a primary brain reward region, are seen at early vs. late time points after cocaine administration. Here we investigate the time-dependent molecular and biochemical processes that regulate this bidirectional synaptic structural plasticity of NAc MSNs and associated changes in cocaine reward in response to chronic cocaine exposure. Our findings reveal key roles for the bidirectional synaptic expression of the Rap1b small GTPase and an associated local-synaptic protein translation network in this process. The transcriptional mechanisms and pathway-specific inputs to NAc that regulate Rap1b expression are also characterized. Collectively, these findings provide a precise mechanism by which nuclear to synaptic interactions induce “metaplasticity” in NAc MSNs, and we reveal the specific effects of this plasticity on reward behavior in a brain circuit-specific manner. PMID:26844834

  20. Activity-dependent synaptic plasticity of a chalcogenide electronic synapse for neuromorphic systems.

    PubMed

    Li, Yi; Zhong, Yingpeng; Zhang, Jinjian; Xu, Lei; Wang, Qing; Sun, Huajun; Tong, Hao; Cheng, Xiaoming; Miao, Xiangshui

    2014-05-09

    Nanoscale inorganic electronic synapses or synaptic devices, which are capable of emulating the functions of biological synapses of brain neuronal systems, are regarded as the basic building blocks for beyond-Von Neumann computing architecture, combining information storage and processing. Here, we demonstrate a Ag/AgInSbTe/Ag structure for chalcogenide memristor-based electronic synapses. The memristive characteristics with reproducible gradual resistance tuning are utilised to mimic the activity-dependent synaptic plasticity that serves as the basis of memory and learning. Bidirectional long-term Hebbian plasticity modulation is implemented by the coactivity of pre- and postsynaptic spikes, and the sign and degree are affected by assorted factors including the temporal difference, spike rate and voltage. Moreover, synaptic saturation is observed to be an adjustment of Hebbian rules to stabilise the growth of synaptic weights. Our results may contribute to the development of highly functional plastic electronic synapses and the further construction of next-generation parallel neuromorphic computing architecture.

  1. Short-term environmental enrichment enhances synaptic plasticity in hippocampal slices from aged rats.

    PubMed

    Stein, Liana R; O'Dell, Kazuko A; Funatsu, Michiyo; Zorumski, Charles F; Izumi, Yukitoshi

    2016-08-04

    Age-associated changes in cognition are mirrored by impairments in cellular models of memory and learning, such as long-term potentiation (LTP) and long-term depression (LTD). In young rodents, environmental enrichment (EE) can enhance memory, alter LTP and LTD, as well as reverse cognitive deficits induced by aging. Whether short-term EE can benefit cognition and synaptic plasticity in aged rodents is unclear. Here, we tested if short-term EE could overcome age-associated impairments in induction of LTP and LTD. LTP and LTD could not be induced in the CA1 region of hippocampal slices in control, aged rats using standard stimuli that are highly effective in young rats. However, exposure of aged littermates to EE for three weeks enabled successful induction of LTP and LTD. EE-facilitated LTP was dependent upon N-methyl-d-aspartate receptors (NMDARs). These alterations in synaptic plasticity occurred with elevated levels of phosphorylated cAMP response element-binding protein and vascular endothelial growth factor, but in the absence of changes in several other synaptic and cellular markers. Importantly, our study suggests that even a relatively short period of EE is sufficient to alter synaptic plasticity and molecular markers linked to cognitive function in aged animals. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

  2. Roles for Regulator of G Protein Signaling Proteins in Synaptic Signaling and Plasticity

    PubMed Central

    Gerber, Kyle J.; Squires, Katherine E.

    2016-01-01

    The regulator of G protein signaling (RGS) family of proteins serves critical roles in G protein-coupled receptor (GPCR) and heterotrimeric G protein signal transduction. RGS proteins are best understood as negative regulators of GPCR/G protein signaling. They achieve this by acting as GTPase activating proteins (GAPs) for Gα subunits and accelerating the turnoff of G protein signaling. Many RGS proteins also bind additional signaling partners that either regulate their functions or enable them to regulate other important signaling events. At neuronal synapses, GPCRs, G proteins, and RGS proteins work in coordination to regulate key aspects of neurotransmitter release, synaptic transmission, and synaptic plasticity, which are necessary for central nervous system physiology and behavior. Accumulating evidence has revealed key roles for specific RGS proteins in multiple signaling pathways at neuronal synapses, regulating both pre- and postsynaptic signaling events and synaptic plasticity. Here, we review and highlight the current knowledge of specific RGS proteins (RGS2, RGS4, RGS7, RGS9-2, and RGS14) that have been clearly demonstrated to serve critical roles in modulating synaptic signaling and plasticity throughout the brain, and we consider their potential as future therapeutic targets. PMID:26655302

  3. CD44: a novel synaptic cell adhesion molecule regulating structural and functional plasticity of dendritic spines

    PubMed Central

    Roszkowska, Matylda; Skupien, Anna; Wójtowicz, Tomasz; Konopka, Anna; Gorlewicz, Adam; Kisiel, Magdalena; Bekisz, Marek; Ruszczycki, Blazej; Dolezyczek, Hubert; Rejmak, Emilia; Knapska, Ewelina; Mozrzymas, Jerzy W.; Wlodarczyk, Jakub; Wilczynski, Grzegorz M.; Dzwonek, Joanna

    2016-01-01

    Synaptic cell adhesion molecules regulate signal transduction, synaptic function, and plasticity. However, their role in neuronal interactions with the extracellular matrix (ECM) is not well understood. Here we report that the CD44, a transmembrane receptor for hyaluronan, modulates synaptic plasticity. High-resolution ultrastructural analysis showed that CD44 was localized at mature synapses in the adult brain. The reduced expression of CD44 affected the synaptic excitatory transmission of primary hippocampal neurons, simultaneously modifying dendritic spine shape. The frequency of miniature excitatory postsynaptic currents decreased, accompanied by dendritic spine elongation and thinning. These structural and functional alterations went along with a decrease in the number of presynaptic Bassoon puncta, together with a reduction of PSD-95 levels at dendritic spines, suggesting a reduced number of functional synapses. Lack of CD44 also abrogated spine head enlargement upon neuronal stimulation. Moreover, our results indicate that CD44 contributes to proper dendritic spine shape and function by modulating the activity of actin cytoskeleton regulators, that is, Rho GTPases (RhoA, Rac1, and Cdc42). Thus CD44 appears to be a novel molecular player regulating functional and structural plasticity of dendritic spines. PMID:27798233

  4. AMPA receptor trafficking and the mechanisms underlying synaptic plasticity and cognitive aging

    PubMed Central

    Henley, Jeremy M.; Wilkinson, Kevin A.

    2013-01-01

    Even in healthy individuals there is an inexorable agerelated decline in cognitive function. This is due, in large part, to reduced synaptic plasticity caused by changes in the molecular composition of the postsynaptic membrane. AMPA receptors (AMPARs) are glutamate-gated cation channels that mediate the overwhelming majority of fast excitatory transmission in the brain. Changes in AMPAR number and/or function are a core feature of synaptic plasticity and age-related cognitive decline, AMPARs are highly dynamic proteins that are subject to highly controlled trafficking, recycling, and/or degradation and replacement. This active regulation of AMPAR synthesis, targeting, synaptic dwell time, and degradation is fundamentally important for memory formation and storage. Further, aberrant AMPAR trafficking and consequent detrimental changes in synapses are strongly implicated in many brain diseases, which represent a vast social and economic burden. The purpose of this article is to provide an overview of the molecular and cellular AMPA receptor trafficking events that control synaptic responsiveness and plasticity, and highlight what is known currently known about how these processes change with age and disease. PMID:23576886

  5. Dietary cholesterol concentration affects synaptic plasticity and dendrite spine morphology of rabbit hippocampal neurons.

    PubMed

    Wang, Desheng; Zheng, Wen

    2015-10-05

    Previous studies have shown dietary cholesterol can enhance learning but retard memory which may be partly due to increased cholesterol levels in hippocampus and reduced afterhyperpolarization (AHP) amplitude of hippocampal CA1 neurons. This study explored the dose-dependent effect of dietary cholesterol on synaptic plasticity of rabbit hippocampal CA1 neurons and spine morphology, the postsynaptic structures responsible for synaptic plasticity. Field potential recordings revealed a low concentration of dietary cholesterol increased long-term potentiation (LTP) expression while high concentrations produced a pronounced reduction in LTP expression. Dietary cholesterol facilitated basal synaptic transmission but did not influence presynaptic function. DiI staining showed dietary cholesterol induced alterations in dendrite spine morphology characterized by increased mushroom spine density and decreased thin spine density, two kinds of dendritic spines that may be linked to memory consolidation and learning acquisition. Dietary cholesterol also modulated the geometric measures of mushroom spines. Therefore, dietary cholesterol dose-dependently modulated both synaptic plasticity and dendrite spine morphologies of hippocampal CA1 neurons that could mediate learning and memory changes previously seen to result from feeding a cholesterol diet.

  6. Neurexin-1 regulates sleep and synaptic plasticity in Drosophila melanogaster.

    PubMed

    Larkin, Aoife; Chen, Ming-Yu; Kirszenblat, Leonie; Reinhard, Judith; van Swinderen, Bruno; Claudianos, Charles

    2015-10-01

    Neurexins are cell adhesion molecules that are important for synaptic plasticity and homeostasis, although links to sleep have not yet been investigated. We examined the effects of neurexin-1 perturbation on sleep in Drosophila, showing that neurexin-1 nulls displayed fragmented sleep and altered circadian rhythm. Conversely, the over-expression of neurexin-1 could increase and consolidate night-time sleep. This was not solely due to developmental effects as it could be induced acutely in adulthood, and was coupled with evidence of synaptic growth. The timing of over-expression could differentially impact sleep patterns, with specific night-time effects. These results show that neurexin-1 was dynamically involved in synaptic plasticity and sleep in Drosophila. Neurexin-1 and a number of its binding partners have been repeatedly associated with mental health disorders, including autism spectrum disorders, schizophrenia and Tourette syndrome, all of which are also linked to altered sleep patterns. How and when plasticity-related proteins such as neurexin-1 function during sleep can provide vital information on the interaction between synaptic homeostasis and sleep, paving the way for more informed treatments of human disorders.

  7. Wnt signaling regulates acetylcholine receptor translocation and synaptic plasticity in the adult nervous system.

    PubMed

    Jensen, Michael; Hoerndli, Frédéric J; Brockie, Penelope J; Wang, Rui; Johnson, Erica; Maxfield, Dane; Francis, Michael M; Madsen, David M; Maricq, Andres V

    2012-03-30

    The adult nervous system is plastic, allowing us to learn, remember, and forget. Experience-dependent plasticity occurs at synapses--the specialized points of contact between neurons where signaling occurs. However, the mechanisms that regulate the strength of synaptic signaling are not well understood. Here, we define a Wnt-signaling pathway that modifies synaptic strength in the adult nervous system by regulating the translocation of one class of acetylcholine receptors (AChRs) to synapses. In Caenorhabditis elegans, we show that mutations in CWN-2 (Wnt ligand), LIN-17 (Frizzled), CAM-1 (Ror receptor tyrosine kinase), or the downstream effector DSH-1 (disheveled) result in similar subsynaptic accumulations of ACR-16/α7 AChRs, a consequent reduction in synaptic current, and predictable behavioral defects. Photoconversion experiments revealed defective translocation of ACR-16/α7 to synapses in Wnt-signaling mutants. Using optogenetic nerve stimulation, we demonstrate activity-dependent synaptic plasticity and its dependence on ACR-16/α7 translocation mediated by Wnt signaling via LIN-17/CAM-1 heteromeric receptors. Copyright © 2012 Elsevier Inc. All rights reserved.

  8. Prior regular exercise prevents synaptic plasticity impairment in sleep deprived female rats.

    PubMed

    Saadati, Hakimeh; Sheibani, Vahid; Esmaeili-Mahani, Saeed; Hajali, Vahid; Mazhari, Shahrzad

    2014-09-01

    Previous studies have indicated that physical exercise plays a preventive role in synaptic plasticity deficits in the hippocampus of sleep-deprived male rats. The objective of the present study was to evaluate the effects of treadmill running on early long term potentiation (E-LTP) at the Cornu Ammonis (CA1) area of the hippocampus in sleep-deprived female rats. Intact and ovariectomiezed (OVX) female Wistar rats were used in the present study. The exercise protocol was four weeks treadmill running and the multiple platform method was applied to induce 72 h sleep deprivation (SD). We examine the effect of exercise and/or SD on synaptic plasticity using in vivo extracellular recording in the CA1 area of the hippocampus. The field excitatory post-synaptic potential (fEPSP) slope was measured before and 2h after high frequency stimulation (HFS) in the experimental groups. Field potential recording indicated that the induction and maintenance phase of E-LTP impaired in the sleep deprived animals compared to the other groups. After 72 h SD, E-LTP impairments were prevented by 4 weeks of regular treadmill exercise. In conclusion, the synaptic plasticity deficit in sleep-deprived female rats was improved by regular physical exercise. Further studies are suggested to evaluate the possible underlying mechanisms.

  9. Postsynaptic regulation of synaptic plasticity by synaptotagmin 4 requires both C2 domains

    PubMed Central

    Barber, Cynthia F.; Jorquera, Ramon A.; Melom, Jan E.

    2009-01-01

    Ca2+ influx into synaptic compartments during activity is a key mediator of neuronal plasticity. Although the role of presynaptic Ca2+ in triggering vesicle fusion though the Ca2+ sensor synaptotagmin 1 (Syt 1) is established, molecular mechanisms that underlie responses to postsynaptic Ca2+ influx remain unclear. In this study, we demonstrate that fusion-competent Syt 4 vesicles localize postsynaptically at both neuromuscular junctions (NMJs) and central nervous system synapses in Drosophila melanogaster. Syt 4 messenger RNA and protein expression are strongly regulated by neuronal activity, whereas altered levels of postsynaptic Syt 4 modify synaptic growth and presynaptic release properties. Syt 4 is required for known forms of activity-dependent structural plasticity at NMJs. Synaptic proliferation and retrograde signaling mediated by Syt 4 requires functional C2A and C2B Ca2+–binding sites, as well as serine 284, an evolutionarily conserved substitution for a key Ca2+-binding aspartic acid found in other synaptotagmins. These data suggest that Syt 4 regulates activity-dependent release of postsynaptic retrograde signals that promote synaptic plasticity, similar to the role of Syt 1 as a Ca2+ sensor for presynaptic vesicle fusion. PMID:19822673

  10. Postsynaptic regulation of synaptic plasticity by synaptotagmin 4 requires both C2 domains.

    PubMed

    Barber, Cynthia F; Jorquera, Ramon A; Melom, Jan E; Littleton, J Troy

    2009-10-19

    Ca(2+) influx into synaptic compartments during activity is a key mediator of neuronal plasticity. Although the role of presynaptic Ca(2+) in triggering vesicle fusion though the Ca(2+) sensor synaptotagmin 1 (Syt 1) is established, molecular mechanisms that underlie responses to postsynaptic Ca(2+) influx remain unclear. In this study, we demonstrate that fusion-competent Syt 4 vesicles localize postsynaptically at both neuromuscular junctions (NMJs) and central nervous system synapses in Drosophila melanogaster. Syt 4 messenger RNA and protein expression are strongly regulated by neuronal activity, whereas altered levels of postsynaptic Syt 4 modify synaptic growth and presynaptic release properties. Syt 4 is required for known forms of activity-dependent structural plasticity at NMJs. Synaptic proliferation and retrograde signaling mediated by Syt 4 requires functional C2A and C2B Ca(2+)-binding sites, as well as serine 284, an evolutionarily conserved substitution for a key Ca(2+)-binding aspartic acid found in other synaptotagmins. These data suggest that Syt 4 regulates activity-dependent release of postsynaptic retrograde signals that promote synaptic plasticity, similar to the role of Syt 1 as a Ca(2+) sensor for presynaptic vesicle fusion.

  11. Effects of pre-natal alcohol exposure on hippocampal synaptic plasticity: Sex, age and methodological considerations.

    PubMed

    Fontaine, Christine J; Patten, Anna R; Sickmann, Helle M; Helfer, Jennifer L; Christie, Brian R

    2016-05-01

    The consumption of alcohol during gestation is detrimental to the developing central nervous system (CNS). The severity of structural and functional brain alterations associated with alcohol intake depends on many factors including the timing and duration of alcohol consumption. The hippocampal formation, a brain region implicated in learning and memory, is highly susceptible to the effects of developmental alcohol exposure. Some of the observed effects of alcohol on learning and memory may be due to changes at the synaptic level, as this teratogen has been repeatedly shown to interfere with hippocampal synaptic plasticity. At the molecular level alcohol interferes with receptor proteins and can disrupt hormones that are important for neuronal signaling and synaptic plasticity. In this review we examine the consequences of prenatal and early postnatal alcohol exposure on hippocampal synaptic plasticity and highlight the numerous factors that can modulate the effects of alcohol. We also discuss some potential mechanisms responsible for these changes as well as emerging therapeutic avenues that are beginning to be explored.

  12. Lavandula angustifolia extract improves deteriorated synaptic plasticity in an animal model of Alzheimer’s disease

    PubMed Central

    Soheili, Masoud; Tavirani, Mostafa Rezaei; Salami, Mahmoud

    2015-01-01

    Objective(s): Neurodegenerative Alzheimer’s disease (AD) is associated with profound deficits in synaptic transmission and synaptic plasticity. Long-term potentiation (LTP), an experimental form of synaptic plasticity, is intensively examined in hippocampus. In this study we evaluated the effect of aqueous extract of lavender (Lavandula angustifolia) on induction of LTP in the CA1 area of hippocampus. In response to stimulation of the Schaffer collaterals the baseline or tetanized field extracellular postsynaptic potentials (fEPSPs) were recorded in the CA1 area. Materials and Methods: The electrophysiological recordings were carried out in four groups of rats; two control groups including the vehicle (CON) and lavender (CE) treated rats and two Alzheimeric groups including the vehicle (ALZ) and lavender (AE) treated animals. Results: The extract inefficiently affected the baseline responses in the four testing groups. While the fEPSPs displayed a considerable LTP in the CON animals, no potentiation was evident in the tetanized responses in the ALZ rats. The herbal medicine effectively restored LTP in the AE group and further potentiated fEPSPs in the CE group. Conclusion: The positive effect of the lavender extract on the plasticity of synaptic transmission supports its previously reported behavioral effects on improvement of impaired spatial memory in the Alzheimeric animals. PMID:26949505

  13. AMPA receptor trafficking and the mechanisms underlying synaptic plasticity and cognitive aging.

    PubMed

    Henley, Jeremy M; Wilkinson, Kevin A

    2013-03-01

    Even in healthy individuals there is an inexorable agerelated decline in cognitive function. This is due, in large part, to reduced synaptic plasticity caused by changes in the molecular composition of the postsynaptic membrane. AMPA receptors (AMPARs) are glutamate-gated cation channels that mediate the overwhelming majority of fast excitatory transmission in the brain. Changes in AMPAR number and/or function are a core feature of synaptic plasticity and age-related cognitive decline, AMPARs are highly dynamic proteins that are subject to highly controlled trafficking, recycling, and/or degradation and replacement. This active regulation of AMPAR synthesis, targeting, synaptic dwell time, and degradation is fundamentally important for memory formation and storage. Further, aberrant AMPAR trafficking and consequent detrimental changes in synapses are strongly implicated in many brain diseases, which represent a vast social and economic burden. The purpose of this article is to provide an overview of the molecular and cellular AMPA receptor trafficking events that control synaptic responsiveness and plasticity, and highlight what is known currently known about how these processes change with age and disease.

