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Sample records for postsynaptic cerebellar ltp

  1. Differential Modulation of GABAA Receptors Underlies Postsynaptic Depolarization- and Purinoceptor-Mediated Enhancement of Cerebellar Inhibitory Transmission: A Non-Stationary Fluctuation Analysis Study.

    PubMed

    Ono, Yumie; Saitow, Fumihito; Konishi, Shiro

    2016-01-01

    Cerebellar GABAergic inhibitory transmission between interneurons and Purkinje cells (PCs) undergoes a long-lasting enhancement following different stimulations, such as brief depolarization or activation of purinergic receptors of postsynaptic PCs. The underlying mechanisms, however, are not completely understood. Using a peak-scaled non-stationary fluctuation analysis, we therefore aimed at characterizing changes in the electrophysiological properties of GABAA receptors in PCs of rat cerebellar cortex during depolarization-induced "rebound potentiation (RP)" and purinoceptor-mediated long-term potentiation (PM-LTP), because both RP and PM-LTP likely depend on postsynaptic mechanisms. Stimulation-evoked inhibitory postsynaptic currents (eIPSCs) were recorded from PCs in neonatal rat cerebellar slices. Our analysis showed that postsynaptic membrane depolarization induced RP of eIPSCs in association with significant increase in the number of synaptic GABAA receptors without changing the channel conductance. By contrast, bath application of ATP induced PM-LTP of eIPSCs with a significant increase of the channel conductance of GABAA receptors without affecting the receptor number. Pretreatment with protein kinase A (PKA) inhibitors, H-89 and cAMPS-Rp, completely abolished the PM-LTP. The CaMKII inhibitor KN-62 reported to abolish RP did not alter PM-LTP. These results suggest that the signaling mechanism underlying PM-LTP could involve ATP-induced phosphorylation of synaptic GABAA receptors, thereby resulting in upregulation of the channel conductance by stimulating adenylyl cyclase-PKA signaling cascade, possibly via activation of P2Y11 purinoceptor. Thus, our findings reveal that postsynaptic GABAA receptors at the interneuron-PC inhibitory synapses are under the control of two distinct forms of long-term potentiation linked with different second messenger cascades. PMID:26930485

  2. Postsynaptic conversion of silent synapses during LTP affects synaptic gain and transmission dynamics.

    PubMed

    Poncer, J C; Malinow, R

    2001-10-01

    Synaptic transmission relies on both the gain and the dynamics of synapses. Activity-dependent changes in synaptic gain are well-documented at excitatory synapses and may represent a substrate for information storage in the brain. Here we examine the mechanisms of changes in transmission dynamics at excitatory synapses. We show that paired-pulse ratios (PPRs) of AMPAR and NMDAR EPSCs onto dentate gyrus granule cells are often different; this difference is reduced during LTP, reflecting PPR changes of AMPAR but not NMDAR EPSCs. Presynaptic manipulations, however, produce parallel changes in AMPAR and NMDAR EPSCs. LTP at these synapses reflects a reduction in the proportion of silent synapses lacking functional AMPARs. Changes in PPR during LTP therefore reflect the initial difference between PPRs of silent and functional synapses. Functional conversion of silent synapses permits postsynaptic sampling from additional release sites and thereby affects the dynamics and gain of signals conveyed between neurons. PMID:11544481

  3. Electron tomographic structure and protein composition of isolated rat cerebellar, hippocampal and cortical postsynaptic densities.

    PubMed

    Farley, M M; Swulius, M T; Waxham, M N

    2015-09-24

    Electron tomography and immunogold labeling were used to analyze similarities and differences in the morphology and protein composition of postsynaptic densities (PSDs) isolated from adult rat cerebella, hippocampi, and cortices. There were similarities in physical dimensions and gross morphology between cortical, hippocampal and most cerebellar PSDs, although the morphology among cerebellar PSDs could be categorized into three distinct groups. The majority of cerebellar PSDs were composed of dense regions of protein, similar to cortical and hippocampal PSDs, while others were either composed of granular or lattice-like protein regions. Significant differences were found in protein composition and organization across PSDs from the different brain regions. The signaling protein, βCaMKII, was found to be a major component of each PSD type and was more abundant than αCaMKII in both hippocampal and cerebellar PSDs. The scaffold molecule PSD-95, a major component of cortical PSDs, was found absent in a fraction of cerebellar PSDs and when present was clustered in its distribution. In contrast, immunogold labeling for the proteasome was significantly more abundant in cerebellar and hippocampal PSDs than cortical PSDs. Together, these results indicate that PSDs exhibit remarkable diversity in their composition and morphology, presumably as a reflection of the unique functional demands placed on different synapses. PMID:26215919

  4. TRPM4-dependent post-synaptic depolarization is essential for the induction of NMDA receptor-dependent LTP in CA1 hippocampal neurons.

    PubMed

    Menigoz, Aurélie; Ahmed, Tariq; Sabanov, Victor; Philippaert, Koenraad; Pinto, Silvia; Kerselaers, Sara; Segal, Andrei; Freichel, Marc; Voets, Thomas; Nilius, Bernd; Vennekens, Rudi; Balschun, Detlef

    2016-04-01

    TRPM4 is a calcium-activated but calcium-impermeable non-selective cation (CAN) channel. Previous studies have shown that TRPM4 is an important regulator of Ca(2+)-dependent changes in membrane potential in excitable and non-excitable cell types. However, its physiological significance in neurons of the central nervous system remained unclear. Here, we report that TRPM4 proteins form a CAN channel in CA1 neurons of the hippocampus and we show that TRPM4 is an essential co-activator of N-methyl-D-aspartate (NMDA) receptors (NMDAR) during the induction of long-term potentiation (LTP). Disrupting the Trpm4 gene in mice specifically eliminates NMDAR-dependent LTP, while basal synaptic transmission, short-term plasticity, and NMDAR-dependent long-term depression are unchanged. The induction of LTP in Trpm4 (-/-) neurons was rescued by facilitating NMDA receptor activation or post-synaptic membrane depolarization. Accordingly, we obtained normal LTP in Trpm4 (-/-) neurons in a pairing protocol, where post-synaptic depolarization was applied in parallel to pre-synaptic stimulation. Taken together, our data are consistent with a novel model of LTP induction in CA1 hippocampal neurons, in which TRPM4 is an essential player in a feed-forward loop that generates the post-synaptic membrane depolarization which is necessary to fully activate NMDA receptors during the induction of LTP but which is dispensable for the induction of long-term depression (LTD). These results have important implications for the understanding of the induction process of LTP and the development of nootropic medication. PMID:26631168

  5. Membrane-tethered AKT kinase regulates basal synaptic transmission and early phase LTP expression by modulation of post-synaptic AMPA receptor level.