  14. Spike timing-dependent plasticity as the origin of the formation of clustered synaptic efficacy engrams.

    PubMed

    Iannella, Nicolangelo Libero; Launey, Thomas; Tanaka, Shigeru

    2010-01-01

    Synapse location, dendritic active properties and synaptic plasticity are all known to play some role in shaping the different input streams impinging onto a neuron. It remains unclear however, how the magnitude and spatial distribution of synaptic efficacies emerge from this interplay. Here, we investigate this interplay using a biophysically detailed neuron model of a reconstructed layer 2/3 pyramidal cell and spike timing-dependent plasticity (STDP). Specifically, we focus on the issue of how the efficacy of synapses contributed by different input streams are spatially represented in dendrites after STDP learning. We construct a simple feed forward network where a detailed model neuron receives synaptic inputs independently from multiple yet equally sized groups of afferent fibers with correlated activity, mimicking the spike activity from different neuronal populations encoding, for example, different sensory modalities. Interestingly, ensuing STDP learning, we observe that for all afferent groups, STDP leads to synaptic efficacies arranged into spatially segregated clusters effectively partitioning the dendritic tree. These segregated clusters possess a characteristic global organization in space, where they form a tessellation in which each group dominates mutually exclusive regions of the dendrite. Put simply, the dendritic imprint from different input streams left after STDP learning effectively forms what we term a "dendritic efficacy mosaic." Furthermore, we show how variations of the inputs and STDP rule affect such an organization. Our model suggests that STDP may be an important mechanism for creating a clustered plasticity engram, which shapes how different input streams are spatially represented in dendrite.

  15. The roles of protein expression in synaptic plasticity and memory consolidation

    PubMed Central

    Rosenberg, Tali; Gal-Ben-Ari, Shunit; Dieterich, Daniela C.; Kreutz, Michael R.; Ziv, Noam E.; Gundelfinger, Eckart D.; Rosenblum, Kobi

    2014-01-01

    The amount and availability of proteins are regulated by their synthesis, degradation, and transport. These processes can specifically, locally, and temporally regulate a protein or a population of proteins, thus affecting numerous biological processes in health and disease states. Accordingly, malfunction in the processes of protein turnover and localization underlies different neuronal diseases. However, as early as a century ago, it was recognized that there is a specific need for normal macromolecular synthesis in a specific fragment of the learning process, memory consolidation, which takes place minutes to hours following acquisition. Memory consolidation is the process by which fragile short-term memory is converted into stable long-term memory. It is accepted today that synaptic plasticity is a cellular mechanism of learning and memory processes. Interestingly, similar molecular mechanisms subserve both memory and synaptic plasticity consolidation. In this review, we survey the current view on the connection between memory consolidation processes and proteostasis, i.e., maintaining the protein contents at the neuron and the synapse. In addition, we describe the technical obstacles and possible new methods to determine neuronal proteostasis of synaptic function and better explain the process of memory and synaptic plasticity consolidation. PMID:25429258

  16. New vistas on synaptic plasticity: the receptor mosaic hypothesis of the engram.

    PubMed

    Agnati, L F; Fuxe, K; Zoli, M; Rondanini, C; Ogren, S O

    1982-08-01

    The concepts of coexistence of transmitters and of receptor-receptor interactions have increased our understanding of the integrative processes regulating synaptic homeostasis and synaptic plasticity. Depending upon the ionotropic or metabotropic characteristics of the cotransmitter, it may be mainly involved in synaptic homeostasis or synaptic plasticity, respectively. A chemical trace of the postsynaptic activity can be obtained because of the plasticity of the receptor molecules. Thus, the heuristic hypothesis is introduced that islands of receptors located on postsynaptic membranes of local circuits can be formed by means of receptor-receptor interactions favouring ordered electrotonic sequences in the local circuits. This hypothesis has been named the receptor mosaic hypothesis of the engram. The islands or clusters of receptors can then store specific and complex information and when activated by the transmitters they may induce unique changes in ion permeability and cell metabolism which, at the local circuit level, can mimic exactly a previous electrotonic sequence. They can therefore represent at least part of the engram. This hypothesis is introduced against the background of the possible existence of different types of encodings of memory.

  17. The BDNF Val66Met polymorphism impairs NMDA receptor-dependent synaptic plasticity in the hippocampus.

    PubMed

    Ninan, Ipe; Bath, Kevin G; Dagar, Karishma; Perez-Castro, Rosalia; Plummer, Mark R; Lee, Francis S; Chao, Moses V

    2010-06-30

    The Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene results in a defect in regulated release of BDNF and affects episodic memory and affective behaviors. However, the precise role of the BDNF Val66Met polymorphism in hippocampal synaptic transmission and plasticity has not yet been studied. Therefore, we examined synaptic properties in the hippocampal CA3-CA1 synapses of BDNF(Met/Met) mice and matched wild-type mice. Although basal glutamatergic neurotransmission was normal, both young and adult mice showed a significant reduction in NMDA receptor-dependent long-term potentiation. We also found that NMDA receptor-dependent long-term depression was decreased in BDNF(Met/Met) mice. However, mGluR-dependent long-term depression was not affected by the BDNF Val66Met polymorphism. Consistent with the NMDA receptor-dependent synaptic plasticity impairment, we observed a significant decrease in NMDA receptor neurotransmission in the CA1 pyramidal neurons of BDNF(Met/Met) mice. Thus, these results show that the BDNF Val66Met polymorphism has a direct effect on NMDA receptor transmission, which may account for changes in synaptic plasticity in the hippocampus.

  18. Activity-Dependent Synaptic Plasticity of a Chalcogenide Electronic Synapse for Neuromorphic Systems

    NASA Astrophysics Data System (ADS)

    Li, Yi; Zhong, Yingpeng; Zhang, Jinjian; Xu, Lei; Wang, Qing; Sun, Huajun; Tong, Hao; Cheng, Xiaoming; Miao, Xiangshui

    2014-05-01

    Nanoscale inorganic electronic synapses or synaptic devices, which are capable of emulating the functions of biological synapses of brain neuronal systems, are regarded as the basic building blocks for beyond-Von Neumann computing architecture, combining information storage and processing. Here, we demonstrate a Ag/AgInSbTe/Ag structure for chalcogenide memristor-based electronic synapses. The memristive characteristics with reproducible gradual resistance tuning are utilised to mimic the activity-dependent synaptic plasticity that serves as the basis of memory and learning. Bidirectional long-term Hebbian plasticity modulation is implemented by the coactivity of pre- and postsynaptic spikes, and the sign and degree are affected by assorted factors including the temporal difference, spike rate and voltage. Moreover, synaptic saturation is observed to be an adjustment of Hebbian rules to stabilise the growth of synaptic weights. Our results may contribute to the development of highly functional plastic electronic synapses and the further construction of next-generation parallel neuromorphic computing architecture.

  19. Pregnenolone sulfate as a modulator of synaptic plasticity

    PubMed Central

    Smith, Conor C.; Gibbs, Terrell T.

    2015-01-01

    Rationale The neurosteroid pregnenolone sulfate (PregS) acts as a cognitive enhancer and modulator of neurotransmission, yet aligning its pharmacological and physiological effects with reliable measurements of endogenous local concentrations and pharmacological and therapeutic targets has remained elusive for over 20 years. Objectives New basic and clinical research concerning neurosteroid modulation of the central nervous system (CNS) function has emerged over the past 5 years, including important data involving pregnenolone and various neurosteroid precursors of PregS that point to a need for a critical status update. Results Highly specific actions of PregS affecting excitatory N-methyl-D-aspartate receptor (NMDAR)-mediated synaptic transmission and the pharmacological effects of PregS on various receptors and ion channels are discussed. The discovery of a high potency (nanomolar) signal transduction pathway for PregS-induced NMDAR trafficking to the cell surface via a Ca2+- and G protein-coupled receptor (GPCR)-dependent mechanism and a potent (EC50 ~2 pM) direct enhancement of intracellular Ca2+ levels is discussed in terms of its agonist effects on long-term potentiation (LTP) and memory. Lastly, preclinical and clinical studies assessing the promnestic effects of PregS and pregnenolone toward cognitive dysfunction in schizophrenia, and altered serum levels in epilepsy and alcohol dependence, are reviewed. Conclusions PregS is present in human and rodent brain at physiologically relevant concentrations and meets most of the criteria for an endogenous neurotransmitter/neuromodulator. PregS likely plays a significant role in modulation of glutamatergic excitatory synaptic transmission underlying learning and memory, yet the molecular target(s) for its action awaits identification. PMID:24997854

  20. Changed Synaptic Plasticity in Neural Circuits of Depressive-Like and Escitalopram-Treated Rats

    PubMed Central

    Li, Xiao-Li; Yuan, Yong-Gui; Xu, Hua; Wu, Di; Gong, Wei-Gang; Geng, Lei-Yu; Wu, Fang-Fang; Tang, Hao; Xu, Lin

    2015-01-01

    Background: Although progress has been made in the detection and characterization of neural plasticity in depression, it has not been fully understood in individual synaptic changes in the neural circuits under chronic stress and antidepressant treatment. Methods: Using electron microscopy and Western-blot analyses, the present study quantitatively examined the changes in the Gray’s Type I synaptic ultrastructures and the expression of synapse-associated proteins in the key brain regions of rats’ depressive-related neural circuit after chronic unpredicted mild stress and/or escitalopram administration. Meanwhile, their depressive behaviors were also determined by several tests. Results: The Type I synapses underwent considerable remodeling after chronic unpredicted mild stress, which resulted in the changed width of the synaptic cleft, length of the active zone, postsynaptic density thickness, and/or synaptic curvature in the subregions of medial prefrontal cortex and hippocampus, as well as the basolateral amygdaloid nucleus of the amygdala, accompanied by changed expression of several synapse-associated proteins. Chronic escitalopram administration significantly changed the above alternations in the chronic unpredicted mild stress rats but had little effect on normal controls. Also, there was a positive correlation between the locomotor activity and the maximal synaptic postsynaptic density thickness in the stratum radiatum of the Cornu Ammonis 1 region and a negative correlation between the sucrose preference and the length of the active zone in the basolateral amygdaloid nucleus region in chronic unpredicted mild stress rats. Conclusion: These findings strongly indicate that chronic stress and escitalopram can alter synaptic plasticity in the neural circuits, and the remodeled synaptic ultrastructure was correlated with the rats’ depressive behaviors, suggesting a therapeutic target for further exploration. PMID:25899067

  1. Learning-facilitated synaptic plasticity occurs in the intermediate hippocampus in association with spatial learning

    PubMed Central

    Kenney, Jana; Manahan-Vaughan, Denise

    2013-01-01

    The dorsoventral axis of the hippocampus is differentiated into dorsal, intermediate, and ventral parts. Whereas the dorsal part is believed to specialize in processing spatial information, the ventral may be equipped to process non-spatial information. The precise role of the intermediate hippocampus is unclear, although recent data suggests it is functionally distinct, at least from the dorsal hippocampus. Learning-facilitated synaptic plasticity describes the ability of hippocampal synapses to respond with robust synaptic plasticity (>24 h) when a spatial learning event is coupled with afferent stimulation that would normally not lead to a lasting plasticity response: in the dorsal hippocampus novel space facilitates robust expression of long-term potentiation (LTP), whereas novel spatial content facilitates long-term depression (LTD). We explored whether the intermediate hippocampus engages in this kind of synaptic plasticity in response to novel spatial experience. In freely moving rats, high-frequency stimulation at 200 Hz (3 bursts of 15 stimuli) elicited synaptic potentiation that lasted for at least 4 h. Coupling of this stimulation with the exploration of a novel holeboard resulted in LTP that lasted for over 24 h. Low frequency afferent stimulation (1 Hz, 900 pulses) resulted in short-term depression (STD) that was significantly enhanced and prolonged by exposure to a novel large orientational (landmark) cues, however LTD was not enabled. Exposure to a holeboard that included novel objects in the holeboard holes elicited a transient enhancement of STD of the population spike (PS) but not field EPSP, and also failed to facilitate the expression of LTD. Our data suggest that the intermediate dentate gyrus engages in processing of spatial information, but is functionally distinct to the dorsal dentate gyrus. This may in turn reflect their assumed different roles in synaptic information processing and memory formation. PMID:24194716

  2. Drug-evoked synaptic plasticity in addiction: from molecular changes to circuit remodeling

    PubMed Central

    Lüscher, Christian; Malenka, Robert C.

    2014-01-01

    Addictive drugs have in common that they target the mesocoticolimbic dopamine (DA) system. This system originates in the ventral tegmental area (VTA) and projects mainly to the nucleus accumbens (NAc) and prefrontal cortex (PFC). Here we review the effects that such drugs leave on glutamatergic and GABAergic synaptic transmission in these three brain areas. We refer to these changes as drug-evoked synaptic plasticity, which outlasts the presence of the drug in the brain and contributes to the reorganization of neural circuits. While in most cases these early changes are not sufficient to induce the disease, with repetitive drug exposure, they may add up and cause addictive behavior. PMID:21338877

  3. Bidirectional synaptic plasticity and spatial memory flexibility require Ca2+-stimulated adenylyl cyclases.

    PubMed

    Zhang, Ming; Storm, Daniel R; Wang, Hongbing

    2011-07-13

    When certain memory becomes obsolete, effective suppression of the previously established memory is essential for animals to adapt to the changing environment. At the cellular level, reversal of synaptic potentiation may be important for neurons to acquire new information and to prevent synaptic saturation. Here, we investigated the function of Ca(2+)-stimulated cAMP signaling in the regulation of bidirectional synaptic plasticity and spatial memory formation in double knock-out mice (DKO) lacking both type 1 and 8 adenylyl cyclases (ACs). In anesthetized animals, the DKO mutants showed defective long-term potentiation (LTP) after a single high-frequency stimulation (HFS) or two spaced HFSs at 100 Hz. However, DKO mice showed normal LTP after a single HFS at 200 Hz or two compressed HFSs at 100 Hz. Interestingly, reversal of synaptic potentiation as well as de novo synaptic depression was impaired in DKO mice. In the Morris water maze, DKO mice showed defective acquisition and memory retention, although the deficits could be attenuated by overtraining or compressed trainings with a shorter intertrial interval. In the reversal platform test, DKO animals were impaired in both relearning and old memory suppression. Furthermore, the extinction of the old spatial memory was not efficient in DKO mice. These data demonstrate that Ca(2+)-stimulated AC activity is important not only for LTP and spatial memory formation but also for the suppression of both previously established synaptic potentiation and old spatial memory.

  4. Antibody-mediated Impairment and Homeostatic Plasticity of Autonomic Ganglionic Synaptic Transmission

    PubMed Central

    Wang, Zhengbei; Low, Phillip A.; Vernino, Steven

    2010-01-01

    Antibodies against ganglionic acetylcholine receptors (AChR) are implicated as the cause of autoimmune autonomic ganglionopathy (AAG). To characterize ganglionic neurotransmission in an animal model of AAG, evoked and spontaneous excitatory post-synaptic potentials (EPSP) were recorded from neurons in isolated mouse superior cervical ganglia (SCG). In vitro exposure of ganglia to IgG from AAG patients progressively inhibited synaptic transmission. After passive transfer of antibody to mice, evoked EPSP amplitude decreased, and some neurons showed no synaptic responses. EPSP amplitude recovered by day seven despite persistence of ganglionic AChR antibody in the mouse serum. There was a more persistent (at least 14 day) reduction in miniature EPSP amplitude consistent with antibody-mediated reduction in post-synaptic AChR. Although the quantal size was reduced, a progressive increase in the frequency of spontaneous synaptic events occurred, suggesting a compensatory increase in presynaptic efficacy. The quantal size returned to baseline by 21 days while the frequency remained increased for at least four weeks. Ganglionic AChR antibodies cause an impairment of autonomic ganglionic synaptic transmission. Homeostatic plasticity in autonomic neurotransmission could help explain the spontaneous clinical recovery seen in some AAG patients and may also play an important role in regulating normal autonomic reflexes. PMID:20044994

  5. Bidirectional synaptic plasticity and spatial memory flexibility require Ca2+-stimulated adenylyl cyclases

    PubMed Central

    Zhang, Ming; Storm, Daniel R; Wang, Hongbing

    2011-01-01

    When certain memory becomes obsolete, effective suppression of the previously established memory is essential for animals to adapt to the changing environment. At the cellular level, reversal of synaptic potentiation may be important for neurons to acquire new information, and to prevent synaptic saturation. Here, we investigated the function of Ca2+-stimulated cAMP signaling in the regulation of bidirectional synaptic plasticity and spatial memory formation in double knockout mice (DKO) lacking both type 1 and 8 adenylyl cyclases (AC). In anaesthetized animals, the DKO mutants showed defective long-term potentiation (LTP) after a single high frequency stimulation (HFS) or two spaced HFSs at 100 Hz. However, DKO mice showed normal LTP after a single HFS at 200 Hz or two compressed HFSs at 100 Hz. Interestingly, reversal of synaptic potentiation as well as de novo synaptic depression was impaired in DKO mice. In the Morris water maze, DKO mice showed defective acquisition and memory retention, though the deficits could be attenuated by overtraining or compressed trainings with a shorter inter-trial interval. In the reversal platform test, DKO animals were impaired in both re-learning and old memory suppression. Furthermore, the extinction of the old spatial memory was not efficient in DKO mice. These data demonstrate that Ca2+-stimulated AC activity is not only important for LTP and spatial memory formation, but also for the suppression of both previously established synaptic potentiation and old spatial memory. PMID:21752993

  6. Mismatch novelty exploration training enhances hippocampal synaptic plasticity: a tool for cognitive stimulation?

    PubMed

    Aidil-Carvalho, M F; Carmo, A J S; Ribeiro, J A; Cunha-Reis, D

    2017-09-08

    Memory formation relies on experience-dependent changes in synaptic strength such as long-term potentiation (LTP) or long-term depression (LTD) of synaptic activity, that in turn depend on previous learning experiences through metaplasticity. Novelty detection is a particularly important cognitive stimulus in this respect, and mismatch novelty has been associated with the activation of the hippocampal CA1 area in human studies. A single exposure a new location of known objects in a familiar environment, a behavioural mismatch novelty paradigm, is known to favour the expression of LTD in hippocampal CA3 to CA1 synaptic transmission in vivo, through short-term metaplasticity. Aiming to shape hippocampal responsiveness to synaptic plasticity phenomena we developed a training program based on exploration of a known environment containing familiar objects everyday presented in a new location. Repeated exposure to this new location of objects for two weeks caused a mild long-lasting decrease in synaptic efficacy. Furthermore, it enhanced both LTP evoked by theta-burst stimulation and depotentiation evoked by low-frequency stimulation of CA3 to CA1 hippocampal synaptic transmission in juvenile rats. This suggests that training programs using these behavioural tasks involving mismatch novelty can be used to reshape brain circuits and promote cognitive recovery in pathologies where LTP/LTD imbalance occurs, such as epilepsy, aging or Dowńs syndrome, an approach that requires further investigation at the behavioural level. Copyright © 2017. Published by Elsevier Inc.