    PubMed

    Pen, Y; Borovok, N; Reichenstein, M; Sheinin, A; Michaelevski, I

    2016-09-01

    The serine/threonine kinase AKT/PKB plays a fundamental role in a wide variety of neuronal functions, including neuronal cell development, axonal growth, and synaptic plasticity. Multiple evidence link AKT signaling pathways to regulation of late phase long-term synaptic plasticity, synaptogenesis, and spinogenesis, as well as long-term memory formation. Nevertheless, the downstream effectors mediating the effects of AKT on early phase long-term potentiation (eLTP) are currently unknown. Here we report that using different regimes of pharmacological activation and inhibition of AKT activity in acute hippocampal slices, we found that AKT regulates the post-synaptic expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA) receptors affecting solely the expression of eLTP, with no effect on its induction and maintenance. We further show that both maintenance of basal synaptic activity and expression of eLTP require plasma membrane tethering by activated AKT and that basal synaptic activity may be regulated via the direct effects of AKT1 on the expression level of post-synaptic AMPA receptors bypassing the canonical AKT signaling. Finally, we establish that eLTP expression requires the involvement of both the canonical AKT signaling pathways and the direct effect of AKT1 on AMPA receptor activity/expression in the post-synaptic membrane. © 2016 Wiley Periodicals, Inc. PMID:27068236

  6. Freeze-fracture study of the postsynaptic membrane of the cerebellar mossy fiber synapse in the frog.

    PubMed

    Korte, G E; Rosenbluth, J

    1980-10-01

    We have examined the postsynaptic membrane of the synaptic junctions of frog cerebellar mossy fibers by electron microscopy of freeze-fracture replicas and thin sections. The intramembranous particles (imps) in the E fracture face of the postsynaptic membrane are approximately 10 nm in size and form conspicuous aggregates which we classified as macular, annular, or anastomotic in form, according to the occurrence and placement of imp-free "windows" within the aggregate. The size and shape of the aggregates appear related in that the area of macular aggregates is consistently smaller than the area of annular or anastomotic aggregates. Measurements of aggregate area range from 0.06 to 0.75 micrometer2. The variable size and shape of the imp aggregate in the postsynaptic membrane sets it apart from other excitatory synapses in the central nervous system, where macular aggregates are usually described. Examination of serial thin sections suggests that the shape of the postsynaptic density is equivalent to that of the imp aggregate observed in the postsynaptic membrane by freeze-fracture. This supports the notion that the region of postsynaptic membrane associated with the postsynaptic density in thin sections corresponds to the particle-rich regions of E face membrane observed in freeze-fracture replicas. PMID:6969269

  7. 2', 3'-cyclic nucleotide 3'-phosphodiesterase is expressed in dissociated rat cerebellar cells and included in the postsynaptic density fraction.

    PubMed

    Cho, Sun-Jung; Jung, Jae Seob; Jin, IngNyol; Moon, Il Soo

    2003-08-31

    We have shown by protein sequencing that the phosphotyrosine-containing 48 kDa protein band of the rat cerebellar postsynaptic density fraction (CBL-PSD) is 2', 3'-cyclic nucleotide 3'-phosphodiesterase 2 (CNP2). Immunoblot analysis indicated that both CNP1 and CNP2 isoforms are present in the CBL-PSD fraction, whereas there is little CNP2 in the forebrain (FB)-PSD fraction. Both isoforms in the CBL-PSD fraction were tyrosine-phosphorylated to a basal extent. They were efficiently dissociated from the complexes in the PSD fraction by salt, but not by non-ionic detergents such as n-octyl glucoside (OG) and Triton X-100. Immunocytochemistry of dissociated cerebellar cultures revealed patchy CNP staining in oligodendrocytes (OLs), Purkinje cells (PCs), and unidentified PSD95-positive cells, but no staining in granule cells (GCs). Our results indicate that both CNP1 and CNP2 are expressed in cerian populations of cerebellar cells in addition to OL, and that they are associated with complexes that are co-isolated with the PSD. PMID:14503857

  8. Activity-induced tissue oxygenation changes in rat cerebellar cortex: interplay of postsynaptic activation and blood flow

    PubMed Central

    Offenhauser, Nikolas; Thomsen, Kirsten; Caesar, Kirsten; Lauritzen, Martin

    2005-01-01

    Functional neuroimaging relies on the robust coupling between neuronal activity, metabolism and cerebral blood flow (CBF), but the physiological basis of the neuroimaging signals is still poorly understood. We examined the mechanisms of activity-dependent changes in tissue oxygenation in relation to variations in CBF responses and postsynaptic activity in rat cerebellar cortex. To increase synaptic activity we stimulated the monosynaptic, glutamatergic climbing fibres that excite Purkinje cells via AMPA receptors. We used local field potentials to indicate synaptic activity, and recorded tissue oxygen partial pressure (Ptiss,O2) by polarographic microelectrodes, and CBF using laser-Doppler flowmetry. The disappearance rate of oxygen in the tissue increased linearly with synaptic activity. This indicated that, without a threshold, oxygen consumption increased as a linear function of synaptic activity. The reduction in Ptiss,O2 preceded the rise in CBF. The time integral (area) of the negative Ptiss,O2 response increased non-linearly showing saturation at high levels of synaptic activity, concomitant with a steep rise in CBF. This was accompanied by a positive change in Ptiss,O2. Neuronal nitric oxide synthase inhibition enhanced the initial negative Ptiss,O2 response (‘dip’), while attenuating the evoked CBF increase and positive Ptiss,O2 response equally. This indicates that increases in CBF counteract activity-induced reductions in Ptiss,O2, and suggests the presence of a tissue oxygen reserve. The changes in Ptiss,O2 and CBF were strongly attenuated by AMPA receptor blockade. Our findings suggest an inverse relationship between negative Ptiss,O2 and CBF responses, and provide direct in vivo evidence for a tight coupling between activity in postsynaptic AMPA receptors and cerebellar oxygen consumption. PMID:15774524