  7. Functional recovery after cervical spinal cord injury: Role of neurotrophin and glutamatergic signaling in phrenic motoneurons.

    PubMed

    Gill, Luther C; Gransee, Heather M; Sieck, Gary C; Mantilla, Carlos B

    2016-06-01

    Cervical spinal cord injury (SCI) interrupts descending neural drive to phrenic motoneurons causing diaphragm muscle (DIAm) paralysis. Recent studies using a well-established model of SCI, unilateral spinal hemisection of the C2 segment of the cervical spinal cord (SH), provide novel information regarding the molecular and cellular mechanisms of functional recovery after SCI. Over time post-SH, gradual recovery of rhythmic ipsilateral DIAm activity occurs. Recovery of ipsilateral DIAm electromyogram (EMG) activity following SH is enhanced by increasing brain-derived neurotrophic factor (BDNF) in the region of the phrenic motoneuron pool. Delivery of exogenous BDNF either via intrathecal infusion or via mesenchymal stem cells engineered to release BDNF similarly enhance recovery. Conversely, recovery after SH is blunted by quenching endogenous BDNF with the fusion-protein TrkB-Fc in the region of the phrenic motoneuron pool or by selective inhibition of TrkB kinase activity using a chemical-genetic approach in TrkB(F616A) mice. Furthermore, the importance of BDNF signaling via TrkB receptors at phrenic motoneurons is highlighted by the blunting of recovery by siRNA-mediated downregulation of TrkB receptor expression in phrenic motoneurons and by the enhancement of recovery evident following virally-induced increases in TrkB expression specifically in phrenic motoneurons. BDNF/TrkB signaling regulates synaptic plasticity in various neuronal systems, including glutamatergic pathways. Glutamatergic neurotransmission constitutes the main inspiratory-related, excitatory drive to motoneurons, and following SH, spontaneous neuroplasticity is associated with increased expression of ionotropic N-methyl-d-aspartate (NMDA) receptors in phrenic motoneurons. Evidence for the role of BDNF/TrkB and glutamatergic signaling in recovery of DIAm activity following cervical SCI is reviewed.

  8. MicroRNA miR124 is required for the expression of homeostatic synaptic plasticity

    PubMed Central

    Hou, Qingming; Ruan, Hongyu; Gilbert, James; Wang, Guan; Ma, Qi; Yao, Wei-Dong; Man, Heng-Ye

    2015-01-01

    Homeostatic synaptic plasticity is a compensatory response to alterations in neuronal activity. Chronic deprivation of neuronal activity results in an increase in synaptic AMPA receptors (AMPARs) and postsynaptic currents. The biogenesis of GluA2-lacking, calcium-permeable AMPARs (CP-AMPARs) plays a crucial role in the homeostatic response; however, the mechanisms leading to CP-AMPAR formation remain unclear. Here we show that the microRNA, miR124, is required for the generation of CP-AMPARs and homeostatic plasticity. miR124 suppresses GluA2 expression via targeting its 3′-UTR, leading to the formation of CP-AMPARs. Blockade of miR124 function abolishes the homeostatic response, whereas miR124 overexpression leads to earlier induction of homeostatic plasticity. miR124 transcription is controlled by an inhibitory transcription factor EVI1, acting by association with the deacetylase HDAC1. Our data support a cellular cascade in which inactivity relieves EVI1/HDAC-mediated inhibition of miR124 gene transcription, resulting in enhanced miR124 expression, formation of CP-AMPARs and subsequent induction of homeostatic synaptic plasticity. PMID:26620774

  9. Inhibition of DNA Methylation Impairs Synaptic Plasticity during an Early Time Window in Rats

    PubMed Central

    Díaz, Paula; Ardiles, Álvaro O.

    2016-01-01

    Although the importance of DNA methylation-dependent gene expression to neuronal plasticity is well established, the dynamics of methylation and demethylation during the induction and expression of synaptic plasticity have not been explored. Here, we combined electrophysiological, pharmacological, molecular, and immunohistochemical approaches to examine the contribution of DNA methylation and the phosphorylation of Methyl-CpG-binding protein 2 (MeCP2) to synaptic plasticity. We found that, at twenty minutes after theta burst stimulation (TBS), the DNA methylation inhibitor 5-aza-2-deoxycytidine (5AZA) impaired hippocampal long-term potentiation (LTP). Surprisingly, after two hours of TBS, when LTP had become a transcription-dependent process, 5AZA treatment had no effect. By comparing these results to those in naive slices, we found that, at two hours after TBS, an intergenic region of the RLN gene was hypomethylated and that the phosphorylation of residue S80 of MeCP2 was decreased, while the phosphorylation of residue S421 was increased. As expected, 5AZA affected only the methylation of the RLN gene and exerted no effect on MeCP2 phosphorylation patterns. In summary, our data suggest that tetanic stimulation induces critical changes in synaptic plasticity that affects both DNA methylation and the phosphorylation of MeCP2. These data also suggest that early alterations in DNA methylation are sufficient to impair the full expression of LTP. PMID:27493805

  10. The requirement of BDNF for hippocampal synaptic plasticity is experience‐dependent

    PubMed Central

    Aarse, Janna; Herlitze, Stefan

    2016-01-01

    ABSTRACT Brain‐derived neurotrophic factor (BDNF) supports neuronal survival, growth, and differentiation and has been implicated in forms of hippocampus‐dependent learning. In vitro, a specific role in hippocampal synaptic plasticity has been described, although not all experience‐dependent forms of synaptic plasticity critically depend on BDNF. Synaptic plasticity is likely to enable long‐term synaptic information storage and memory, and the induction of persistent (>24 h) forms, such as long‐term potentiation (LTP) and long‐term depression (LTD) is tightly associated with learning specific aspects of a spatial representation. Whether BDNF is required for persistent (>24 h) forms of LTP and LTD, and how it contributes to synaptic plasticity in the freely behaving rodent has never been explored. We examined LTP, LTD, and related forms of learning in the CA1 region of freely dependent mice that have a partial knockdown of BDNF (BDNF+/−). We show that whereas early‐LTD (<90min) requires BDNF, short‐term depression (<45 min) does not. Furthermore, BDNF is required for LTP that is induced by mild, but not strong short afferent stimulation protocols. Object‐place learning triggers LTD in the CA1 region of mice. We observed that object‐place memory was impaired and the object‐place exploration failed to induce LTD in BDNF+/− mice. Furthermore, spatial reference memory, that is believed to be enabled by LTP, was also impaired. Taken together, these data indicate that BDNF is required for specific, but not all, forms of hippocampal‐dependent information storage and memory. Thus, very robust forms of synaptic plasticity may circumvent the need for BDNF, rather it may play a specific role in the optimization of weaker forms of plasticity. The finding that both learning‐facilitated LTD and spatial reference memory are both impaired in BDNF+/− mice, suggests moreover, that it is critically required for the physiological encoding of hippocampus

  11. 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…

  12. 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…

  13. UPF1 Governs Synaptic Plasticity through Association with a STAU2 RNA Granule.

    PubMed

    Graber, Tyson E; Freemantle, Erika; Anadolu, Mina N; Hébert-Seropian, Sarah; MacAdam, Robyn L; Shin, Unkyung; Hoang, Huy-Dung; Alain, Tommy; Lacaille, Jean-Claude; Sossin, Wayne S

    2017-09-20

    Neuronal mRNAs can be packaged in reversibly stalled polysome granules before their transport to distant synaptic locales. Stimulation of synaptic metabotropic glutamate receptors (mGluRs) reactivates translation of these particular mRNAs to produce plasticity-related protein; a phenomenon exhibited during mGluR-mediated LTD. This form of plasticity is deregulated in Fragile X Syndrome, a monogenic form of autism in humans, and understanding the stalling and reactivation mechanism could reveal new approaches to therapies. Here, we demonstrate that UPF1, known to stall peptide release during nonsense-mediated RNA decay, is critical for assembly of stalled polysomes in rat hippocampal neurons derived from embryos of either sex. Moreover, UPF1 and its interaction with the RNA binding protein STAU2 are necessary for proper transport and local translation from a prototypical RNA granule substrate and for mGluR-LTD in hippocampal neurons. These data highlight a new, neuronal role for UPF1, distinct from its RNA decay functions, in regulating transport and/or translation of mRNAs that are critical for synaptic plasticity.SIGNIFICANCE STATEMENT The elongation and/or termination steps of mRNA translation are emerging as important control points in mGluR-LTD, a form of synaptic plasticity that is compromised in a severe monogenic form of autism, Fragile X Syndrome. Deciphering the molecular mechanisms controlling this type of plasticity may thus open new therapeutic opportunities. Here, we describe a new role for the ATP-dependent helicase UPF1 and its interaction with the RNA localization protein STAU2 in mediating mGluR-LTD through the regulation of mRNA translation complexes stalled at the level of elongation and/or termination. Copyright © 2017 the authors 0270-6474/17/379116-16$15.00/0.

  14. Temporal profiles of synaptic plasticity-related signals in adult mouse hippocampus with methotrexate treatment.

    PubMed

    Yang, Miyoung; Kim, Juhwan; Kim, Sung-Ho; Kim, Joong-Sun; Shin, Taekyun; Moon, Changjong

    2012-07-25

    Methotrexate, which is used to treat many malignancies and autoimmune diseases, affects brain functions including hippocampal-dependent memory function. However, the precise mechanisms underlying methotrexate-induced hippocampal dysfunction are poorly understood. To evaluate temporal changes in synaptic plasticity-related signals, the expression and activity of N-methyl-D-aspartic acid receptor 1, calcium/calmodulin-dependent protein kinase II, extracellular signal-regulated kinase 1/2, cAMP responsive element-binding protein, glutamate receptor 1, brain-derived neurotrophic factor, and glial cell line-derived neurotrophic factor were examined in the hippocampi of adult C57BL/6 mice after methotrexate (40 mg/kg) intraperitoneal injection. Western blot analysis showed biphasic changes in synaptic plasticity-related signals in adult hippocampi following methotrexate treatment. N-methyl-D-aspartic acid receptor 1, calcium/calmodulin-dependent protein kinase II, and glutamate receptor 1 were acutely activated during the early phase (1 day post-injection), while extracellular signal-regulated kinase 1/2 and cAMP responsive element-binding protein activation showed biphasic increases during the early (1 day post-injection) and late phases (7-14 days post-injection). Brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor expression increased significantly during the late phase (7-14 days post-injection). Therefore, methotrexate treatment affects synaptic plasticity-related signals in the adult mouse hippocampus, suggesting that changes in synaptic plasticity-related signals may be associated with neuronal survival and plasticity-related cellular remodeling.

  15. Questions about STDP as a General Model of Synaptic Plasticity

    PubMed Central

    Lisman, John; Spruston, Nelson

    2010-01-01

    According to spike-timing-dependent plasticity (STDP), the timing of the Na+ spike relative to the EPSP determines whether LTP or LTD will occur. Here, we review our reservations about STDP. Most investigations of this process have been done under conditions in which the spike is evoked by postsynaptic current injection. Under more realistic conditions, in which the spike is evoked by the EPSP, the results do not generally support STDP. For instance, low-frequency stimulation of a group of synapses can cause LTD, not the LTP predicted by the pre-before-post sequence in STDP; this is true regardless of whether or not the EPSP is large enough to produce a Na+ spike. With stronger or more frequent stimulation, LTP can be induced by the same pre-before-post timing, but in this case block of Na+ spikes does not necessarily prevent LTP induction. Thus, Na+ spikes may facilitate LTP and/or LTD under some conditions, but they are not necessary, a finding consistent with their small size relative to the EPSP in many parts of pyramidal cell dendrites. The nature of the dendritic depolarizing events that control bidirectional plasticity is of central importance to understanding neural function. There are several candidates, including backpropagating action potentials, but also dendritic Ca2+ spikes, the AMPA receptor-mediated EPSP, and NMDA receptor-mediated EPSPs or spikes. These often appear to be more important than the Na+ spike in providing the depolarization necessary for plasticity. We thus feel that it is premature to accept STDP-like processes as the major determinant of LTP/LTD. PMID:21423526

  16. Hippocampal Insulin Resistance Impairs Spatial Learning and Synaptic Plasticity

    PubMed Central

    Piroli, Gerardo G.; Lawrence, Robert C.; Wrighten, Shayna A.; Green, Adrienne J.; Wilson, Steven P.; Sakai, Randall R.; Kelly, Sandra J.; Wilson, Marlene A.; Mott, David D.; Reagan, Lawrence P.

    2015-01-01

    Insulin receptors (IRs) are expressed in discrete neuronal populations in the central nervous system, including the hippocampus. To elucidate the functional role of hippocampal IRs independent of metabolic function, we generated a model of hippocampal-specific insulin resistance using a lentiviral vector expressing an IR antisense sequence (LV-IRAS). LV-IRAS effectively downregulates IR expression in the rat hippocampus without affecting body weight, adiposity, or peripheral glucose homeostasis. Nevertheless, hippocampal neuroplasticity was impaired in LV-IRAS–treated rats. High-frequency stimulation, which evoked robust long-term potentiation (LTP) in brain slices from LV control rats, failed to evoke LTP in LV-IRAS–treated rats. GluN2B subunit levels, as well as the basal level of phosphorylation of GluA1, were reduced in the hippocampus of LV-IRAS rats. Moreover, these deficits in synaptic transmission were associated with impairments in spatial learning. We suggest that alterations in the expression and phosphorylation of glutamate receptor subunits underlie the alterations in LTP and that these changes are responsible for the impairment in hippocampal-dependent learning. Importantly, these learning deficits are strikingly similar to the impairments in complex task performance observed in patients with diabetes, which strengthens the hypothesis that hippocampal insulin resistance is a key mediator of cognitive deficits independent of glycemic control. PMID:26216852

  17. Variations on the Theme of Synaptic Filtering: A Comparison of Integrate-and-Express Models of Synaptic Plasticity for Memory Lifetimes.

    PubMed

    Elliott, Terry

    2016-09-14

    Integrate-and-express models of synaptic plasticity propose that synapses integrate plasticity induction signals before expressing synaptic plasticity. By discerning trends in their induction signals, synapses can control destabilizing fluctuations in synaptic strength. In a feedforward perceptron framework with binary-strength synapses for associative memory storage, we have previously shown that such a filter-based model outperforms other, nonintegrative, "cascade"-type models of memory storage in most regions of biologically relevant parameter space. Here, we consider some natural extensions of our earlier filter model, including one specifically tailored to binary-strength synapses and one that demands a fixed, consecutive number of same-type induction signals rather than merely an excess before expressing synaptic plasticity. With these extensions, we show that filter-based models outperform nonintegrative models in all regions of biologically relevant parameter space except for a small sliver in which all models encode memories only weakly. In this sliver, which model is superior depends on the metric used to gauge memory lifetimes (whether a signal-to-noise ratio or a mean first passage time). After comparing and contrasting these various filter models, we discuss the multiple mechanisms and timescales that underlie both synaptic plasticity and memory phenomena and suggest that multiple different filtering mechanisms may operate at single synapses.

  18. Functional roles of short-term synaptic plasticity with an emphasis on inhibition.

    PubMed

    Anwar, Haroon; Li, Xinping; Bucher, Dirk; Nadim, Farzan

    2017-04-01

    Almost all synapses show activity-dependent dynamic changes in efficacy. Numerous studies have explored the mechanisms underlying different forms of short-term synaptic plasticity (STP), but the functional role of STP for circuit output and animal behavior is less understood. This is particularly true for inhibitory synapses that can play widely varied roles in circuit activity. We review recent findings on the role of synaptic STP in sensory, pattern generating, thalamocortical, and hippocampal networks, with a focus on synaptic inhibition. These studies show a variety of functions including sensory adaptation and gating, dynamic gain control and rhythm generation. Because experimental manipulations of STP are difficult and nonspecific, a clear demonstration of STP function often requires a combination of experimental and computational techniques. Copyright © 2017 Elsevier Ltd. All rights reserved.

  19. The AAA+ ATPase, Thorase Regulates AMPA Receptor-Dependent Synaptic Plasticity and Behavior

    PubMed Central

    Zhang, Jianmin; Wang, Yue; Chi, Zhikai; Keuss, Matthew J.; Pai, Ying-Min Emily; Kang, Ho Chul; Shin, Jooho; Bugayenko, Artem; Wang, Hong; Xiong, Yulan; Pletnikov, Mikhail V.; Mattson, Mark P.; Dawson, Ted M.; Dawson, Valina L.

    2011-01-01

    SUMMARY The synaptic insertion or removal of AMPA receptors (AMPAR) plays critical roles in the regulation of synaptic activity reflected in the expression of long-term potentiation (LTP) and long-term depression (LTD). The cellular events underlying this important process in learning and memory are still being revealed. Here we describe and characterize the AAA+ ATPase, Thorase, that regulates the expression of surface AMPAR. In an ATPase-dependent manner Thorase mediates the internalization of AMPAR by disassembling the AMPAR-GRIP1 complex. Following genetic deletion of Thorase, the internalization of AMPAR is substantially reduced, leading to increased amplitudes of miniature excitatory postsynaptic currents, enhancement of LTP and elimination of LTD. These molecular events are expressed as deficits in learning and memory in Thorase null mice. This study identifies an AAA+ ATPase that plays a critical role in regulating the surface expression of AMPAR and thereby regulates synaptic plasticity and learning and memory. PMID:21496646

  20. 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.