  9. Cerebellar Norepinephrine Modulates Learning of Delay Classical Eyeblink Conditioning: Evidence for Post-Synaptic Signaling via PKA

    ERIC Educational Resources Information Center

    Fister, Mathew; Bickford, Paula C.; Cartford, M. Claire; Samec, Amy

    2004-01-01

    The neurotransmitter norepinephrine (NE) has been shown to modulate cerebellar-dependent learning and memory. Lesions of the nucleus locus coeruleus or systemic blockade of noradrenergic receptors has been shown to delay the acquisition of several cerebellar-dependent learning tasks. To date, no studies have shown a direct involvement of…

  10. GABA(A) receptor expression and inhibitory post-synaptic currents in cerebellar Purkinje cells in dystrophin-deficient mdx mice.

    PubMed

    Kueh, S L L; Head, S I; Morley, J W

    2008-02-01

    1. Duchenne muscular dystrophy (DMD) is the second most common fatal genetic disease and arises as a consequence of an absence or disruption of the protein dystrophin. In addition to wasting of the skeletal musculature, boys with DMD have a significant degree of cognitive impairment. 2. We show here that there is no difference between littermate control and mdx mice (a murine model of DMD) in the overall expression of the GABA(A) receptor a1-subunit, supporting the suggestion that it is the clustering at the synapse that is affected and not the expression of the GABA(A) receptor protein. 3. We report a significant reduction in both the frequency and amplitude of spontaneous inhibitory post-synaptic currents in cerebellar Purkinje cells of mdx mice compared with littermate controls, consistent with the reported reduction in the number and size of GABA(A) receptor clusters immunoreactive for a1- and a2-subunits at the post-synaptic densities. 4. These results may explain some of the behavioural problems and cognitive impairment reported in DMD. PMID:17941889

  11. Modulation of inhibitory post-synaptic currents (IPSCs) in mouse cerebellar Purkinje and basket cells by snake and scorpion toxin K+ channel blockers

    PubMed Central

    Southan, Andrew P; Robertson, Brian

    1998-01-01

    Using an in vitro mouse cerebellar slice preparation and whole-cell electrophysiological recording techniques we have characterized Purkinje and basket cell inhibitory post-synaptic currents (IPSCs), and examined the effects of a number of selective peptidergic K+ channel blockers.Spontaneous IPSC amplitude ranged from ∼10 pA up to ∼3 nA for both cell types [mean values: Purkinje cells −122.8±20.0 pA (n=24 cells); basket cells −154.8±15.9 pA (n=26 cells)]. Frequency varied from ∼3 up to ∼40 Hz, [mean values: basket cells 14.9±1.7 Hz (n=26 cells); Purkinje cells 17.9±2.2 Hz (n=24 cells)]. 5 μM bicuculline eliminated virtually all spontaneous currents.IPSC rise times were fast (∼0.6 ms) and the decay phase was best fit with the sum of two exponential functions (τ1 and τ2: ∼4 ms and ∼20 ms, n=40; for both cell types).The snake toxins alpha-dendrotoxin (α-DTX) and toxin K greatly enhanced IPSC frequency and amplitude in both cell types; the closely related homologues toxin I and gamma-dendrotoxin (γ-DTX) produced only marginal enhancements (all at 200 nM).Two scorpion toxins, margatoxin (MgTX) and agitoxin-2 (AgTX-2) had only minor effects on IPSC frequency or amplitude (both at 10 nM).Low concentrations of tetraethylammonium (TEA; 200 μM) had no overall effect on cerebellar IPSCs, whilst higher concentrations (10 mM) increased both the frequency and amplitude.The results suggest that native K+ channels, containing Kv1.1 and Kv1.2 channel subunits, play an influential role in controlling GABAergic inhibitory transmission from cerebellar basket cells. PMID:9863670

  12. Enhanced AMPA receptor function promotes cerebellar long-term depression rather than potentiation

    PubMed Central

    van Beugen, Boeke J.; Qiao, Xin; Simmons, Dana H.; De Zeeuw, Chris I.

    2014-01-01

    Ampakines are allosteric modulators of AMPA receptors that facilitate hippocampal long-term potentiation (LTP) and learning, and have been considered for the treatment of cognition and memory deficits. Here, we show that the ampakine CX546 raises the amplitude and slows the decay time of excitatory postsynaptic currents (EPSCs) at cerebellar parallel fiber (PF) to Purkinje cell synapses, thus resembling CX546 effects described at hippocampal synapses. Using the fluorescent calcium indicator dye Oregon Green BAPTA-2 and an ultra-high-speed CCD camera, we also monitored calcium transients in Purkinje cell dendrites. In the presence of CX546 in the bath, PF-evoked calcium transients were enhanced and prolonged, suggesting that CX546 not only enhances synaptic transmission, but also boosts dendritic calcium signaling at cerebellar synapses. In contrast to previous observations in the hippocampus, however, CX546 applied during cerebellar recordings facilitates long-term depression (LTD) rather than LTP at PF synapses. These findings show that ampakines selectively modify the LTP–LTD balance depending on the brain area and type of synapse, and may provide tools for the targeted regulation of synaptic memories. PMID:25403454

  13. Expression mechanisms underlying long-term potentiation: a postsynaptic view, 10 years on

    PubMed Central

    Granger, Adam J.; Nicoll, Roger A.

    2014-01-01

    This review focuses on the research that has occurred over the past decade which has solidified a postsynaptic expression mechanism for long-term potentiation (LTP). However, experiments that have suggested a presynaptic component are also summarized. It is argued that the pairing of glutamate uncaging onto single spines with postsynaptic depolarization provides the final and most elegant demonstration of a postsynaptic expression mechanism for NMDA receptor-dependent LTP. The fact that the magnitude of this LTP is similar to that evoked by pairing synaptic stimulation and depolarization leaves little room for a substantial presynaptic component. Finally, recent data also require a revision in our thinking about the way AMPA receptors (AMPARs) are recruited to the postsynaptic density during LTP. This recruitment is independent of subunit type, but does require an adequate reserve pool of extrasynaptic receptors. PMID:24298139

  14. Cyclin Y inhibits plasticity-induced AMPA receptor exocytosis and LTP

    PubMed Central

    Cho, Eunsil; Kim, Dong-Hyun; Hur, Young-Na; Whitcomb, Daniel J.; Regan, Philip; Hong, Jung-Hwa; Kim, Hanna; Ho Suh, Young; Cho, Kwangwook; Park, Mikyoung

    2015-01-01

    Cyclin Y (CCNY) is a member of the cyclin protein family, known to regulate cell division in proliferating cells. Interestingly, CCNY is expressed in neurons that do not undergo cell division. Here, we report that CCNY negatively regulates long-term potentiation (LTP) of synaptic strength through inhibition of AMPA receptor trafficking. CCNY is enriched in postsynaptic fractions from rat forebrain and is localized adjacent to postsynaptic sites in dendritic spines in rat hippocampal neurons. Using live-cell imaging of a pH-sensitive AMPA receptor, we found that during LTP-inducing stimulation, CCNY inhibits AMPA receptor exocytosis in dendritic spines. Furthermore, CCNY abolishes LTP in hippocampal slices. Taken together, our findings demonstrate that CCNY inhibits plasticity-induced AMPA receptor delivery to synapses and thereby blocks LTP, identifying a novel function for CCNY in post-mitotic cells. PMID:26220330

  15. The 5-HT7 receptor triggers cerebellar long-term synaptic depression via PKC-MAPK.

    PubMed

    Lippiello, Pellegrino; Hoxha, Eriola; Speranza, Luisa; Volpicelli, Floriana; Ferraro, Angela; Leopoldo, Marcello; Lacivita, Enza; Perrone-Capano, Carla; Tempia, Filippo; Miniaci, Maria Concetta

    2016-02-01

    The 5-HT7 receptor (5-HT7R) mediates important physiological effects of serotonin, such as memory and emotion, and is emerging as a therapeutic target for the treatment of cognitive disorders and depression. Although previous studies have revealed an expression of 5-HT7R in cerebellum, particularly at Purkinje cells, its functional role and signaling mechanisms have never been described. Using patch-clamp recordings in cerebellar slices of adult mice, we investigated the effects of a selective 5-HT7R agonist, LP-211, on the main plastic site of the cerebellar cortex, the parallel fiber-Purkinje cell synapse. Here we show that 5-HT7R activation induces long-term depression of parallel fiber-Purkinje cell synapse via a postsynaptic mechanism that involves the PKC-MAPK signaling pathway. Moreover, a 5-HT7R antagonist abolished the expression of PF-LTD, produced by pairing parallel fiber stimulation with Purkinje cell depolarization; whereas, application of a 5-HT7R agonist impaired LTP induced by 1 Hz parallel fiber stimulation. Our results indicate for the first time that 5-HT7R exerts a fine regulation of cerebellar bidirectional synaptic plasticity that might be involved in cognitive processes and neuropsychiatric disorders involving the cerebellum. PMID:26482421

  16. Coexistence of Two Forms of LTP in ACC Provides a Synaptic Mechanism for the Interactions between Anxiety and Chronic Pain

    PubMed Central

    Koga, Kohei; Descalzi, Giannina; Chen, Tao; Ko, Hyoung-Gon; Lu, Jinshan; Li, Shermaine; Son, Junehee; Kim, TaeHyun; Kwak, Chuljung; Huganir, Richard L.; Zhao, Ming-gao; Kaang, Bong-Kiun; Collingridge, Graham L.; Zhuo, Min

    2015-01-01

    SUMMARY Chronic pain can lead to anxiety and anxiety can enhance the sensation of pain. Unfortunately, little is known about the synaptic mechanisms that mediate these re-enforcing interactions. Here we characterized two forms of long-term potentiation (LTP) in the anterior cingulate cortex (ACC); a presynaptic form (pre-LTP) that requires kainate receptors and a postsynaptic form (post-LTP) that requires N-methyl-D-aspartate receptors. Pre-LTP also involves adenylyl cyclase and protein kinase A and is expressed via a mechanism involving hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. Interestingly, chronic pain and anxiety both result in selective occlusion of pre-LTP. Significantly, microinjection of the HCN blocker ZD7288 into the ACC in vivo produces both anxiolytic and analgesic effects. Our results provide a mechanism by which two forms of LTP in the ACC may converge to mediate the interaction between anxiety and chronic pain. PMID:25556835

  17. 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. PMID:25417189

  18. Action Potentials are required for nitric oxide dependent LTP in CA1 neurons of adult GluR1 knockout and Wild-type mice

    PubMed Central

    Phillips, Keith G.; Hardingham, Neil R.; Fox, Kevin

    2009-01-01

    Neocortical LTP consists of both pre- and postsynaptic components that rely on nitric oxide (NO) and GluR1 respectively. In this study, we found that hippocampal LTP, induced by theta-burst stimulation in mature (> 8 week old) GluR1 knockout mice was almost entirely NO-dependent and involved both the α splice variant of NO synthase-1 (αNOS-1) and the NO synthase-3 (NOS-3) isoforms of NO synthase. Theta-burst induced LTP was also partly NO-dependent in wild-type mice, and made up approximately 50% of the potentiation 2 hours post-tetanus. Theta-burst stimulation reliably produced postsynaptic spikes including a high probability of complex spikes. Inhibition of postsynaptic somatic spikes with intracellular QX314 or local TTX application prevented LTP in the GluR1 knockout mice and also blocked the NO-component of LTP in wild-types. We conclude that theta-burst stimulation is particularly well suited to producing the somatic postsynaptic spikes required for NO-dependent LTP. PMID:19109486