  1. Neuromuscular plasticity in the locust after permanent removal of an excitatory motoneuron of the extensor tibiae muscle.

    PubMed

    Büschges, A; Djokaj, S; Bässler, D; Bässler, U; Rathmayer, W

    2000-01-01

    The capacity of the larval insect nervous system to compensate for the permanent loss of one of the two excitatory motoneurons innervating a leg muscle was investigated in the locust (Locusta migratoria). In the fourth instar, the fast extensor tibiae (FETi) motoneuron in the mesothoracic ganglion was permanently removed by photoinactivation with a helium-cadmium laser. Subsequently, the animals were allowed to develop into adulthood. When experimental animals were tested as adults after final ecdysis, fast-contracting fibers in the most proximal region of the corresponding extensor muscle, which are normally predominantly innervated by FETi only, uniformly responded to activity of the slow extensor tibiae (SETi) neuron. In adult operated animals, single pulses to SETi elicited large junctional responses in the fibers which resulted in twitch contractions of these fibers similar to the responses to FETi activity in control animals. The total number of muscle fibers, their properties as histochemically determined contractional types (fast and slow), and their distribution were not affected by photoinactivation of FETi. Possible mechanisms enabling the larval neuromuscular system to compensate for the loss of FETi through functionally similar innervation by a different motoneuron, i.e. SETi, are discussed. Copyright 2000 John Wiley & Sons, Inc.

  2. Diabetes impairs synaptic plasticity in the superior cervical ganglion: possible role for BDNF and oxidative stress.

    PubMed

    Alzoubi, K H; Khabour, O F; Alhaidar, I A; Aleisa, A M; Alkadhi, K A

    2013-11-01

    The majority of diabetics develop serious disorders of the autonomic nervous system; however, there is no clear understanding on the causes of these complications. In this study, we examined the effect of streptozocin (STZ)-induced diabetes on activity-dependent synaptic plasticity, associated levels of brain-derived neurotrophic factor (BDNF) and antioxidant biomarkers in the rat sympathetic superior cervical ganglion. Diabetes (STZ-induced) was achieved by a single intraperitoneal injection of streptozocin (55 mg/kg).Compound action potentials were recorded from isolated ganglia before (basal) and after repetitive stimulation, or trains of paired pulses to express ganglionic long-term potentiation (gLTP) or long-term depression (gLTD). The input/output curves of ganglia from STZ-treated animals showed a marked rightward shift along most stimulus intensities, compared to those of ganglia from control animals, indicating impaired basal synaptic transmission in ganglia from STZ-induced diabetic animals. Repetitive stimulation induced robust gLTP and gLTD in ganglia isolated from control animals; the same protocols failed to induce gLTP or gLTD in ganglia from STZ-induced diabetic animals, indicating impairment of activity-dependent synaptic plasticity in these animals. Molecular analysis revealed significant reduction in the levels of BDNF and the ratio of glutathione/oxidized glutathione. Additionally, the activity of glutathione peroxidase, glutathione reductase, catalase, and the levels of thiobarbituric acid-reactive substances were increased in ganglia from STZ-treated animals. In conclusion, impaired basal synaptic transmission and synaptic plasticity are associated with reduced BDNF and altered oxidative stress biomarkers in the sympathetic ganglia from STZ-induced diabetic animals, suggesting a possible correlation of these factors with the manifestations of STZ-induced diabetes in the peripheral nervous system.

  3. Synaptic Plasticity, Neurogenesis, and Functional Recovery after Spinal Cord Injury

    PubMed Central

    Darian-Smith, Corinna

    2010-01-01

    Spinal cord injury research has greatly expanded in recent years, but our understanding of the mechanisms that underlie the functional recovery that can occur over the weeks and months following the initial injury, is far from complete. To grasp the scope of the problem, it is important to begin by defining the sensorimotor pathways that might be involved by a spinal injury. This is done in the rodent and nonhuman primate, which are two of the most commonly used animal models in basic and translational spinal injury research. Many of the better known experimentally induced models are then reviewed in terms of the pathways they involve and the reorganization and recovery that have been shown to follow. The better understood neuronal mechanisms mediating such post-injury plasticity, including dendritic spine growth and axonal sprouting, are then examined. PMID:19307422

  4. Pten deficiency in brain causes defects in synaptic structure, transmission and plasticity, and myelination abnormalities

    PubMed Central

    Fraser, Melissa M.; Bayazitov, Ildar T.; Zakharenko, Stanislav S.; Baker, Suzanne J.

    2008-01-01

    The phosphatidylinositol 3-kinase (PI3K) signaling pathway modulates growth, proliferation and cell survival in diverse tissue types and plays specialized roles in the nervous system including influences on neuronal polarity, dendritic branching and synaptic plasticity. The tumor-suppressor phosphatase with tensin homology (PTEN) is the central negative regulator of the PI3K pathway. Germline PTEN mutations result in cancer predisposition, macrocephaly and benign hamartomas in many tissues, including Lhermitte-Duclos disease, a cerebellar growth disorder. Neurological abnormalities including autism, seizures and ataxia have been observed in association with inherited PTEN mutation with variable penetrance. It remains unclear how loss of PTEN activity contributes to neurological dysfunction. To explore the effects of Pten deficiency on neuronal structure and function, we analyzed several ultra-structural features of Pten-deficient neurons in Pten conditional knockout mice. Using Golgi stain to visualize full neuronal morphology, we observed that increased size of nuclei and somata in Pten-deficient neurons was accompanied by enlarged caliber of neuronal projections and increased dendritic spine density. Electron microscopic evaluation revealed enlarged abnormal synaptic structures in the cerebral cortex and cerebellum. Severe myelination defects included thickening and unraveling of the myelin sheath surrounding hypertrophic axons in the corpus callosum. Defects in myelination of axons of normal caliber were observed in the cerebellum, suggesting intrinsic abnormalities in Pten-deficient oligodendrocytes. We did not observe these abnormalities in wild-type or conditional Pten heterozygous mice. Moreover, conditional deletion of Pten drastically weakened synaptic transmission and synaptic plasticity at excitatory synapses between CA3 and CA1 pyramidal neurons in the hippocampus. These data suggest that Pten is involved in mechanisms that control development of

  5. EPO induces changes in synaptic transmission and plasticity in the dentate gyrus of rats.

    PubMed

    Almaguer-Melian, William; Mercerón-Martínez, Daymara; Delgado-Ocaña, Susana; Pavón-Fuentes, Nancy; Ledón, Nuris; Bergado, Jorge A

    2016-06-01

    Erythropoietin has shown wide physiological effects on the central nervous system in animal models of disease, and in healthy animals. We have recently shown that systemic EPO administration 15 min, but not 5 h, after daily training in a water maze is able to induce the recovery of spatial memory in fimbria-fornix chronic-lesioned animals, suggesting that acute EPO triggers mechanisms which can modulate the active neural plasticity mechanism involved in spatial memory acquisition in lesioned animals. Additionally, this EPO effect is accompanied by the up-regulation of plasticity-related early genes. More remarkably, this time-dependent effects on learning recovery could signify that EPO in nerve system modulate specific living-cellular processes. In the present article, we focus on the question if EPO could modulate the induction of long-term synaptic plasticity like LTP and LTD, which presumably could support our previous published data. Our results show that acute EPO peripheral administration 15 min before the induction of synaptic plasticity is able to increase the magnitude of the LTP (more prominent in PSA than fEPSP-Slope) to facilitate the induction of LTD, and to protect LTP from depotentiation. These findings showing that EPO modulates in vivo synaptic plasticity sustain the assumption that EPO can act not only as a neuroprotective substance, but is also able to modulate transient neural plasticity mechanisms and therefore to promote the recovery of nerve function after an established chronic brain lesion. According to these results, EPO could be use as a molecular tool for neurorestaurative treatments.

  6. P2Y Receptors in Synaptic Transmission and Plasticity: Therapeutic Potential in Cognitive Dysfunction.

    PubMed

    Guzman, Segundo J; Gerevich, Zoltan

    2016-01-01

    ATP released from neurons and astrocytes during neuronal activity or under pathophysiological circumstances is able to influence information flow in neuronal circuits by activation of ionotropic P2X and metabotropic P2Y receptors and subsequent modulation of cellular excitability, synaptic strength, and plasticity. In the present paper we review cellular and network effects of P2Y receptors in the brain. We show that P2Y receptors inhibit the release of neurotransmitters, modulate voltage- and ligand-gated ion channels, and differentially influence the induction of synaptic plasticity in the prefrontal cortex, hippocampus, and cerebellum. The findings discussed here may explain how P2Y1 receptor activation during brain injury, hypoxia, inflammation, schizophrenia, or Alzheimer's disease leads to an impairment of cognitive processes. Hence, it is suggested that the blockade of P2Y1 receptors may have therapeutic potential against cognitive disturbances in these states.

  7. Domestication of the dog from the wolf was promoted by enhanced excitatory synaptic plasticity: a hypothesis.

    PubMed

    Li, Yan; Wang, Guo-Dong; Wang, Ming-Shan; Irwin, David M; Wu, Dong-Dong; Zhang, Ya-Ping

    2014-11-05

    Dogs shared a much closer relationship with humans than any other domesticated animals, probably due to their unique social cognitive capabilities, which were hypothesized to be a by-product of selection for tameness toward humans. Here, we demonstrate that genes involved in glutamate metabolism, which account partially for fear response, indeed show the greatest population differentiation by whole-genome comparison of dogs and wolves. However, the changing direction of their expression supports a role in increasing excitatory synaptic plasticity in dogs rather than reducing fear response. Because synaptic plasticity are widely believed to be cellular correlates of learning and memory, this change may alter the learning and memory abilities of ancient scavenging wolves, weaken the fear reaction toward humans, and prompt the initial interspecific contact. © The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

  8. Hierarchical Chunking of Sequential Memory on Neuromorphic Architecture with Reduced Synaptic Plasticity

    PubMed Central

    Li, Guoqi; Deng, Lei; Wang, Dong; Wang, Wei; Zeng, Fei; Zhang, Ziyang; Li, Huanglong; Song, Sen; Pei, Jing; Shi, Luping

    2016-01-01

    Chunking refers to a phenomenon whereby individuals group items together when performing a memory task to improve the performance of sequential memory. In this work, we build a bio-plausible hierarchical chunking of sequential memory (HCSM) model to explain why such improvement happens. We address this issue by linking hierarchical chunking with synaptic plasticity and neuromorphic engineering. We uncover that a chunking mechanism reduces the requirements of synaptic plasticity since it allows applying synapses with narrow dynamic range and low precision to perform a memory task. We validate a hardware version of the model through simulation, based on measured memristor behavior with narrow dynamic range in neuromorphic circuits, which reveals how chunking works and what role it plays in encoding sequential memory. Our work deepens the understanding of sequential memory and enables incorporating it for the investigation of the brain-inspired computing on neuromorphic architecture. PMID:28066223

  9. Curcumin improves synaptic plasticity impairment induced by HIV-1gp120 V3 loop

    PubMed Central

    Shen, Ling-ling; Jiang, Ming-liang; Liu, Si-si; Cai, Min-chun; Hong, Zhong-qiu; Lin, Li-qing; Xing, Yan-yan; Chen, Gui-lin; Pan, Rui; Yang, Li-juan; Xu, Ying; Dong, Jun

    2015-01-01

    Curcumin has been shown to significantly improve spatial memory impairment induced by HIV-1 gp120 V3 in rats, but the electrophysiological mechanism remains unknown. Using extracellular microelectrode recording techniques, this study confirmed that the gp120 V3 loop could suppress long-term potentiation in the rat hippocampal CA1 region and synaptic plasticity, and that curcumin could antagonize these inhibitory effects. Using a Fura-2/AM calcium ion probe, we found that curcumin resisted the effects of the gp120 V3 loop on hippocampal synaptosomes and decreased Ca2+ concentration in synaptosomes. This effect of curcumin was identical to nimodipine, suggesting that curcumin improved the inhibitory effects of gp120 on synaptic plasticity, ameliorated damage caused to the central nervous system, and might be a potential neuroprotective drug. PMID:26199609

  10. Self-tuning of neural circuits through short-term synaptic plasticity.

    PubMed

    Sussillo, David; Toyoizumi, Taro; Maass, Wolfgang

    2007-06-01

    Numerous experimental data show that cortical networks of neurons are not silent in the absence of external inputs, but rather maintain a low spontaneous firing activity. This aspect of cortical networks is likely to be important for their computational function, but is hard to reproduce in models of cortical circuits of neurons because the low-activity regime is inherently unstable. Here we show-through theoretical analysis and extensive computer simulations-that short-term synaptic plasticity endows models of cortical circuits with a remarkable stability in the low-activity regime. This short-term plasticity works as a homeostatic mechanism that stabilizes the overall activity level in spite of drastic changes in external inputs and internal circuit properties, while preserving reliable transient responses to signals. The contribution of synaptic dynamics to this stability can be predicted on the basis of general principles from control theory.

  11. An objective function for Hebbian self-limiting synaptic plasticity rules

    NASA Astrophysics Data System (ADS)

    Gros, Claudius; Eckmann, Samuel; Echeveste, Rodrigo

    Objective functions, formulated in terms of information theoretical measures with respect to the input and output probability distributions, provide a useful framework for the formulation of guiding principles for information processing systems, such as neural networks. In the present work, a guiding principle for neural plasticity is formulated in terms of an objective function expressed as the Fisher information with respect to an operator that we denote as the synaptic flux. By minimization of this objective function, we obtain Hebbian self-limiting synaptic plasticity rules, avoiding unbounded weight growth. Furthermore, we show how the rules are selective to directions of maximal negative excess kurtosis, making them suitable for independent component analysis. As an application, the non-linear bars problem is studied, in which each neuron is presented with a non-linear superposition of horizontal and vertical bars. We show that, under the here presented rules, the neurons are able to find the independent components of the input.

  12. Sleep and the Price of Plasticity: From Synaptic and Cellular Homeostasis to Memory Consolidation and Integration

    PubMed Central

    Tononi, Giulio; Cirelli, Chiara

    2014-01-01

    Summary Sleep is universal, tightly regulated, and its loss impairs cognition. But why does the brain need to disconnect from the environment for hours every day? The synaptic homeostasis hypothesis (SHY) proposes that sleep is the price the brain pays for plasticity. During a waking episode, learning statistical regularities about the current environment requires strengthening connections throughout the brain. This increases cellular needs for energy and supplies, decreases signal-to-noise ratios, and saturates learning. During sleep, spontaneous activity renormalizes net synaptic strength and restores cellular homeostasis. Activity-dependent down-selection of synapses can also explain the benefits of sleep on memory acquisition, consolidation, and integration. This happens through the off-line, comprehensive sampling of statistical regularities incorporated in neuronal circuits over a lifetime. This review considers the rationale and evidence for SHY and points to open issues related to sleep and plasticity. PMID:24411729

  13. P2Y Receptors in Synaptic Transmission and Plasticity: Therapeutic Potential in Cognitive Dysfunction

    PubMed Central

    Guzman, Segundo J.; Gerevich, Zoltan

    2016-01-01

    ATP released from neurons and astrocytes during neuronal activity or under pathophysiological circumstances is able to influence information flow in neuronal circuits by activation of ionotropic P2X and metabotropic P2Y receptors and subsequent modulation of cellular excitability, synaptic strength, and plasticity. In the present paper we review cellular and network effects of P2Y receptors in the brain. We show that P2Y receptors inhibit the release of neurotransmitters, modulate voltage- and ligand-gated ion channels, and differentially influence the induction of synaptic plasticity in the prefrontal cortex, hippocampus, and cerebellum. The findings discussed here may explain how P2Y1 receptor activation during brain injury, hypoxia, inflammation, schizophrenia, or Alzheimer's disease leads to an impairment of cognitive processes. Hence, it is suggested that the blockade of P2Y1 receptors may have therapeutic potential against cognitive disturbances in these states. PMID:27069691

  14. Thrombin regulation of synaptic transmission and plasticity: implications for health and disease

    PubMed Central

    Ben Shimon, Marina; Lenz, Maximilian; Ikenberg, Benno; Becker, Denise; Shavit Stein, Efrat; Chapman, Joab; Tanne, David; Pick, Chaim G.; Blatt, Ilan; Neufeld, Miri; Vlachos, Andreas; Maggio, Nicola

    2015-01-01

    Thrombin, a serine protease involved in the blood coagulation cascade has been shown to affect neural function following blood-brain barrier breakdown. However, several lines of evidence exist that thrombin is also expressed in the brain under physiological conditions, suggesting an involvement of thrombin in the regulation of normal brain functions. Here, we review ours’ as well as others’ recent work on the role of thrombin in synaptic transmission and plasticity through direct or indirect activation of Protease-Activated Receptor-1 (PAR1). These studies propose a novel role of thrombin in synaptic plasticity, both in physiology as well as in neurological diseases associated with increased brain thrombin/PAR1 levels. PMID:25954157

  15. Dopamine in Motor Cortex Is Necessary for Skill Learning and Synaptic Plasticity

    PubMed Central

    Molina-Luna, Katiuska; Pekanovic, Ana; Röhrich, Sebastian; Hertler, Benjamin; Schubring-Giese, Maximilian; Rioult-Pedotti, Mengia-Seraina; Luft, Andreas R.

    2009-01-01

    Preliminary evidence indicates that dopamine given by mouth facilitates the learning of motor skills and improves the recovery of movement after stroke. The mechanism of these phenomena is unknown. Here, we describe a mechanism by demonstrating in rat that dopaminergic terminals and receptors in primary motor cortex (M1) enable motor skill learning and enhance M1 synaptic plasticity. Elimination of dopaminergic terminals in M1 specifically impaired motor skill acquisition, which was restored upon DA substitution. Execution of a previously acquired skill was unaffected. Reversible blockade of M1 D1 and D2 receptors temporarily impaired skill acquisition but not execution, and reduced long-term potentiation (LTP) within M1, a form of synaptic plasticity critically involved in skill learning. These findings identify a behavioral and functional role of dopaminergic signaling in M1. DA in M1 optimizes the learning of a novel motor skill. PMID:19759902

  16. Hierarchical Chunking of Sequential Memory on Neuromorphic Architecture with Reduced Synaptic Plasticity.

    PubMed

    Li, Guoqi; Deng, Lei; Wang, Dong; Wang, Wei; Zeng, Fei; Zhang, Ziyang; Li, Huanglong; Song, Sen; Pei, Jing; Shi, Luping

    2016-01-01

    Chunking refers to a phenomenon whereby individuals group items together when performing a memory task to improve the performance of sequential memory. In this work, we build a bio-plausible hierarchical chunking of sequential memory (HCSM) model to explain why such improvement happens. We address this issue by linking hierarchical chunking with synaptic plasticity and neuromorphic engineering. We uncover that a chunking mechanism reduces the requirements of synaptic plasticity since it allows applying synapses with narrow dynamic range and low precision to perform a memory task. We validate a hardware version of the model through simulation, based on measured memristor behavior with narrow dynamic range in neuromorphic circuits, which reveals how chunking works and what role it plays in encoding sequential memory. Our work deepens the understanding of sequential memory and enables incorporating it for the investigation of the brain-inspired computing on neuromorphic architecture.