  19. Postsynaptic density-95 mimics and occludes hippocampal long-term potentiation and enhances long-term depression.

    PubMed

    Stein, Valentin; House, David R C; Bredt, David S; Nicoll, Roger A

    2003-07-01

    Previous studies have shown that overexpression of the protein PSD-95 (postsynaptic density-95) selectively enhances AMPA receptor-mediated synaptic responses in hippocampal pyramidal cells. To determine whether this effect is related to synaptic plasticity at these synapses, we examined whether PSD-95 expression mimics long-term potentiation (LTP), and also whether it influences LTP and long-term depression (LTD) in hippocampal slice cultures. Using simultaneous recording from transfected or infected cells and control pyramidal cells, we found that PSD-95, similar to LTP, increases the amplitude and frequency of miniature EPSCs. It also converts silent synapses to functional synapses, as does LTP. In addition, LTP is completely occluded in cells expressing PSD-95, whereas LTD is greatly enhanced. These results suggest that common mechanisms are involved in controlling synaptic AMPA receptors by PSD-95 and synaptic plasticity. PMID:12843250

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

    PubMed Central

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

    2011-01-01

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

  1. Acid-sensing ion channel-1a is not required for normal hippocampal LTP and spatial memory.

    PubMed

    Wu, Pu-Yeh; Huang, Yu-Yin; Chen, Chien-Chun; Hsu, Tsan-Ting; Lin, Yen-Chu; Weng, Ju-Yun; Chien, Ta-Chun; Cheng, Irene H; Lien, Cheng-Chang

    2013-01-30

    Acid-sensing ion channel-1a (ASIC1a) is localized in brain regions with high synaptic density and is thought to contribute to synaptic plasticity, learning, and memory. A prominent hypothesis is that activation of postsynaptic ASICs promotes depolarization, thereby augmenting N-methyl-d-aspartate receptor function and contributing to the induction of long-term potentiation (LTP). However, evidence for activation of postsynaptic ASICs during neurotransmission has not been established. Here, we re-examined the role of ASIC1a in LTP in the hippocampus using pharmacological and genetic approaches. Our results showed that a tarantula peptide psalmotoxin, which profoundly blocked ASIC currents in the hippocampal neurons, had no effect on LTP. Similarly, normal LTP was robustly generated in ASIC1a-null mice. A further behavioral analysis showed that mice lacking ASIC1a had normal performance in hippocampus-dependent spatial memory. In summary, our results indicate that ASIC1a is not required for hippocampal LTP and spatial memory. We therefore propose that the role of ASIC1a in LTP and spatial learning should be reassessed. PMID:23365222

  2. Essential role of presynaptic NMDA receptors in activity-dependent BDNF secretion and corticostriatal LTP.

    PubMed

    Park, Hyungju; Popescu, Andrei; Poo, Mu-ming

    2014-12-01

    Activation of N-methyl-D-aspartate subtype of glutamate receptors (NMDARs) in postsynaptic dendrites is required for long-term potentiation (LTP) of many excitatory synapses, but the role of presynaptic axonal NMDARs in synaptic plasticity remains to be clarified. Here we report that axonal NMDARs play an essential role in LTP induction at mouse corticostriatal synapses by triggering activity-induced presynaptic secretion of brain-derived neurotrophic factor (BDNF). Genetic depletion of either BDNF or the NMDAR subunit GluN1 specifically in cortical axons abolished corticostriatal LTP in response to theta burst stimulation (TBS). Furthermore, functional axonal NMDARs were required for TBS-triggered prolonged axonal Ca(2+) elevation and BDNF secretion, supporting the notion that activation of axonal NMDARs induces BDNF secretion via enhancing Ca(2+) signals in the presynaptic nerve terminals. These results demonstrate that presynaptic NMDARs are equally important as postsynaptic NMDARs in LTP induction of corticostriatal synapses due to their role in mediating activity-induced presynaptic BDNF secretion. PMID:25467984

  3. Simulation of Postsynaptic Glutamate Receptors Reveals Critical Features of Glutamatergic Transmission

    PubMed Central

    Greget, Renaud; Pernot, Fabien; Bouteiller, Jean-Marie C.; Ghaderi, Viviane; Allam, Sushmita; Keller, Anne Florence; Ambert, Nicolas; Legendre, Arnaud; Sarmis, Merdan; Haeberle, Olivier; Faupel, Michel; Bischoff, Serge; Berger, Theodore W.; Baudry, Michel

    2011-01-01

    Activation of several subtypes of glutamate receptors contributes to changes in postsynaptic calcium concentration at hippocampal synapses, resulting in various types of changes in synaptic strength. Thus, while activation of NMDA receptors has been shown to be critical for long-term potentiation (LTP) and long term depression (LTD) of synaptic transmission, activation of metabotropic glutamate receptors (mGluRs) has been linked to either LTP or LTD. While it is generally admitted that dynamic changes in postsynaptic calcium concentration represent the critical elements to determine the direction and amplitude of the changes in synaptic strength, it has been difficult to quantitatively estimate the relative contribution of the different types of glutamate receptors to these changes under different experimental conditions. Here we present a detailed model of a postsynaptic glutamatergic synapse that incorporates ionotropic and mGluR type I receptors, and we use this model to determine the role of the different receptors to the dynamics of postsynaptic calcium with different patterns of presynaptic activation. Our modeling framework includes glutamate vesicular release and diffusion in the cleft and a glutamate transporter that modulates extracellular glutamate concentration. Our results indicate that the contribution of mGluRs to changes in postsynaptic calcium concentration is minimal under basal stimulation conditions and becomes apparent only at high frequency of stimulation. Furthermore, the location of mGluRs in the postsynaptic membrane is also a critical factor, as activation of distant receptors contributes significantly less to calcium dynamics than more centrally located ones. These results confirm the important role of glutamate transporters and of the localization of mGluRs in postsynaptic sites in their signaling properties, and further strengthen the notion that mGluR activation significantly contributes to postsynaptic calcium dynamics only following

  4. Opposite effects of lead exposure on taurine- and HFS-induced LTP in rat hippocampus.

    PubMed

    Yu, Kuai; Yu, Shan-Shan; Ruan, Di-Yun

    2005-01-30

    The effect of lead exposure on taurine-induced long-term potentiation (LTP(TAU)) was examined and compared with high-frequency stimulation-induced one (LTP(HFS)). Field excitatory postsynaptic potentials (fEPSP) and fiber volley (FV) in area CA1 of hippocampal slice were recorded in control and lead-exposed rats. In contrast to the inhibitory effects of lead exposure on LTP(HFS), the amplitude of LTP(TAU) in the lead-exposed rats (199.3+/-13.7%, n=12) was significantly larger than that in controls (152.3+/-17.0%, n=12). It was also observed that taurine induced greater FV potentiation in lead-exposed rats (162.6+/-9.0%, n=10) than controls (132.1+/-6.9%, n=11). In addition, after a previous HFS, sequent perfusion of taurine could further increase the synaptic efficacy in lead-exposed rats. These results provide the first evidence that chronic lead exposure has opposite effects on the two types of LTP resulting from different lead toxicity sites. PMID:15639549

  5. Protein kinases paralleling late-phase LTP formation in dorsal hippocampus in the rat.

    PubMed

    Li, Lin; Wan, Jia; Sase, Sunetra; Gröger, Marion; Pollak, Arnold; Korz, Volker; Lubec, Gert

    2014-10-01

    Hippocampal long term potentiation (LTP), representing a cellular model for learning and memory formation, can be dissociated into at least two phases: a protein-synthesis-independent early phase, lasting about 4h and a protein-synthesis-dependent late phase LTP lasting 6h or longer, or even days. A large series of protein kinases have been shown to be involved and herein, a distinct set of protein kinases proposed to be involved in memory retrieval in previous work was tested in dorsal hippocampus of the rat following induction of late-phase LTP. A bipolar stimulation electrode was chronically implanted into the perforant path, while two monopolar recording electrodes were implanted into the dentate gyrus of the dorsal hippocampus. The recording electrode was measuring extracellular excitatory postsynaptic potentials, while the other one measured population spikes. Protein kinases were determined by immunoblotting and immunoflourescence on hippocampal areas showed the distribution pattern of protein kinases PKN1 and NEK7. Induction of LTP was proven, elevated levels for protein kinases PKN1, RPS6KB1, STK4, CDC42BPB, PRKG, TLK, BMX and decreased levels for NEK7, MAK14 and PLK1 were observed. A remarkable overlap of protein kinases observed in spatial memory processes with those proposed in LTP formation was demonstrated. The findings may be relevant for design of future studies on protein kinases and for the interpretation of previous work. PMID:24911953

  6. Cerebellar Hypoplasia

    MedlinePlus

    ... disorders that begin in early childhood, such as ataxia telangiectasia. In an infant or young child, symptoms of a disorder that features cerebellar hypoplasia might include floppy muscle tone, developmental or ...

  7. Cerebellar Degeneration

    MedlinePlus

    ... Degeneration? Cerebellar degeneration is a process in which neurons in the cerebellum - the area of the brain ... proteins that are necessary for the survival of neurons. Associated diseases: Diseases that are specific to the ...

  8. Cerebellar liponeurocytoma.

    PubMed

    Owler, Brian K; Makeham, John M; Shingde, Meena; Besser, Michael

    2005-04-01

    A case of cerebellar liponeurocytoma in a 34-year-old man is reported. There are only 19 other cases reporting this entity in the medical literature. The diagnostic, radiological and clinical features associated with this tumour are reviewed and discussed in relation to our case. The differences in behaviour and prognosis between medulloblastoma and cerebellar liponeurocytoma are presented with the corresponding implications for management. PMID:15851097

  9. Blueberry-enriched diet ameliorates age-related declines in NMDA receptor-dependent LTP

    PubMed Central

    Bickford, Paula C.; Browning, Michael D.

    2008-01-01

    NMDA receptor-dependent long-term potentiation (LTP) in the hippocampus is widely accepted as a cellular substrate for memory formation. Age-related declines in the expression of both NMDAR-dependent LTP and NMDAR subunit proteins in the CA1 region of the hippocampus have been well characterized and likely underlie age-related memory impairment. In the current study, we examined NMDAR-dependent LTP in young Fischer 344 rats (4 months old) and aged rats (24 months old) given either a control diet or a diet supplemented with blueberry extract for 6–8 weeks. NMDAR-dependent LTP was evoked by high-frequency stimulation (HFS) in the presence of nifedipine, to eliminate voltage-gated calcium channel LTP. Field excitatory postsynaptic potentials (fEPSPs) were increased by 57% 1 h after HFS in young animals, but this potentiation was reduced to 31% in aged animals. Supplementation of the diet with blueberry extract elevated LTP (63%) in aged animals to levels seen in young. The normalization of LTP may be due to the blueberry diet preventing a decline in synaptic strength, as measured by the slope of the fEPSP for a given fiber potential. The blueberry diet did not prevent age-related declines in NMDAR protein expression. However, phosphorylation of a key tyrosine residue on the NR2B subunit, important for increasing NMDAR function, was enhanced by the diet, suggesting that an increase in NMDAR function might overcome the loss in protein. This report provides evidence that dietary alterations later in life may prevent or postpone the cognitive declines associated with aging. PMID:19424850

  10. Metaplastic effect of apamin on LTP and paired-pulse facilitation

    PubMed Central

    Ris, Laurence; Capron, Brigitte; Sclavons, Coralie; Liégeois, Jean-François; Seutin, Vincent; Godaux, Emile

    2007-01-01

    In area CA1 of hippocampal slices, a single 1-sec train of 100-Hz stimulation generally triggers a short-lasting long-term potentiation (S-LTP) of 1–2 h. Here, we found that when such a train was applied 45 min after application of the small conductance Ca2+-activated K+ (SK) channel blocker apamin, it induced a long-lasting LTP (L-LTP) of several hours, instead of an S-LTP. Apamin-induced SK channel blockage is known to resist washing. Nevertheless, the aforementioned effect is not a mere delayed effect; it is metaplastic. Indeed, when a single train was delivered to the Schaffer’s collaterals during apamin application, it induced an S-LTP, like in the control situation. At the moment of this LTP induction (15th min of apamin application), the SK channel blockage was nevertheless complete. Indeed, at that time, under the influence of apamin, the amplitude of the series of field excitatory postsynaptic potentials (fEPSPs) triggered by a stimulation train was increased. We found that the metaplastic effect of apamin on LTP was crucially dependent on the NO-synthase pathway, whereas the efficacy of the NMDA receptors was not modified at the time of its occurrence. We also found that apamin produced an increase in paired-pulse facilitation not during, but after, the application of the drug. Finally, we found that the induction of each of these two metaplastic phenomena was mediated by NMDA receptors. A speculative unitary hypothesis to explain these phenomena is proposed. PMID:17551097

  11. Long-term potentiation modulates synaptic phosphorylation networks and reshapes the structure of the postsynaptic interactome.