  17. 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

  18. Using Inspiration from Synaptic Plasticity Rules to Optimize Traffic Flow in Distributed Engineered Networks.

    PubMed

    Suen, Jonathan Y; Navlakha, Saket

    2017-02-09

    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.

  19. Domestication of the Dog from the Wolf Was Promoted by Enhanced Excitatory Synaptic Plasticity: A Hypothesis

    PubMed Central

    Wang, Ming-Shan; Irwin, David M.; Wu, Dong-Dong; Zhang, Ya-Ping

    2014-01-01

    Dogs shared a much closer relationship with humans than any other domesticated animals, probably due to their unique social cognitive capabilities, which were hypothesized to be a by-product of selection for tameness toward humans. Here, we demonstrate that genes involved in glutamate metabolism, which account partially for fear response, indeed show the greatest population differentiation by whole-genome comparison of dogs and wolves. However, the changing direction of their expression supports a role in increasing excitatory synaptic plasticity in dogs rather than reducing fear response. Because synaptic plasticity are widely believed to be cellular correlates of learning and memory, this change may alter the learning and memory abilities of ancient scavenging wolves, weaken the fear reaction toward humans, and prompt the initial interspecific contact. PMID:25377939

  20. Identification of functional synaptic plasticity from spiking activities using nonlinear dynamical modeling.

    PubMed

    Song, Dong; Chan, Rosa H M; Robinson, Brian S; Marmarelis, Vasilis Z; Opris, Ioan; Hampson, Robert E; Deadwyler, Sam A; Berger, Theodore W

    2015-04-15

    This paper presents a systems identification approach for studying the long-term synaptic plasticity using natural spiking activities. This approach consists of three modeling steps. First, a multi-input, single-output (MISO), nonlinear dynamical spiking neuron model is formulated to estimate and represent the synaptic strength in means of functional connectivity between input and output neurons. Second, this MISO model is extended to a nonstationary form to track the time-varying properties of the synaptic strength. Finally, a Volterra modeling method is used to extract the synaptic learning rule, e.g., spike-timing-dependent plasticity, for the explanation of the input-output nonstationarity as the consequence of the past input-output spiking patterns. This framework is developed to study the underlying mechanisms of learning and memory formation in behaving animals, and may serve as the computational basis for building the next-generation adaptive cortical prostheses. Copyright © 2014 Elsevier B.V. All rights reserved.

  1. Telencephalic neurocircuitry and synaptic plasticity in rodent spatial learning and memory.

    PubMed

    Pooters, Tine; Van der Jeugd, Ann; Callaerts-Vegh, Zsuzsanna; D'Hooge, Rudi

    2015-09-24

    Spatial learning and memory in rodents represent close equivalents of human episodic declarative memory, which is especially sensitive to cerebral aging, neurodegeneration, and various neuropsychiatric disorders. Many tests and protocols are available for use in laboratory rodents, but Morris water maze and radial-arm maze remain the most widely used as well as the most valid and reliable spatial tests. Telencephalic neurocircuitry that plays functional roles in spatial learning and memory includes hippocampus, dorsal striatum and medial prefrontal cortex. Prefrontal-hippocampal circuitry comprises the major associative system in the rodent brain, and is critical for navigation in physical space, whereas interconnections between prefrontal cortex and dorsal striatum are probably more important for motivational or goal-directed aspects of spatial learning. Two major forms of synaptic plasticity, namely long-term potentiation, a lasting increase in synaptic strength between simultaneously activated neurons, and long-term depression, a decrease in synaptic strength, have been found to occur in hippocampus, dorsal striatum and medial prefrontal cortex. These and other phenomena of synaptic plasticity are probably crucial for the involvement of telencephalic neurocircuitry in spatial learning and memory. They also seem to play a role in the pathophysiology of two brain pathologies with episodic declarative memory impairments as core symptoms, namely Alzheimer's disease and schizophrenia. Further research emphasis on rodent telencephalic neurocircuitry could be relevant to more valid and reliable preclinical research on these most devastating brain disorders. This article is part of a Special Issue entitled SI: Brain and Memory.

  2. 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

  3. Acute and chronic effects of ethanol on learning-related synaptic plasticity.

    PubMed

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

    2014-02-01

    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. Copyright © 2014 Elsevier Inc. All rights reserved.

  4. Plasticity, synaptic strength, and epilepsy: what can we learn from ultrastructural data?

    PubMed

    Leite, João Pereira; Neder, Luciano; Arisi, Gabriel Maisonnave; Carlotti, Carlos Gilberto; Assirati, João Alberto; Moreira, Jorge Eduardo

    2005-01-01

    Central nervous system synapses have an intrinsic plastic capacity to adapt to new conditions with rapid changes in their structure. Such activity-dependent refinement occurs during development and learning, and shares features with diseases such as epilepsy. Quantitative ultrastructural studies based on serial sectioning and reconstructions have shown various structural changes associated with synaptic strength involving both dendritic spines and postsynaptic densities (PSDs) during long-term potentiation (LTP). In this review, we focus on experimental studies that have analyzed at the ultrastructural level the consequences of LTP in rodents, and plastic changes in the hippocampus of experimental models of epilepsy and human tissue obtained during surgeries for intractable temporal lobe epilepsy (TLE). Modifications in spine morphology, increases in the proportion of synapses with perforated PSDs, and formation of multiple spine boutons arising from the same dendrite are the possible sequence of events that accompany hippocampal LTP. Structural remodeling of mossy fiber synapses and formation of aberrant synaptic contacts in the dentate gyrus are common features in experimental models of epilepsy and in human TLE. Combined electrophysiological and ultrastructural studies in kindled rats and chronic epileptic animals have indicated the occurrence of seizure- and neuron loss-induced changes in the hippocampal network. In these experiments, the synaptic contacts on granule cells are similar to those described for LTP. Such changes could be associated with enhancement of synaptic efficiency and may be important in epileptogenesis.

  5. Gene expression parallels synaptic excitability and plasticity changes in Alzheimer’s disease

    PubMed Central

    Saura, Carlos A.; Parra-Damas, Arnaldo; Enriquez-Barreto, Lilian

    2015-01-01

    Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by abnormal accumulation of β-amyloid and tau and synapse dysfunction in memory-related neural circuits. Pathological and functional changes in the medial temporal lobe, a region essential for explicit memory encoding, contribute to cognitive decline in AD. Surprisingly, functional imaging studies show increased activity of the hippocampus and associated cortical regions during memory tasks in presymptomatic and early AD stages, whereas brain activity declines as the disease progresses. These findings suggest an emerging scenario where early pathogenic events might increase neuronal excitability leading to enhanced brain activity before clinical manifestations of the disease, a stage that is followed by decreased brain activity as neurodegeneration progresses. The mechanisms linking pathology with synaptic excitability and plasticity changes leading to memory loss in AD remain largely unclear. Recent studies suggest that increased brain activity parallels enhanced expression of genes involved in synaptic transmission and plasticity in preclinical stages, whereas expression of synaptic and activity-dependent genes are reduced by the onset of pathological and cognitive symptoms. Here, we review recent evidences indicating a relationship between transcriptional deregulation of synaptic genes and neuronal activity and memory loss in AD and mouse models. These findings provide the basis for potential clinical applications of memory-related transcriptional programs and their regulatory mechanisms as novel biomarkers and therapeutic targets to restore brain function in AD and other cognitive disorders. PMID:26379494

  6. Localization of Presynaptic Plasticity Mechanisms Enables Functional Independence of Synaptic and Ectopic Transmission in the Cerebellum

    PubMed Central

    Dobson, Katharine L.; Bellamy, Tomas C.

    2015-01-01

    In the cerebellar molecular layer parallel fibre terminals release glutamate from both the active zone and from extrasynaptic “ectopic” sites. Ectopic release mediates transmission to the Bergmann glia that ensheathe the synapse, activating Ca2+-permeable AMPA receptors and glutamate transporters. Parallel fibre terminals exhibit several forms of presynaptic plasticity, including cAMP-dependent long-term potentiation and endocannabinoid-dependent long-term depression, but it is not known whether these presynaptic forms of long-term plasticity also influence ectopic transmission to Bergmann glia. Stimulation of parallel fibre inputs at 16 Hz evoked LTP of synaptic transmission, but LTD of ectopic transmission. Pharmacological activation of adenylyl cyclase by forskolin caused LTP at Purkinje neurons, but only transient potentiation at Bergmann glia, reinforcing the concept that ectopic sites lack the capacity to express sustained cAMP-dependent potentiation. Activation of mGluR1 caused depression of synaptic transmission via retrograde endocannabinoid signalling but had no significant effect at ectopic sites. In contrast, activation of NMDA receptors suppressed both synaptic and ectopic transmission. The results suggest that the signalling mechanisms for presynaptic LTP and retrograde depression by endocannabinoids are restricted to the active zone at parallel fibre synapses, allowing independent modulation of synaptic transmission to Purkinje neurons and ectopic transmission to Bergmann glia. PMID:26171253

  7. Homeostatic synaptic plasticity in developing spinal networks driven by excitatory GABAergic currents

    PubMed Central

    Wenner, Peter

    2013-01-01

    Homeostatic plasticity refers to mechanisms that the cell or network engage in order to homeostatically maintain a preset level of activity. These mechanisms include compensatory changes in cellular excitability, excitatory and inhibitory synaptic strength and are typically studied at a developmental stage when GABA or glycine are inhibitory. Here we focus on the expression of homeostatic plasticity in the chick embryo spinal cord at a stage when GABA is excitatory. When spinal activity is perturbed in the living embryo there are compensatory changes in postsynaptic AMPA receptors and in the driving force for GABAergic currents. These changes are triggered by reduced GABAA receptor signaling, which appears to be part of the sensing machinery for triggering homeostatic plasticity. We compare and contrast these findings to homeostatic plasticity expressed in spinal systems at different stages of development, and to the developing retina at a stage when GABA is depolarizing. PMID:23727439

  8. Cdk5 Modulates Long-Term Synaptic Plasticity and Motor Learning in Dorsolateral Striatum

    PubMed Central

    Hernandez, Adan; Tan, Chunfeng; Mettlach, Gabriel; Pozo, Karine; Plattner, Florian; Bibb, James A.

    2016-01-01

    The striatum controls multiple cognitive aspects including motivation, reward perception, decision-making and motor planning. In particular, the dorsolateral striatum contributes to motor learning. Here we define an approach for investigating synaptic plasticity in mouse dorsolateral cortico-striatal circuitry and interrogate the relative contributions of neurotransmitter receptors and intracellular signaling components. Consistent with previous studies, we show that long-term potentiation (LTP) in cortico-striatal circuitry is facilitated by dopamine, and requires activation of D1-dopamine receptors, as well as NMDA receptors (NMDAR) and their calcium-dependent downstream effectors, including CaMKII. Moreover, we assessed the contribution of the protein kinase Cdk5, a key neuronal signaling molecule, in cortico-striatal LTP. Pharmacological Cdk5 inhibition, brain-wide Cdk5 conditional knockout, or viral-mediated dorsolateral striatal-specific loss of Cdk5 all impaired dopamine-facilitated LTP or D1-dopamine receptor-facilitated LTP. Selective loss of Cdk5 in dorsolateral striatum increased locomotor activity and attenuated motor learning. Taken together, we report an approach for studying synaptic plasticity in mouse dorsolateral striatum and critically implicate D1-dopamine receptor, NMDAR, Cdk5, and CaMKII in cortico-striatal plasticity. Furthermore, we associate striatal plasticity deficits with effects upon behaviors mediated by this circuitry. This approach should prove useful for the study of the molecular basis of plasticity in the dorsolateral striatum. PMID:27443506

  9. Does Spike-Timing-Dependent Synaptic Plasticity Couple or Decouple Neurons Firing in Synchrony?

    PubMed Central

    Knoblauch, Andreas; Hauser, Florian; Gewaltig, Marc-Oliver; Körner, Edgar; Palm, Günther

    2012-01-01

    Spike synchronization is thought to have a constructive role for feature integration, attention, associative learning, and the formation of bidirectionally connected Hebbian cell assemblies. By contrast, theoretical studies on spike-timing-dependent plasticity (STDP) report an inherently decoupling influence of spike synchronization on synaptic connections of coactivated neurons. For example, bidirectional synaptic connections as found in cortical areas could be reproduced only by assuming realistic models of STDP and rate coding. We resolve this conflict by theoretical analysis and simulation of various simple and realistic STDP models that provide a more complete characterization of conditions when STDP leads to either coupling or decoupling of neurons firing in synchrony. In particular, we show that STDP consistently couples synchronized neurons if key model parameters are matched to physiological data: First, synaptic potentiation must be significantly stronger than synaptic depression for small (positive or negative) time lags between presynaptic and postsynaptic spikes. Second, spike synchronization must be sufficiently imprecise, for example, within a time window of 5–10 ms instead of 1 ms. Third, axonal propagation delays should not be much larger than dendritic delays. Under these assumptions synchronized neurons will be strongly coupled leading to a dominance of bidirectional synaptic connections even for simple STDP models and low mean firing rates at the level of spontaneous activity. PMID:22936909

  10. Synaptic transmission and plasticity require AMPA receptor anchoring via its N-terminal domain

    PubMed Central

    Watson, Jake F; Ho, Hinze; Greger, Ingo H

    2017-01-01

    AMPA-type glutamate receptors (AMPARs) mediate fast excitatory neurotransmission and are selectively recruited during activity-dependent plasticity to increase synaptic strength. A prerequisite for faithful signal transmission is the positioning and clustering of AMPARs at postsynaptic sites. The mechanisms underlying this positioning have largely been ascribed to the receptor cytoplasmic C-termini and to AMPAR-associated auxiliary subunits, both interacting with the postsynaptic scaffold. Here, using mouse organotypic hippocampal slices, we show that the extracellular AMPAR N-terminal domain (NTD), which projects midway into the synaptic cleft, plays a fundamental role in this process. This highly sequence-diverse domain mediates synaptic anchoring in a subunit-selective manner. Receptors lacking the NTD exhibit increased mobility in synapses, depress synaptic transmission and are unable to sustain long-term potentiation (LTP). Thus, synaptic transmission and the expression of LTP are dependent upon an AMPAR anchoring mechanism that is driven by the NTD. DOI: http://dx.doi.org/10.7554/eLife.23024.001 PMID:28290985

  11. Modulating Effect of Cytokines on Mechanisms of Synaptic Plasticity in the Brain.

    PubMed

    Levin, S G; Godukhin, O V

    2017-03-01

    After accumulation of data showing that resident brain cells (neurons, astrocytes, and microglia) produce mediators of the immune system, such as cytokines and their receptors under normal physiological conditions, a critical need emerged for investigating the role of these mediators in cognitive processes. The major problem for understanding the functional role of cytokines in the mechanisms of synaptic plasticity, de novo neurogenesis, and learning and memory is the small number of investigated cytokines. Existing concepts are based on data from just three proinflammatory cytokines: interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha. The amount of information in the literature on the functional role of antiinflammatory cytokines in the mechanisms of synaptic plasticity and cognitive functions of mature mammalian brain is dismally low. However, they are of principle importance for understanding the mechanisms of local information processing in the brain, since they modulate the activity of individual cells and local neural networks, being able to reconstruct the processes of synaptic plasticity and intercellular communication, in general, depending on the local ratio of the levels of different cytokines in certain areas of the brain. Understanding the functional role of cytokines in cellular mechanisms of information processing and storage in the brain would allow developing preventive and therapeutic means for the treatment of neuropathologies related to impairment of these mechanisms.

  12. Bidirectional synaptic plasticity in the dentate gyrus of the awake freely behaving mouse

    PubMed Central

    Koranda, Jessica L.; Masino, Susan A.; Blaise, J. Harry

    2008-01-01

    There is significant interest in in vivo synaptic plasticity in mice due to the many relevant genetic mutants now available. Nevertheless, use of in vivo models remains limited. To date long-term potentiation (LTP) has been studied infrequently, and long-term depression (LTD) has not been characterized in the mouse in vivo. Herein we describe protocols and improved methodologies we developed to record hippocampal synaptic plasticity reliably from the dentate gyrus of the awake freely behaving mouse. Seven days prior to recording, we implanted microelectrodes encapsulated within a lightweight, low-profile headstage assembly. On the day of recording, we induced either LTP or LTD in the awake freely behaving animal and monitored subsequent changes in population spike amplitude for at least 24 hrs. Using this protocol we attained 80% success in inducing and maintaining either LTP or LTD. Recording from a chronic implant using this improved methodology is best suited to reveal naturally occurring brain activity, and avoids both acute effects of local electrode insertion and drifts in neuronal excitability associated with anesthesia. Ultimately a reliable freely behaving mouse model of bidirectional synaptic plasticity is invaluable for full characterization of genetic models of disease states and manipulations of the mechanisms implicated in learning and memory. PMID:17875326

  13. Effects of Myoga on Memory and Synaptic Plasticity by Regulating Nerve Growth Factor-Mediated Signaling.

    PubMed

    Kim, Hyo Geun; Lim, Soonmin; Hong, Jongki; Kim, Ae-Jung; Oh, Myung Sook

    2016-02-01

    The flower bud of Zingiber mioga Roscoe, known as 'myoga' or Japanese ginger, has a pungent aroma and is commonly consumed as a spice, with pickles, or as a health supplement in Eastern Asia. Here, we evaluated the activity of myoga in the brain, focusing especially on nerve growth factor (NGF), which is believed to mediate synaptic plasticity, supporting learning and memory. In a rat primary hippocampal astrocyte culture system, treatment with myoga extract for 24 h significantly stimulated the production of NGF. In mice administered myoga extract for 14 days, 200 and 400 mg/kg/day treatment resulted in increased NGF levels in the hippocampus. Myoga extract treatment also regulated the phosphorylation of extracellular signal-regulated kinases and cAMP response element-binding protein in the mouse hippocampus, leading to increased synaptic plasticity. In addition, it significantly increased novel object recognition time and spontaneous alternation, indicating improvement in learning and memory. These results suggest that myoga helps regulate NGF and synaptic plasticity, increasing memory ability.

  14. A potential role for pro-inflammatory cytokines in regulating synaptic plasticity in major depressive disorder

    PubMed Central

    Khairova, Rushaniya A.; Machado-Vieira, Rodrigo; Du, Jing; Manji, Husseini K.

    2009-01-01

    A growing body of data suggests that hyperactivation of the immune system has been implicated in the pathophysiology of major depressive disorder (MDD). Several pro-inflammatory cytokines, such as tumour necrosis factor-alpha (TNF-α) and interleukin-1 (IL-1) have been found to be significantly increased in patients with MDD. This review focuses on these two cytokines based on multiple lines of evidence from genetic, animal behaviour, and clinical studies showing that altered levels of serum TNF-α and IL-1 are associated with increased risk of depression, cognitive impairments, and reduced responsiveness to treatment. In addition, recent findings have shown that centrally expressed TNF-α and IL-1 play a dual role in the regulation of synaptic plasticity. In this paper, we review and critically appraise the mechanisms by which cytokines regulate synaptic and neural plasticity, and their implications for the pathophysiology and treatment of MDD. Finally, we discuss the therapeutic potential of anti-inflammatory-based approaches for treating patients with severe mood disorders. This is a promising field for increasing our understanding of the mechanistic interaction between the immune system, synaptic plasticity, and antidepressants, and for the ultimate development of novel and improved therapeutics for severe mood disorders. PMID:19224657

  15. Docosahexaenoic acid dietary supplementation enhances the effects of exercise on synaptic plasticity and cognition.

    PubMed

    Wu, A; Ying, Z; Gomez-Pinilla, F

    2008-08-26

    Omega-3 fatty acids (i.e. docosahexaenoic acid; DHA), similar to exercise, improve cognitive function, promote neuroplasticity, and protect against neurological lesion. In this study, we investigated a possible synergistic action between DHA dietary supplementation and voluntary exercise on modulating synaptic plasticity and cognition. Rats received DHA dietary supplementation (1.25% DHA) with or without voluntary exercise for 12 days. We found that the DHA-enriched diet significantly increased spatial learning ability, and these effects were enhanced by exercise. The DHA-enriched diet increased levels of pro-brain-derived neurotrophic factor (BDNF) and mature BDNF, whereas the additional application of exercise boosted the levels of both. Furthermore, the levels of the activated forms of CREB and synapsin I were incremented by the DHA-enriched diet with greater elevation by the concurrent application of exercise. While the DHA diet reduced hippocampal oxidized protein levels, a combination of a DHA diet and exercise resulted in a greater reduction rate. The levels of activated forms of hippocampal Akt and CaMKII were increased by the DHA-enriched diet, and with even greater elevation by a combination of diet and exercise. Akt and CaMKII signaling are crucial step by which BDNF exerts its action on synaptic plasticity and learning and memory. These results indicate that the DHA diet enhanced the effects of exercise on cognition and BDNF-related synaptic plasticity, a capacity that may be used to promote mental health and reduce risk of neurological disorders.

  16. Effects of Synaptic Plasticity on Phase and Period Locking in a Network of Two Oscillatory Neurons

    PubMed Central

    2014-01-01

    We study the effects of synaptic plasticity on the determination of firing period and relative phases in a network of two oscillatory neurons coupled with reciprocal inhibition. We combine the phase response curves of the neurons with the short-term synaptic plasticity properties of the synapses to define Poincaré maps for the activity of an oscillatory network. Fixed points of these maps correspond to the phase-locked modes of the network. These maps allow us to analyze the dependence of the resulting network activity on the properties of network components. Using a combination of analysis and simulations, we show how various parameters of the model affect the existence and stability of phase-locked solutions. We find conditions on the synaptic plasticity profiles and the phase response curves of the neurons for the network to be able to maintain a constant firing period, while varying the phase of locking between the neurons or vice versa. A generalization to cobwebbing for two-dimensional maps is also discussed. PMID:24791223

  17. Visualization of NMDA receptor-dependent AMPA receptor synaptic plasticity in vivo

    PubMed Central

    Zhang, Yong; Cudmore, Robert H.; Lin, Da-Ting; Linden, David J.; Huganir, Richard L.

    2015-01-01

    Regulation of AMPA receptor (AMPAR) membrane trafficking plays a critical role in synaptic plasticity and learning and memory. However, how AMPAR trafficking occurs in vivo remains elusive. Using in vivo two-photon microscopy in the mouse somatosensory barrel cortex, we found that acute whisker stimulation leads to a significant increase in the surface expression of the AMPAR GluA1 subunit (sGluA1) in both spines and dendritic shafts and small increases in spine size. Interestingly, initial spine properties bias spine changes following whisker stimulation. Changes in spine sGluA1 are positively correlated with changes in spine size and dendritic shaft sGluA1 following whisker stimulation. The increase in spine sGluA1 evoked by whisker stimulation is NMDA receptor dependent and long lasting, similar to major forms of synaptic plasticity in the brain. These results reveal experience dependent AMPAR trafficking in real time and characterize, in vivo, a major form of synaptic plasticity in the brain. PMID:25643295

  18. Kalirin-7 is necessary for normal NMDA receptor-dependent synaptic plasticity

    PubMed Central

    2011-01-01

    Background Dendritic spines represent the postsynaptic component of the vast majority of excitatory synapses present in the mammalian forebrain. The ability of spines to rapidly alter their shape, size, number and receptor content in response to stimulation is considered to be of paramount importance during the development of synaptic plasticity. Indeed, long-term potentiation (LTP), widely believed to be a cellular correlate of learning and memory, has been repeatedly shown to induce both spine enlargement and the formation of new dendritic spines. In our studies, we focus on Kalirin-7 (Kal7), a Rho GDP/GTP exchange factor (Rho-GEF) localized to the postsynaptic density that plays a crucial role in the development and maintenance of dendritic spines both in vitro and in vivo. Previous studies have shown that mice lacking Kal7 (Kal7KO) have decreased dendritic spine density in the hippocampus as well as focal hippocampal-dependent learning impairments. Results We have performed a detailed electrophysiological characterization of the role of Kal7 in hippocampal synaptic plasticity. We show that loss of Kal7 results in impaired NMDA receptor-dependent LTP and long-term depression, whereas a NMDA receptor-independent form of LTP is shown to be normal in the absence of Kal7. Conclusions These results indicate that Kal7 is an essential and selective modulator of NMDA receptor-dependent synaptic plasticity in the hippocampus. PMID:22182308

  19. Reactive Oxygen Species in the Regulation of Synaptic Plasticity and Memory

    PubMed Central

    Klann, Eric

    2011-01-01

    Abstract The brain is a metabolically active organ exhibiting high oxygen consumption and robust production of reactive oxygen species (ROS). The large amounts of ROS are kept in check by an elaborate network of antioxidants, which sometimes fail and lead to neuronal oxidative stress. Thus, ROS are typically categorized as neurotoxic molecules and typically exert their detrimental effects via oxidation of essential macromolecules such as enzymes and cytoskeletal proteins. Most importantly, excessive ROS are associated with decreased performance in cognitive function. However, at physiological concentrations, ROS are involved in functional changes necessary for synaptic plasticity and hence, for normal cognitive function. The fine line of role reversal of ROS from good molecules to bad molecules is far from being fully understood. This review focuses on identifying the multiple sources of ROS in the mammalian nervous system and on presenting evidence for the critical and essential role of ROS in synaptic plasticity and memory. The review also shows that the inability to restrain either age- or pathology-related increases in ROS levels leads to opposite, detrimental effects that are involved in impairments in synaptic plasticity and memory function. Antioxid. Redox Signal. 14, 2013–2054. PMID:20649473

  20. The HVC microcircuit: the synaptic basis for interactions between song motor and vocal plasticity pathways.

    PubMed

    Mooney, Richard; Prather, Jonathan F

    2005-02-23

    Synaptic interactions between telencephalic neurons innervating descending motor or basal ganglia pathways are essential in the learning, planning, and execution of complex movements. Synaptic interactions within the songbird telencephalic nucleus HVC are implicated in motor and auditory activity associated with learned vocalizations. HVC contains projection neurons (PNs) (HVC(RA)) that innervate song premotor areas, other PNs (HVC(X)) that innervate a basal ganglia pathway necessary for vocal plasticity, and interneurons (HVC(INT)). During singing, HVC(RA) fire in temporally sparse bursts, possibly because of HVC(INT)-HVC(RA) interactions, and a corollary discharge can be detected in the basal ganglia pathway, likely because of synaptic transmission from HVC(RA) to HVC(X) cells. During song playback, local interactions, including inhibition onto HVC(X) cells, shape highly selective responses that distinguish HVC from its auditory afferents. To better understand the synaptic substrate for the motor and auditory properties of HVC, we made intracellular recordings from pairs of HVC neurons in adult male zebra finch brain slices and used spike-triggered averages to assess synaptic connectivity. A major synaptic interaction between the PNs was a disynaptic inhibition from HVC(RA) to HVC(X), which could link song motor signals in the two outputs of HVC and account for some of the song playback-evoked inhibition in HVC(X) cells. Furthermore, single interneurons made divergent connections onto PNs of both types, and either PN type could form reciprocal connections with interneurons. In these two regards, the synaptic architecture of HVC resembles that described in some pattern-generating networks, underscoring features likely to be important to singing and song learning.

  1. Environmental enrichment delays limbic epileptogenesis and restricts pathologic synaptic plasticity.

    PubMed

    Yang, Meng; Ozturk, Ezgi; Salzberg, Michael R; Rees, Sandra; Morris, Margaret; O'Brien, Terence J; Jones, Nigel C

    2016-03-01

    Environmental exposures impart powerful effects on vulnerability to many brain diseases, including epilepsy. Mesial temporal lobe epilepsy (MTLE) is a common form of epilepsy, and it is often accompanied by neuropsychiatric comorbidities. This study tests the hypothesis that environmental enrichment (EE) confers antiepileptogenic, psychoprotective, and neuroprotective effects in the amygdala kindling model of MTLE, and explores potential neurobiologic mechanisms. At weaning, male Wistar rats were allocated into either EE (large cages containing running wheels and toys; n = 43) or standard housing (SH; standard laboratory cages; n = 39) conditions. At P56, a bipolar electrode was implanted into the left amygdala, and rats underwent rapid amygdala kindling until experiencing five class V seizures (Racine scale, fully kindled). The elevated plus maze was used to assess anxiety. Postmortem histologic and molecular analyses investigated potential biologic mediators of effects. EE significantly delayed kindling epileptogenesis, with EE rats requiring a significantly greater number of kindling stimulations to reach a fully kindled state compared to SH rats (p < 0.05). EE and kindling both reduced anxiety (p < 0.05). Timm's staining revealed significant reductions in aberrant mossy fiber sprouting in EE rats (p < 0.05), and these effects of EE were accompanied by reduced expression of TrkB and CRH genes. We identify beneficial effects of EE on vulnerability to limbic epileptogenesis and anxiety, and identify reduced pathologic neuroplasticity and plasticity-related gene expression as potential underlying mechanisms. Enhanced environmental stimulation represents a potential antiepileptogenic strategy that might also mitigate the common psychiatric comorbidities of MTLE. Wiley Periodicals, Inc. © 2016 International League Against Epilepsy.

  2. Nonspecific synaptic plasticity improves the recognition of sparse patterns degraded by local noise.

    PubMed

    Safaryan, Karen; Maex, Reinoud; Davey, Neil; Adams, Rod; Steuber, Volker

    2017-04-20

    Many forms of synaptic plasticity require the local production of volatile or rapidly diffusing substances such as nitric oxide. The nonspecific plasticity these neuromodulators may induce at neighboring non-active synapses is thought to be detrimental for the specificity of memory storage. We show here that memory retrieval may benefit from this non-specific plasticity when the applied sparse binary input patterns are degraded by local noise. Simulations of a biophysically realistic model of a cerebellar Purkinje cell in a pattern recognition task show that, in the absence of noise, leakage of plasticity to adjacent synapses degrades the recognition of sparse static patterns. However, above a local noise level of 20%, the model with nonspecific plasticity outperforms the standard, specific model. The gain in performance is greatest when the spatial distribution of noise in the input matches the range of diffusion-induced plasticity. Hence non-specific plasticity may offer a benefit in noisy environments or when the pressure to generalize is strong.

  3. Plasticity in respiratory motor neurons in response to reduced synaptic inputs: A form of homeostatic plasticity in respiratory control?

    PubMed

    Braegelmann, K M; Streeter, K A; Fields, D P; Baker, T L

    2017-01-01

    For most individuals, the respiratory control system produces a remarkably stable and coordinated motor output-recognizable as a breath-from birth until death. Very little is understood regarding the processes by which the respiratory control system maintains network stability in the presence of changing physiological demands and network properties that occur throughout life. An emerging principle of neuroscience is that neural activity is sensed and adjusted locally to assure that neurons continue to operate in an optimal range, yet to date, it is unknown whether such homeostatic plasticity is a feature of the neurons controlling breathing. Here, we review the evidence that local mechanisms sense and respond to perturbations in respiratory neural activity, with a focus on plasticity in respiratory motor neurons. We discuss whether these forms of plasticity represent homeostatic plasticity in respiratory control. We present new analyses demonstrating that reductions in synaptic inputs to phrenic motor neurons elicit a compensatory enhancement of phrenic inspiratory motor output, a form of plasticity termed inactivity-induced phrenic motor facilitation (iPMF), that is proportional to the magnitude of activity deprivation. Although the physiological role of iPMF is not understood, we hypothesize that it has an important role in protecting the drive to breathe during conditions of prolonged or intermittent reductions in respiratory neural activity, such as following spinal cord injury or during central sleep apnea.

  4. Interactions between behaviorally relevant rhythms and synaptic plasticity alter coding in the piriform cortex

    PubMed Central

    Urban, Nathaniel N.

    2012-01-01

    Understanding how neural and behavioral timescales interact to influence cortical activity and stimulus coding is an important issue in sensory neuroscience. In air-breathing animals, voluntary changes in respiratory frequency alter the temporal patterning olfactory input. In the olfactory bulb, these behavioral timescales are reflected in the temporal properties of mitral/tufted (M/T) cell spike trains. As the odor information contained in these spike trains is relayed from the bulb to the cortex, interactions between presynaptic spike timing and short-term synaptic plasticity dictate how stimulus features are represented in cortical spike trains. Here we demonstrate how the timescales associated with respiratory frequency, spike timing and short-term synaptic plasticity interact to shape cortical responses. Specifically, we quantified the timescales of short-term synaptic facilitation and depression at excitatory synapses between bulbar M/T cells and cortical neurons in slices of mouse olfactory cortex. We then used these results to generate simulated M/T population synaptic currents that were injected into real cortical neurons. M/T population inputs were modulated at frequencies consistent with passive respiration or active sniffing. We show how the differential recruitment of short-term plasticity at breathing versus sniffing frequencies alters cortical spike responses. For inputs at sniffing frequencies, cortical neurons linearly encoded increases in presynaptic firing rates with increased phase locked, firing rates. In contrast, at passive breathing frequencies, cortical responses saturated with changes in presynaptic rate. Our results suggest that changes in respiratory behavior can gate the transfer of stimulus information between the olfactory bulb and cortex. PMID:22553016

  5. Estimating short-term synaptic plasticity from pre- and postsynaptic spiking.

    PubMed

    Ghanbari, Abed; Malyshev, Aleksey; Volgushev, Maxim; Stevenson, Ian H

    2017-09-01

    Short-term synaptic plasticity (STP) critically affects the processing of information in neuronal circuits by reversibly changing the effective strength of connections between neurons on time scales from milliseconds to a few seconds. STP is traditionally studied using intracellular recordings of postsynaptic potentials or currents evoked by presynaptic spikes. However, STP also affects the statistics of postsynaptic spikes. Here we present two model-based approaches for estimating synaptic weights and short-term plasticity from pre- and postsynaptic spike observations alone. We extend a generalized linear model (GLM) that predicts postsynaptic spiking as a function of the observed pre- and postsynaptic spikes and allow the connection strength (coupling term in the GLM) to vary as a function of time based on the history of presynaptic spikes. Our first model assumes that STP follows a Tsodyks-Markram description of vesicle depletion and recovery. In a second model, we introduce a functional description of STP where we estimate the coupling term as a biophysically unrestrained function of the presynaptic inter-spike intervals. To validate the models, we test the accuracy of STP estimation using the spiking of pre- and postsynaptic neurons with known synaptic dynamics. We first test our models using the responses of layer 2/3 pyramidal neurons to simulated presynaptic input with different types of STP, and then use simulated spike trains to examine the effects of spike-frequency adaptation, stochastic vesicle release, spike sorting errors, and common input. We find that, using only spike observations, both model-based methods can accurately reconstruct the time-varying synaptic weights of presynaptic inputs for different types of STP. Our models also capture the differences in postsynaptic spike responses to presynaptic spikes following short vs long inter-spike intervals, similar to results reported for thalamocortical connections. These models may thus be useful

  6. Spike Timing-Dependent Plasticity as the Origin of the Formation of Clustered Synaptic Efficacy Engrams

    PubMed Central

    Iannella, Nicolangelo Libero; Launey, Thomas; Tanaka, Shigeru

    2010-01-01

    Synapse location, dendritic active properties and synaptic plasticity are all known to play some role in shaping the different input streams impinging onto a neuron. It remains unclear however, how the magnitude and spatial distribution of synaptic efficacies emerge from this interplay. Here, we investigate this interplay using a biophysically detailed neuron model of a reconstructed layer 2/3 pyramidal cell and spike timing-dependent plasticity (STDP). Specifically, we focus on the issue of how the efficacy of synapses contributed by different input streams are spatially represented in dendrites after STDP learning. We construct a simple feed forward network where a detailed model neuron receives synaptic inputs independently from multiple yet equally sized groups of afferent fibers with correlated activity, mimicking the spike activity from different neuronal populations encoding, for example, different sensory modalities. Interestingly, ensuing STDP learning, we observe that for all afferent groups, STDP leads to synaptic efficacies arranged into spatially segregated clusters effectively partitioning the dendritic tree. These segregated clusters possess a characteristic global organization in space, where they form a tessellation in which each group dominates mutually exclusive regions of the dendrite. Put simply, the dendritic imprint from different input streams left after STDP learning effectively forms what we term a “dendritic efficacy mosaic.” Furthermore, we show how variations of the inputs and STDP rule affect such an organization. Our model suggests that STDP may be an important mechanism for creating a clustered plasticity engram, which shapes how different input streams are spatially represented in dendrite. PMID:20725522

  7. NgR1: A Tunable Sensor Regulating Memory Formation, Synaptic, and Dendritic Plasticity

    PubMed Central

    Karlsson, Tobias E.; Smedfors, Gabriella; Brodin, Alvin T. S.; Åberg, Elin; Mattsson, Anna; Högbeck, Isabelle; Wellfelt, Katrin; Josephson, Anna; Brené, Stefan; Olson, Lars