    PubMed

    Li, Jing; Wilkinson, Brent; Clementel, Veronica A; Hou, Junjie; O'Dell, Thomas J; Coba, Marcelo P

    2016-01-01

    The postsynaptic site of neurons is composed of more than 1500 proteins arranged in protein-protein interaction complexes, the composition of which is modulated by protein phosphorylation through the actions of complex signaling networks. Components of these networks function as key regulators of synaptic plasticity, in particular hippocampal long-term potentiation (LTP). The postsynaptic density (PSD) is a complex multicomponent structure that includes receptors, enzymes, scaffold proteins, and structural proteins. We triggered LTP in the mouse hippocampus CA1 region and then performed large-scale analyses to identify phosphorylation-mediated events in the PSD and changes in the protein-protein interactome of the PSD that were associated with LTP induction. Our data indicated LTP-induced reorganization of the PSD. The dynamic reorganization of the PSD links glutamate receptor signaling to kinases (writers) and phosphatases (erasers), as well as the target proteins that are modulated by protein phosphorylation and the proteins that recognize the phosphorylation status of their binding partners (readers). Protein phosphorylation and protein interaction networks converged at highly connected nodes within the PSD network. Furthermore, the LTP-regulated phosphoproteins, which included the scaffold proteins Shank3, Syngap1, Dlgap1, and Dlg4, represented the "PSD risk" for schizophrenia and autism spectrum disorder, such that without these proteins in the analysis, the association with the PSD and these two psychiatric diseases was not present. These data are a rich resource for future studies of LTP and suggest that the PSD holds the keys to understanding the molecular events that contribute to complex neurological disorders that affect synaptic plasticity. PMID:27507650

  12. Acute cerebellar ataxia

    MedlinePlus

    Cerebellar ataxia; Ataxia - acute cerebellar; Cerebellitis; Post-varicella acute cerebellar ataxia; PVACA ... Acute cerebellar ataxia in children, especially younger than age 3, may occur several weeks after an illness caused by a virus. ...

  13. Neuroligin 1 is dynamically exchanged at postsynaptic sites

    PubMed Central

    Schapitz, Inga U.; Behrend, Bardo; Pechmann, Yvonne; Lappe-Siefke, Corinna; Kneussel, Silas J.; Wallace, Karen E.; Stempel, A. Vanessa; Buck, Fritz; Grant, Seth G. N.; Schweizer, Michaela; Schmitz, Dietmar; Schwarz, Jürgen R.; Holzbaur, Erika L. F.; Kneussel, Matthias

    2011-01-01

    Neuroligins are postsynaptic cell adhesion molecules that associate with presynaptic neurexins. Both factors form a transsynaptic connection, mediate signalling across the synapse, specify synaptic functions and play a role in synapse formation. Neuroligin dysfunction impairs synaptic transmission, disrupts neuronal networks and is thought to participate in cognitive diseases. Here we report that chemical treatment designed to induce LTP or LTD induces neuroligin 1/3 turnover, leading to either increased or decreased surface membrane protein levels, respectively. Despite its structural role at a crucial transsynaptic position, GFP-neuroligin 1 leaves synapses in hippocampal neurons over time with chemical LTD-induced neuroligin internalization depending on an intact microtubule cytoskeleton. Accordingly, neuroligin 1 and its binding partner PSD-95 associate with components of the dynein motor complex and undergo retrograde co-transport with a dynein-subunit. Transgenic depletion of dynein function in mice causes postsynaptic NLG1/3 and PSD-95 enrichment. In parallel, postsynaptic density (PSD) lengths and spine head sizes are significantly increased, a similar phenotype as observed upon transgenic overexpression of NLG1 (Dahlhaus et al., 2009). Moreover, application of a competitive PSD-95 peptide or neuroligin 1 C-terminal mutagenesis, specifically alter neuroligin 1 surface membrane expression and interfere with its internalization. Our data suggest the concept that synaptic plasticity regulates neuroligin turnover through active cytoskeleton transport. PMID:20861378

  14. Distinct Eligibility Traces for LTP and LTD in Cortical Synapses.

    PubMed

    He, Kaiwen; Huertas, Marco; Hong, Su Z; Tie, XiaoXiu; Hell, Johannes W; Shouval, Harel; Kirkwood, Alfredo

    2015-11-01

    In reward-based learning, synaptic modifications depend on a brief stimulus and a temporally delayed reward, which poses the question of how synaptic activity patterns associate with a delayed reward. A theoretical solution to this so-called distal reward problem has been the notion of activity-generated "synaptic eligibility traces," silent and transient synaptic tags that can be converted into long-term changes in synaptic strength by reward-linked neuromodulators. Here we report the first experimental demonstration of eligibility traces in cortical synapses. We demonstrate the Hebbian induction of distinct traces for LTP and LTD and their subsequent timing-dependent transformation into lasting changes by specific monoaminergic receptors anchored to postsynaptic proteins. Notably, the temporal properties of these transient traces allow stable learning in a recurrent neural network that accurately predicts the timing of the reward, further validating the induction and transformation of eligibility traces for LTP and LTD as a plausible synaptic substrate for reward-based learning. PMID:26593091

  15. Role of postsynaptic inositol 1, 4, 5-trisphosphate receptors in depotentiation in guinea pig hippocampal CA1 neurons.