    2016-01-01

    Nogo receptor 1 (NgR1) is expressed in forebrain neurons and mediates nerve growth inhibition in response to Nogo and other ligands. Neuronal activity downregulates NgR1 and the inability to downregulate NgR1 impairs long-term memory. We investigated behavior in a serial behavioral paradigm in mice that overexpress or lack NgR1, finding impaired locomotor behavior and recognition memory in mice lacking NgR1 and impaired sequential spatial learning in NgR1 overexpressing mice. We also investigated a role for NgR1 in drug-mediated sensitization and found that repeated cocaine exposure caused stronger locomotor responses but limited development of stereotypies in NgR1 overexpressing mice. This suggests that NgR1-regulated synaptic plasticity is needed to develop stereotypies. Ex vivo magnetic resonance imaging and diffusion tensor imaging analyses of NgR1 overexpressing brains did not reveal any major alterations. NgR1 overexpression resulted in significantly reduced density of mature spines and dendritic complexity. NgR1 overexpression also altered cocaine-induced effects on spine plasticity. Our results show that NgR1 is a negative regulator of both structural synaptic plasticity and dendritic complexity in a brain region-specific manner, and highlight anterior cingulate cortex as a key area for memory-related plasticity. PMID:26838771

  8. Multiple forms of long-term synaptic plasticity at hippocampal mossy fiber synapses onto interneurons

    PubMed Central

    Galván, Emilio J.; Cosgrove, Kathleen E.; Barrionuevo, Germán

    2010-01-01

    The hippocampal mossy fiber (MF) pathway originates from the dentate gyrus granule cells and provides a powerful excitatory synaptic drive to neurons in the dentate gyrus hilus and area CA3. Much of the early work on the MF pathway focused on its electrophysiological properties, and ability to drive CA3 pyramidal cell activity. Over the last ten years, however, a new focus on the synaptic interaction between granule cells with inhibitory interneurons has emerged. These data have revealed an immense heterogeneity of long-term plasticity at MF synapses on various interneuron targets. Interestingly, these studies also indicate that the mechanisms of MF long-term plasticity in some interneuron subtypes may be more similar to pyramidal cells than previously appreciated. In this review, we first define the synapse types at each of the interneuron targets based on the receptors present. We then describe the different forms of long-term plasticity observed, and the mechanisms underlying each form as they are currently understood. Finally we highlight various open questions surrounding MF long-term plasticity in interneurons, focusing specifically on the induction and maintenance of LTP, and what the functional impact of persistent changes in efficacy at MF – interneuron synapses might be on the emergent properties of the inhibitory network dynamics in area CA3. PMID:21093459

  9. A Role for Calcium-Permeable AMPA Receptors in Synaptic Plasticity and Learning

    PubMed Central

    Gray, Erin E.; Abdipranoto, Andrea; Thangthaeng, Nopporn; Jacobs, Nate; Saab, Faysal; Tonegawa, Susumu; Heinemann, Stephen F.; O'Dell, Thomas J.; Fanselow, Michael S.; Vissel, Bryce

    2010-01-01

    A central concept in the field of learning and memory is that NMDARs are essential for synaptic plasticity and memory formation. Surprisingly then, multiple studies have found that behavioral experience can reduce or eliminate the contribution of these receptors to learning. The cellular mechanisms that mediate learning in the absence of NMDAR activation are currently unknown. To address this issue, we examined the contribution of Ca2+-permeable AMPARs to learning and plasticity in the hippocampus. Mutant mice were engineered with a conditional genetic deletion of GluR2 in the CA1 region of the hippocampus (GluR2-cKO mice). Electrophysiology experiments in these animals revealed a novel form of long-term potentiation (LTP) that was independent of NMDARs and mediated by GluR2-lacking Ca2+-permeable AMPARs. Behavioral analyses found that GluR2-cKO mice were impaired on multiple hippocampus-dependent learning tasks that required NMDAR activation. This suggests that AMPAR-mediated LTP interferes with NMDAR-dependent plasticity. In contrast, NMDAR-independent learning was normal in knockout mice and required the activation of Ca2+-permeable AMPARs. These results suggest that GluR2-lacking AMPARs play a functional and previously unidentified role in learning; they appear to mediate changes in synaptic strength that occur after plasticity has been established by NMDARs. PMID:20927382

  10. PLPP/CIN regulates bidirectional synaptic plasticity via GluN2A interaction with postsynaptic proteins

    PubMed Central

    Kim, Ji-Eun; Kim, Yeon-Joo; Lee, Duk-Shin; Kim, Ji Yang; Ko, Ah-Reum; Hyun, Hye-Won; Kim, Min Ju; Kang, Tae-Cheon

    2016-01-01

    Dendritic spines are dynamic structures whose efficacies and morphologies are modulated by activity-dependent synaptic plasticity. The actin cytoskeleton plays an important role in stabilization and structural modification of spines. However, the regulatory mechanism by which it alters the plasticity threshold remains elusive. Here, we demonstrate the role of pyridoxal-5′-phosphate phosphatase/chronophin (PLPP/CIN), one of the cofilin-mediated F-actin regulators, in modulating synaptic plasticity in vivo. PLPP/CIN transgenic (Tg) mice had immature spines with small heads, while PLPP/CIN knockout (KO) mice had gigantic spines. Furthermore, PLPP/CIN Tg mice exhibited enhanced synaptic plasticity, but KO mice showed abnormal synaptic plasticity. The PLPP/CIN-induced alterations in synaptic plasticity were consistent with the acquisition and the recall capacity of spatial learning. PLPP/CIN also enhanced N-methyl-D-aspartate receptor (GluN) functionality by regulating the coupling of GluN2A with interacting proteins, particularly postsynaptic density-95 (PSD95). Therefore, these results suggest that PLPP/CIN may be an important factor for regulating the plasticity threshold. PMID:27212638

  11. Contribution of motoneuron intrinsic properties to fictive motor pattern generation

    PubMed Central

    Calabrese, Ronald L.

    2011-01-01

    Previously, we reported a canonical ensemble model of the heart motoneurons that underlie heartbeat in the medicinal leech. The model motoneurons contained a minimal set of electrical intrinsic properties and received a synaptic input pattern based on measurements performed in the living system. Although the model captured the synchronous and peristaltic motor patterns observed in the living system, it did not match quantitatively the motor output observed. Because the model motoneurons had minimal intrinsic electrical properties, the mismatch between model and living system suggests a role for additional intrinsic properties in generating the motor pattern. We used the dynamic clamp to test this hypothesis. We introduced the same segmental input pattern used in the model to motoneurons isolated pharmacologically from their endogenous input in the living system. We show that, although the segmental input pattern determines the segmental phasing differences observed in motoneurons, the intrinsic properties of the motoneurons play an important role in determining their phasing, particularly when receiving the synchronous input pattern. We then used trapezoidal input waveforms to show that the intrinsic properties present in the living system promote phase advances compared with our model motoneurons. Electrical coupling between heart motoneurons also plays a role in shaping motoneuron output by synchronizing the activity of the motoneurons within a segment. These experiments provide a direct assessment of how motoneuron intrinsic properties interact with their premotor pattern of synaptic drive to produce rhythmic output. PMID:21562194

  12. Dynamic modulation of short term synaptic plasticity in the auditory cortex: the role of norepinephrine

    PubMed Central

    Humberto, Salgado; Francisco, García-Oscos; Lu, Dinh

    2010-01-01

    Norepinephrine (NE) is an important modulator of neuronal activity in the auditory cortex. Using patch-clamp recording and a pair pulse protocol on an auditory cortex slice preparation we recently demonstrated that NE affects cortical inhibition in a layer-specific manner, by decreasing apical but increasing basal inhibition onto layer II/III pyramidal cell dendrites. In the present study we used a similar protocol to investigate the dependence of noradrenergic modulation of inhibition on stimulus frequency, using 1s-long train pulses at 5, 10, and 20 Hz. The study was conducted using pharmacologically isolated inhibitory post-synaptic currents (IPSCs) evoked by electrical stimulation of axons either in layer I (LI-eIPSCs) or in layer II/III (LII/III-eIPSCs). We found that: 1) LI-eIPSC display less synaptic depression than LII/III-eIPSCs at all the frequencies tested, 2) in both type of synapses depression had a presynaptic component which could be altered manipulating [Ca2+]o, 3) NE modestly altered short-term synaptic plasticity at low or intermediate (5–10 Hz) frequencies, but selectively enhanced synaptic facilitation in LI-eIPSCs while increasing synaptic depression of LII/III-eIPSCs in the latest (>250 ms) part of the response, at high stimulation frequency (20 Hz). We speculate that these mechanisms may limit the temporal window for top-down synaptic integration as well as the duration and intensity of stimulus-evoked gamma oscillations triggered by complex auditory stimuli during alertness. PMID:20816739

  13. Miglustat Reverts the Impairment of Synaptic Plasticity in a Mouse Model of NPC Disease

    PubMed Central

    D'Arcangelo, G.; Grossi, D.; Racaniello, M.; Cardinale, A.; Zaratti, A.; Rufini, S.; Cutarelli, A.; Tancredi, V.; Merlo, D.; Frank, C.

    2016-01-01

    Niemann-Pick type C disease is an autosomal recessive storage disorder, characterized by abnormal sequestration of unesterified cholesterol within the late endolysosomal compartment of cells and accumulation of gangliosides and other sphingolipids. Progressive neurological deterioration and insurgence of symptoms like ataxia, seizure, and cognitive decline until severe dementia are pathognomonic features of the disease. Here, we studied synaptic plasticity phenomena and evaluated ERKs activation in the hippocampus of BALB/c NPC1−/− mice, a well described animal model of the disease. Our results demonstrated an impairment of both induction and maintenance of long term synaptic potentiation in NPC1−/− mouse slices, associated with the lack of ERKs phosphorylation. We then investigated the effects of Miglustat, a recent approved drug for the treatment of NPCD. We found that in vivo Miglustat administration in NPC1−/− mice was able to rescue synaptic plasticity deficits, to restore ERKs activation and to counteract hyperexcitability. Overall, these data indicate that Miglustat may be effective for treating the neurological deficits associated with NPCD, such as seizures and dementia. PMID:26885401

  14. UBE3A regulates synaptic plasticity and learning and memory by controlling SK2 channel endocytosis

    PubMed Central

    Sun, Jiandong; Zhu, Guoqi; Liu, Yan; Standley, Steve; Ji, Angela; Tunuguntla, Rashmi; Wang, Yubin; Claus, Chad; Luo, Lyna; Baudry, Michel; Bi, Xiaoning

    2015-01-01

    Summary Gated solely by activity-induced changes in intracellular calcium, small conductance potassium channels (SKs) are critical for a variety of functions in the CNS, from learning and memory to rhythmic activity and sleep. While there is a wealth of information on SK2 gating, kinetics and Ca2+ sensitivity, little is known regarding the regulation of SK2 subcellular localization. We report here that synaptic SK2 levels are regulated by the E3 ubiquitin ligase UBE3A, whose deficiency results in Angelman syndrome and over-expression in increased risk of autistic spectrum disorder. UBE3A directly ubiquitinates SK2 in the C-terminal domain, which facilitates endocytosis. In UBE3A-deficient mice, increased postsynaptic SK2 levels result in decreased NMDA receptor activation, thereby impairing hippocampal long-term synaptic plasticity. Impairments in both synaptic plasticity and fear conditioning memory in UBE3A-deficient mice are significantly ameliorated by blocking SK2. These results elucidate a mechanism by which UBE3A directly influences cognitive function. PMID:26166566

  15. Gene control of synaptic plasticity and memory formation: implications for diseases and therapeutic strategies.

    PubMed

    Vaillend, C; Rampon, C; Davis, S; Laroche, S

    2002-11-01

    There has been nearly a century of interest in the idea that information is stored in the brain as changes in the efficacy of synaptic connections between neurons that are activated during learning. The discovery and detailed report of the phenomenon generally known as long-term potentiation opened a new chapter in the study of synaptic plasticity in the vertebrate brain, and this form of synaptic plasticity has now become the dominant model in the search for the cellular and molecular bases of learning and memory. Accumulating evidence suggests that the rapid activation of the genetic machinery is a key mechanism underlying the enduring modification of neural networks required for the laying down of memory. Here we briefly review these mechanisms and illustrate with a few examples of animal models of neurological disorders how new knowledge about these mechanisms can provide valuable insights into identifying the mechanisms that go awry when memory is deficient, and how, in turn, characterisation of the dysfunctional mechanisms offers prospects to design and evaluate molecular and biobehavioural strategies for therapeutic prevention and rescue.

  16. Magnesium Protects Cognitive Functions and Synaptic Plasticity in Streptozotocin-Induced Sporadic Alzheimer’s Model

    PubMed Central

    Bao, Jian; Wang, Zhi-Hao; Zeng, Juan; Liu, En-Jie; Li, Xiao-Guang; Huang, Rong-Xi; Gao, Di; Li, Meng-Zhu; Zhang, Yao; Liu, Gong-Ping; Wang, Jian-Zhi

    2014-01-01

    Alzheimer’s disease (AD) is characterized by profound synapse loss and impairments of learning and memory. Magnesium affects many biochemical mechanisms that are vital for neuronal properties and synaptic plasticity. Recent studies have demonstrated that the serum and brain magnesium levels are decreased in AD patients; however, the exact role of magnesium in AD pathogenesis remains unclear. Here, we found that the intraperitoneal administration of magnesium sulfate increased the brain magnesium levels and protected learning and memory capacities in streptozotocin-induced sporadic AD model rats. We also found that magnesium sulfate reversed impairments in long-term potentiation (LTP), dendritic abnormalities, and the impaired recruitment of synaptic proteins. Magnesium sulfate treatment also decreased tau hyperphosphorylation by increasing the inhibitory phosphorylation of GSK-3β at serine 9, thereby increasing the activity of Akt at Ser473 and PI3K at Tyr458/199, and improving insulin sensitivity. We conclude that magnesium treatment protects cognitive function and synaptic plasticity by inhibiting GSK-3β in sporadic AD model rats, which suggests a potential role for magnesium in AD therapy. PMID:25268773

  17. Impaired novelty acquisition and synaptic plasticity in congenital hyperammonemia caused by hepatic glutamine synthetase deficiency

    PubMed Central

    Chepkova, Aisa N.; Sergeeva, Olga A.; Görg, Boris; Haas, Helmut L.; Klöcker, Nikolaj; Häussinger, Dieter

    2017-01-01

    Genetic defects in ammonia metabolism can produce irreversible damage of the developing CNS causing an impairment of cognitive and motor functions. We investigated alterations in behavior, synaptic plasticity and gene expression in the hippocampus and dorsal striatum of transgenic mice with systemic hyperammonemia resulting from conditional knockout of hepatic glutamine synthetase (LGS-ko). These mice showed reduced exploratory activity and delayed habituation to a novel environment. Field potential recordings from LGS-ko brain slices revealed significantly reduced magnitude of electrically-induced long-term potentiation (LTP) in both CA3-CA1 hippocampal and corticostriatal synaptic transmission. Corticostriatal but not hippocampal slices from LGS-ko brains demonstrated also significant alterations in long-lasting effects evoked by pharmacological activation of glutamate receptors. Real-time RT-PCR revealed distinct patterns of dysregulated gene expression in the hippocampus and striatum of LGS-ko mice: LGS-ko hippocampus showed significantly modified expression of mRNAs for mGluR1, GluN2B subunit of NMDAR, and A1 adenosine receptors while altered expression of mRNAs for D1 dopamine receptors, the M1 cholinoreceptor and the acetylcholine-synthetizing enzyme choline-acetyltransferase was observed in LGS-ko striatum. Thus, inborn systemic hyperammonemia resulted in significant deficits in novelty acquisition and disturbed synaptic plasticity in corticostriatal and hippocampal pathways involved in learning and goal-directed behavior. PMID:28067279

  18. Electroacupuncture Regulates Hippocampal Synaptic Plasticity via miR-134-Mediated LIMK1 Function in Rats with Ischemic Stroke

    PubMed Central

    Liu, Weilin; Wu, Jie; Zhuo, Peiyuan; Lin, Yunjiao; Wang, Lulu; Lin, Ruhui

    2017-01-01

    MircoRNAs (miRs) have been implicated in learning and memory, by regulating LIM domain kinase (LIMK1) to induce synaptic-dendritic plasticity. The study aimed to investigate whether miRNAs/LIMK1 signaling was involved in electroacupuncture- (EA-) mediated synaptic-dendritic plasticity in a rat model of middle cerebral artery occlusion induced cognitive deficit (MICD). Compared to untreatment or non-acupoint-EA treatment, EA at DU20 and DU24 acupoints could shorten escape latency and increase the frequency of crossing platform in Morris water maze test. T2-weighted imaging showed that the MICD rat brain lesions were located in cortex, hippocampus, corpus striatum, and thalamus regions and injured volumes were reduced after EA. Furthermore, we found that the density of dendritic spine and the number of synapses in the hippocampal CA1 pyramidal cells were obviously reduced at Day 14 after MICD. However, synaptic-dendritic loss could be rescued after EA. Moreover, the synaptic-dendritic plasticity was associated with increases of the total LIMK1 and phospho-LIMK1 levels in hippocampal CA1 region, wherein EA decreased the expression of miR-134, negatively regulating LIMK1 to enhance synaptic-dendritic plasticity. Therefore, miR-134-mediated LIMK1 was involved in EA-induced hippocampal synaptic plasticity, which served as a contributor to improving learning and memory during the recovery stage of ischemic stroke. PMID:28116173

  19. Evolutionarily conserved differences in pallial and thalamic short-term synaptic plasticity in striatum

    PubMed Central

    Ericsson, Jesper; Stephenson-Jones, Marcus; Kardamakis, Andreas; Robertson, Brita; Silberberg, Gilad; Grillner, Sten

    2013-01-01

    The striatum of the basal ganglia is conserved throughout the vertebrate phylum. Tracing studies in lamprey have shown that its afferent inputs are organized in a manner similar to that of mammals. The main inputs arise from the thalamus (Th) and lateral pallium (LPal; the homologue of cortex) that represents the two principal excitatory glutamatergic inputs in mammals. The aim here was to characterize the pharmacology and synaptic dynamics of afferent fibres from the LPal and Th onto identified striatal neurons to understand the processing taking place in the lamprey striatum. We used whole-cell current-clamp recordings in acute slices of striatum with preserved fibres from the Th and LPal, as well as tract tracing and immunohistochemistry. We show that the Th and LPal produce monosynaptic excitatory glutamatergic input through NMDA and AMPA receptors. The synaptic input from the LPal displayed short-term facilitation, unlike the Th input that instead displayed strong short-term synaptic depression. There was also an activity-dependent recruitment of intrastriatal oligosynaptic inhibition from both inputs. These results indicate that the two principal inputs undergo different activity-dependent short-term synaptic plasticity in the lamprey striatum. The difference observed between Th and LPal (cortical) input is also observed in mammals, suggesting a conserved trait throughout vertebrate evolution. PMID:23148315

  20. Synaptic plasticity through activation of GluA3-containing AMPA-receptors

    PubMed Central

    Gutierrez-Castellanos, Nicolas; Reinders, Niels R; van Huijstee, Aile N; Xiong, Hui; Lodder, Tessa R

    2017-01-01

    Excitatory synaptic transmission is mediated by AMPA-type glutamate receptors (AMPARs). In CA1 pyramidal neurons of the hippocampus two types of AMPARs predominate: those that contain subunits GluA1 and GluA2 (GluA1/2), and those that contain GluA2 and GluA3 (GluA2/3). Whereas subunits GluA1 and GluA2 have been extensively studied, the contribution of GluA3 to synapse physiology has remained unclear. Here we show in mice that GluA2/3s are in a low-conductance state under basal conditions, and although present at synapses they contribute little to synaptic currents. When intracellular cyclic AMP (cAMP) levels rise, GluA2/3 channels shift to a high-conductance state, leading to synaptic potentiation. This cAMP-driven synaptic potentiation requires the activation of both protein kinase A (PKA) and the GTPase Ras, and is induced upon the activation of β-adrenergic receptors. Together, these experiments reveal a novel type of plasticity at CA1 hippocampal synapses that is expressed by the activation of GluA3-containing AMPARs. PMID:28762944

  1. Shaping synaptic plasticity: the role of activity-mediated epigenetic regulation on gene transcription.

    PubMed

    Cortés-Mendoza, Javier; Díaz de León-Guerrero, Sol; Pedraza-Alva, Gustavo; Pérez-Martínez, Leonor

    2013-10-01

    Learning and memory are basic functions of the brain that allowed human evolution. It is well accepted that during learning and memory formation the dynamic establishment of new active synaptic connections is crucial. Persistent synaptic activation leads to molecular events that include increased release of neurotransmitters, increased expression of receptors on the postsynaptic neuron, thus creating a positive feedback that results in the activation of distinct signaling pathways that temporally and permanently alter specific patterns of gene expression. However, the epigenetic changes that allow the establishment of long term genetic programs that control learning and memory are not completely understood. Even less is known regarding the signaling events triggered by synaptic activity that regulate these epigenetic marks. Here we review the current understanding of the molecular mechanisms controlling activity-dependent gene transcription leading synaptic plasticity and memory formation. We describe how Ca(2+) entry through N-methyl-d-aspartate-type glutamate neurotransmitter receptors result in the activation of specific signaling pathways leading to changes in gene expression, giving special emphasis to the recent data pointing out different epigenetic mechanisms (histone acetylation, methylation and phosphorylation as well as DNA methylation and hydroxymethylation) underlying learning and memory.

  2. Proteostasis and RNA Binding Proteins in Synaptic Plasticity and in the Pathogenesis of Neuropsychiatric Disorders

    PubMed Central

    Klein, Matthew E.; Monday, Hannah; Jordan, Bryen A.

    2016-01-01

    Decades of research have demonstrated that rapid alterations in protein abundance are required for synaptic plasticity, a cellular correlate for learning and memory. Control of protein abundance, known as proteostasis, is achieved across a complex neuronal morphology that includes a tortuous axon as well as an extensive dendritic arbor supporting thousands of individual synaptic compartments. To regulate the spatiotemporal synthesis of proteins, neurons must efficiently coordinate the transport and metabolism of mRNAs. Among multiple levels of regulation, transacting RNA binding proteins (RBPs) control proteostasis by binding to mRNAs and mediating their transport and translation in response to synaptic activity. In addition to synthesis, protein degradation must be carefully balanced for optimal proteostasis, as deviations resulting in excess or insufficient abundance of key synaptic factors produce pathologies. As such, mutations in components of the proteasomal or translational machinery, including RBPs, have been linked to the pathogenesis of neurological disorders such as Fragile X Syndrome (FXS), Fragile X Tremor Ataxia Syndrome (FXTAS), and Autism Spectrum Disorders (ASD). In this review, we summarize recent scientific findings, highlight ongoing questions, and link basic molecular mechanisms to the pathogenesis of common neuropsychiatric disorders. PMID:26904297

  3. Proteostasis and RNA Binding Proteins in Synaptic Plasticity and in the Pathogenesis of Neuropsychiatric Disorders.

    PubMed

    Klein, Matthew E; Monday, Hannah; Jordan, Bryen A

    2016-01-01

    Decades of research have demonstrated that rapid alterations in protein abundance are required for synaptic plasticity, a cellular correlate for learning and memory. Control of protein abundance, known as proteostasis, is achieved across a complex neuronal morphology that includes a tortuous axon as well as an extensive dendritic arbor supporting thousands of individual synaptic compartments. To regulate the spatiotemporal synthesis of proteins, neurons must efficiently coordinate the transport and metabolism of mRNAs. Among multiple levels of regulation, transacting RNA binding proteins (RBPs) control proteostasis by binding to mRNAs and mediating their transport and translation in response to synaptic activity. In addition to synthesis, protein degradation must be carefully balanced for optimal proteostasis, as deviations resulting in excess or insufficient abundance of key synaptic factors produce pathologies. As such, mutations in components of the proteasomal or translational machinery, including RBPs, have been linked to the pathogenesis of neurological disorders such as Fragile X Syndrome (FXS), Fragile X Tremor Ataxia Syndrome (FXTAS), and Autism Spectrum Disorders (ASD). In this review, we summarize recent scientific findings, highlight ongoing questions, and link basic molecular mechanisms to the pathogenesis of common neuropsychiatric disorders.

  4. Stargazin (TARP gamma-2) is required for compartment-specific AMPA receptor trafficking and synaptic plasticity in cerebellar stellate cells.

    PubMed

    Jackson, Alexander C; Nicoll, Roger A

    2011-03-16

    In the cerebellar cortex, parallel fiber-to-stellate cell (PF-SC) synapses exhibit a form of synaptic plasticity manifested as a switch in the subunit composition of synaptic AMPA receptors (AMPARs) from calcium-permeable, GluA2-lacking to calcium-impermeable, GluA2-containing receptors. Here, we examine the role of stargazin (γ-2), canonical member of the transmembrane AMPAR regulatory protein (TARP) family, in the regulation of GluA2-lacking AMPARs and synaptic plasticity in SCs from epileptic and ataxic stargazer mutant mice. We found that AMPAR-mediated synaptic transmission is severely diminished in stargazer SCs, and that the rectification index (RI) of AMPAR current is reduced. Activity-dependent plasticity in the rectification of synaptic AMPARs is also impaired in stargazer SCs. Despite the dramatic loss in synaptic AMPARs, extrasynaptic AMPARs are preserved. We then examined the role of stargazin in regulating the rectification of extrasynaptic AMPARs in nucleated patches and found, in contrast to previous reports, that wild-type extrasynaptic AMPARs have moderate RI values (average RI = 0.38), while those in stargazer SCs are low (average RI = 0.24). The GluA2-lacking AMPAR blocker, philanthotoxin-433 (PhTx-433), was used as an alternative measure of GluA2 content in wild-type and stargazer SCs. Despite the difference in RI, PhTx-433 sensitivity of both synaptic and extrasynaptic AMPARs remains unchanged, suggesting that the dramatic changes in RI and the impairment in synaptic plasticity observed in the stargazer mouse are not the result of a specific impairment in GluA2 trafficking. Together, these data suggest that stargazin regulates compartment-specific AMPAR trafficking, as well as activity-dependent plasticity in synaptic AMPAR rectification at cerebellar PF-SC synapses.

  5. More than synaptic plasticity: Role of nonsynaptic plasticity in learning and memory

    PubMed Central

    Mozzachiodi, Riccardo; Byrne, John H.

    2009-01-01

    Decades of research on the cellular mechanisms of memory have led to the widely-held view that memories are stored as modifications of synaptic strength. These changes involve presynaptic processes, such as direct modulation of the release machinery, or postsynaptic processes, such as modulation of receptor properties. Parallel studies have revealed that memories may also be stored by nonsynaptic processes, such as modulation of voltage-dependent membrane conductances, which are expressed as changes in neuronal excitability. Although in some cases nonsynaptic changes may function as part of the engram itself, they may also serve as mechanisms through which a neural circuit is set to a permissive state to facilitate synaptic modifications that are necessary for memory storage. PMID:19889466

  6. Plasticity and mTOR: Towards Restoration of Impaired Synaptic Plasticity in mTOR-Related Neurogenetic Disorders

    PubMed Central

    Gipson, Tanjala T.; Johnston, Michael V.

    2012-01-01

    Objective. To review the recent literature on the clinical features, genetic mutations, neurobiology associated with dysregulation of mTOR (mammalian target of rapamycin), and clinical trials for tuberous sclerosis complex (TSC), neurofibromatosis-1 (NF1) and fragile X syndrome (FXS), and phosphatase and tensin homolog hamartoma syndromes (PTHS), which are neurogenetic disorders associated with abnormalities in synaptic plasticity and mTOR signaling. Methods. Pubmed and Clinicaltrials.gov were searched using specific search strategies. Results/Conclusions. Although traditionally thought of as irreversible disorders, significant scientific progress has been made in both humans and preclinical models to understand how pathologic features of these neurogenetic disorders can be reduced or reversed. This paper revealed significant similarities among the conditions. Not only do they share features of impaired synaptic plasticity and dysregulation of mTOR, but they also share clinical features—autism, intellectual disability, cutaneous lesions, and tumors. Although scientific advances towards discovery of effective treatment in some disorders have outpaced others, progress in understanding the signaling pathways that connect the entire group indicates that the lesser known disorders will become treatable as well. PMID:22619737

  7. A light-stimulated synaptic transistor with synaptic plasticity and memory functions based on InGaZnOx-Al2O3 thin film structure

    NASA Astrophysics Data System (ADS)

    Li, H. K.; Chen, T. P.; Liu, P.; Hu, S. G.; Liu, Y.; Zhang, Q.; Lee, P. S.

    2016-06-01

    In this work, a synaptic transistor based on the indium gallium zinc oxide (IGZO)-aluminum oxide (Al2O3) 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/Al2O3 interface and/or in the Al2O3 layer.

  8. X-linked mental retardation: focus on synaptic function and plasticity.

    PubMed

    Humeau, Yann; Gambino, Frédéric; Chelly, Jamel; Vitale, Nicolas

    2009-04-01

    Among mental disorders, mental retardation has been shown to be caused by various factors including a large array of genetic mutations. On the basis of remarkable progress, the emerging view is that defects in the regulation of synaptic activity and morphogenesis of dendritic spines are apparently common features associated with mutations in several genes implicated in mental retardation. In this review, we will discuss X-linked MR-related gene products that are potentially involved in the normal structure and function of the synapses, with a particular focus on pre- and/or post-synaptic plasticity mechanisms. Progress in understanding the underlying conditions leading to mental retardation will undoubtedly be gained from a closer collaboration of geneticists, physiologists and cognitive neuroscientists, which should enable the establishment of standardized approaches.

  9. Neuroligin 1 regulates spines and synaptic plasticity via LIMK1/cofilin-mediated actin reorganization

    PubMed Central

    Liu, An; Zhou, Zikai; Dang, Rui; Zhu, Yuehua; Qi, Junxia; He, Guiqin; Leung, Celeste; Pak, Daniel

    2016-01-01

    Neuroligin (NLG) 1 is important for synapse development and function, but the underlying mechanisms remain unclear. It is known that at least some aspects of NLG1 function are independent of the presynaptic neurexin, suggesting that the C-terminal domain (CTD) of NLG1 may be sufficient for synaptic regulation. In addition, NLG1 is subjected to activity-dependent proteolytic cleavage, generating a cytosolic CTD fragment, but the significance of this process remains unknown. In this study, we show that the CTD of NLG1 is sufficient to (a) enhance spine and synapse number, (b) modulate synaptic plasticity, and (c) exert these effects via its interaction with spine-associated Rap guanosine triphosphatase–activating protein and subsequent activation of LIM-domain protein kinase 1/cofilin–mediated actin reorganization. Our results provide a novel postsynaptic mechanism by which NLG1 regulates synapse development and function. PMID:26880202

  10. Synaptic plasticity in the mesolimbic system: therapeutic implications for substance abuse.

    PubMed

    Chen, Billy T; Hopf, F Woodward; Bonci, Antonello

    2010-02-01

    In an ever-changing environment, animals must learn new behavioral strategies for the successful procurement of food, sex, and other needs. Synaptic plasticity within the mesolimbic system, a key reward circuit, affords an animal the ability to adapt and perform essential goal-directed behaviors. Ironically, drugs of abuse can also induce synaptic changes within the mesolimbic system, and such changes are hypothesized to promote deleterious drug-seeking behaviors in lieu of healthy, adaptive behaviors. In this review, we will discuss drug-induced neuroadaptations in excitatory transmission in the ventral tegmental area and the nucleus accumbens, two critical regions of the mesolimbic system, and the possible role of dopamine receptors in the development of these neuroadaptations. In particular, we will focus our discussion on recent studies showing changes in AMPA receptor function as a common molecular target of addictive drugs, and the possible behavioral consequences of such neuroadaptations.

  11. Memory and synaptic plasticity are impaired by dysregulated hippocampal O-GlcNAcylation

    PubMed Central

    Yang, Yong Ryoul; Song, Seungju; Hwang, Hongik; Jung, Jung Hoon; Kim, Su-Jeong; Yoon, Sora; Hur, Jin-Hoe; Park, Jae-Il; Lee, Cheol; Nam, Dougu; Seo, Young-Kyo; Kim, Joung-Hun; Rhim, Hyewhon; Suh, Pann-Ghill

    2017-01-01

    O-GlcNAcylated proteins are abundant in the brain and are associated with neuronal functions and neurodegenerative diseases. Although several studies have reported the effects of aberrant regulation of O-GlcNAcylation on brain function, the roles of O-GlcNAcylation in synaptic function remain unclear. To understand the effect of aberrant O-GlcNAcylation on the brain, we used Oga+/− mice which have an increased level of O-GlcNAcylation, and found that Oga+/− mice exhibited impaired spatial learning and memory. Consistent with this result, Oga+/− mice showed a defect in hippocampal synaptic plasticity. Oga heterozygosity causes impairment of both long-term potentiation and long-term depression due to dysregulation of AMPA receptor phosphorylation. These results demonstrate a role for hyper-O-GlcNAcylation in learning and memory. PMID:28368052

  12. Learning and retrieval behavior in recurrent neural networks with pre-synaptic dependent homeostatic plasticity

    NASA Astrophysics Data System (ADS)

    Mizusaki, Beatriz E. P.; Agnes, Everton J.; Erichsen, Rubem; Brunnet, Leonardo G.

    2017-08-01

    The plastic character of brain synapses is considered to be one of the foundations for the formation of memories. There are numerous kinds of such phenomenon currently described in the literature, but their role in the development of information pathways in neural networks with recurrent architectures is still not completely clear. In this paper we study the role of an activity-based process, called pre-synaptic dependent homeostatic scaling, in the organization of networks that yield precise-timed spiking patterns. It encodes spatio-temporal information in the synaptic weights as it associates a learned input with a specific response. We introduce a correlation measure to evaluate the precision of the spiking patterns and explore the effects of different inhibitory interactions and learning parameters. We find that large learning periods are important in order to improve the network learning capacity and discuss this ability in the presence of distinct inhibitory currents.

  13. Role of Atypical Protein Kinases in Maintenance of Long-Term Memory and Synaptic Plasticity.

    PubMed

    Borodinova, A A; Zuzina, A B; Balaban, P M

    2017-03-01

    Investigation of biochemical mechanisms underlying the long-term storage of information in nervous system is one of main problems of modern neurobiology. As a molecular basis of long-term memory, long-term changes in kinase activities, increase in the level and changes in the subunit composition of receptors in synaptic membranes, local activity of prion-like proteins, and epigenetic modifications of chromatin have been proposed. Perhaps a combination of all or of some of these factors underlies the storage of long-term memory in the brain. Many recent studies have shown an exclusively important role of atypical protein kinases (PKCζ, PKMζ, and PKCι/λ) in processes of learning, consolidation and maintenance of memory. The present review is devoted to consideration of mechanisms of transcriptional and translational control of atypical protein kinases and their roles in induction and maintenance of long-term synaptic plasticity and memory in vertebrates and invertebrates.

  14. Protective effect of tetrahydroxy stilbene glucoside on learning and memory by regulating synaptic plasticity

    PubMed Central

    Luo, Hong-bo; Li, Yun; Liu, Zun-jing; Cao, Li; Zhang, Zhi-qiang; Wang, Yong; Zhang, Xiao-yan; Liu, Zhao; Shi, Xiang-qun

    2016-01-01

    Damage to synaptic plasticity induced by neurotoxicity of amyloid-beta is regarded to be one of the pathological mechanisms of learning and memory disabilities in Alzheimer's disease patients. This study assumed that the damage of amyloid-beta to learning and memory abilities was strongly associated with the changes in the Fyn/N-methyl-D-aspartate receptor 2B (NR2B) expression. An APP695V7171 transgenic mouse model of Alzheimer's disease was used and treatment with tetrahydroxy-stilbene glucoside was administered intragastrically. Results showed that intragastric administration of tetrahydroxy-stilbene glucoside improved the learning and memory abilities of the transgenic mice through increasing NR2B receptors and Fyn expression. It also reversed parameters for synaptic interface structure of gray type I. These findings indicate that tetrahydroxy stilbene glucoside has protective effects on the brain, and has prospects for its clinical application to improve the learning and memory abilities and treat Alzheimer's disease. PMID:27857754

  15. From abnormal hippocampal synaptic plasticity in down syndrome mouse models to cognitive disability in down syndrome.

    PubMed

    Cramer, Nathan; Galdzicki, Zygmunt

    2012-01-01

    Down syndrome (DS) is caused by the overexpression of genes on triplicated regions of human chromosome 21 (Hsa21). While the resulting physiological and behavioral phenotypes vary in their penetrance and severity, all individuals with DS have variable but significant levels of cognitive disability. At the core of cognitive processes is the phenomenon of synaptic plasticity, a functional change in the strength at points of communication between neurons. A wide variety of evidence from studies on DS individuals and mouse models of DS indicates that synaptic plasticity is adversely affected in human trisomy 21 and mouse segmental trisomy 16, respectively, an outcome that almost certainly extensively contributes to the cognitive impairments associated with DS. In this review, we will highlight some of the neurophysiological changes that we believe reduce the ability of trisomic neurons to undergo neuroplasticity-related ad