    PubMed

    Sugita, Makoto; Yamazaki, Yoshihiko; Goto, Jun-Ichi; Fujiwara, Hiroki; Aihara, Takeshi; Mikoshiba, Katsuhiko; Fujii, Satoshi

    2016-07-01

    The long-term potentiation (LTP) in the field excitatory postsynaptic potential (EPSP) induced at hippocampal CA1 pyramidal neuron synapses by delivery of high frequency stimulation (HFS), a tetanus of 100 pulses at 100Hz, is decreased (depotentiation) by a train of low frequency stimulation (LFS) of 1000 pulses at 2Hz applied 30min later. Inositol 1, 4, 5-trisphosphate receptors (IP3Rs) activated both during the HFS and after the LFS are involved in this depotentiation, the former triggering, and the latter modifying, LTP induction (decreasing the amplitude of the LTP established by the priming HFS). Furthermore, the decrease in the LTP at CA1 synapses requires activation of IP3Rs during LFS and activation of calcineurin after LFS. These results suggest that, at hippocampal CA1 neuron synapses, HFS-induced IP3R activation, which is modulated by the subsequent LFS, results in postsynaptic protein dephosphorylation after the LFS, leading to a decrease in the field EPSP and in the HFS-induced LTP. PMID:27018292

  16. [Cerebellar stroke].

    PubMed

    Paradowski, Michał; Zimny, Anna; Paradowski, Bogusław

    2015-01-01

    Cerebellar stroke belongs to a group of rare diseases of vascular origin. Cerebellum, supplied by three pairs of arteries (AICA, PICA, SCA) with many anastomoses between them is less susceptible for a stroke, especially ischemic one. Diagnosis of the stroke in this region is harder due to lower sensibility of commonly used CT of the head in case of stroke suspicion. The authors highlight clinical symptoms distinguishing between vascular territories or topographical locations of the stroke, diagnostic procedures, classical and surgical treatment, the most common misdiagnoses are also mentioned. The authors suggest a diagnostic and therapeutic algorithm development, including rtPA treatment criteria for ischemic cerebellar stroke. PMID:26181157

  17. Cerebellar abiotrophy.

    PubMed

    DeBowes, R M; Leipold, H W; Turner-Beatty, M

    1987-08-01

    Cerebellar abiotrophy is a degenerative condition of Arabian horses that produces signs of head tremors and ataxia. Affected foals demonstrate clinical signs between the time of birth and 6 months of age. The condition is untreatable, although some animals have reportedly improved to varying degrees. The disease is believed to be inherited; however, definitive evidence is lacking at this time. PMID:3497695

  18. ASIC-dependent LTP at multiple glutamatergic synapses in amygdala network is required for fear memory

    PubMed Central

    Chiang, Po-Han; Chien, Ta-Chun; Chen, Chih-Cheng; Yanagawa, Yuchio; Lien, Cheng-Chang

    2015-01-01

    Genetic variants in the human ortholog of acid-sensing ion channel-1a subunit (ASIC1a) gene are associated with panic disorder and amygdala dysfunction. Both fear learning and activity-induced long-term potentiation (LTP) of cortico-basolateral amygdala (BLA) synapses are impaired in ASIC1a-null mice, suggesting a critical role of ASICs in fear memory formation. In this study, we found that ASICs were differentially expressed within the amygdala neuronal population, and the extent of LTP at various glutamatergic synapses correlated with the level of ASIC expression in postsynaptic neurons. Importantly, selective deletion of ASIC1a in GABAergic cells, including amygdala output neurons, eliminated LTP in these cells and reduced fear learning to the same extent as that found when ASIC1a was selectively abolished in BLA glutamatergic neurons. Thus, fear learning requires ASIC-dependent LTP at multiple amygdala synapses, including both cortico-BLA input synapses and intra-amygdala synapses on output neurons. PMID:25988357

  19. Postsynaptic Clustering and Activation of Pyk2 by PSD-95

    PubMed Central

    Bartos, Jason A.; Ulrich, Jason D.; Li, Hongbin; Beazely, Michael A.; Chen, Yucui; MacDonald, John F.; Hell, Johannes W.

    2010-01-01

    The tyrosine kinase Pyk2 plays a unique role in intracellular signal transduction by linking Ca2+ influx to tyrosine phosphorylation, but the molecular mechanism of Pyk2 activation is unknown. We report that Pyk2 oligomerization by antibodies in vitro or overexpression of PSD-95 in PC6-3 cells induces trans-autophosphorylation of Tyr402, the first step in Pyk2 activation. In neurons, Ca2+ influx through NMDA-type glutamate receptors (NMDAR) causes postsynaptic clustering and autophosphorylation of endogenous Pyk2 via Ca2+- and calmodulin-stimulated binding to PSD-95. Accordingly, Ca2+ influx promotes oligomerization and thereby autoactivation of Pyk2 by stimulating its interaction with PSD-95. We show that this mechanism of Pyk2 activation is critical for LTP in the hippocampus CA1 region, which is thought to underlie learning and memory. PMID:20071509

  20. Enhanced AMPA Receptor Function Promotes Cerebellar Long-Term Depression Rather than Potentiation

    ERIC Educational Resources Information Center

    van Beugen, Boeke J.; Qiao, Xin; Simmons, Dana H.; De Zeeuw, Chris I.; Hansel, Christian

    2014-01-01

    Ampakines are allosteric modulators of AMPA receptors that facilitate hippocampal long-term potentiation (LTP) and learning, and have been considered for the treatment of cognition and memory deficits. Here, we show that the ampakine CX546 raises the amplitude and slows the decay time of excitatory postsynaptic currents (EPSCs) at cerebellar…

  1. Redistribution of Ionotropic Glutamate Receptors Detected by Laser Microdissection of the Rat Dentate Gyrus 48 h following LTP Induction In Vivo

    PubMed Central

    Kennard, Jeremy T. T.; Guévremont, Diane; Mason-Parker, Sara E.; Abraham, Wickliffe C.; Williams, Joanna M.

    2014-01-01

    The persistence and input specificity of long-term potentiation (LTP) make it attractive as a mechanism of information storage. In its initial phase, both in vivo and in vitro studies have shown that LTP is associated with increased membrane localization of AMPA receptor subunits, but the molecular basis of LTP maintenance over the long-term is still unclear. We have previously shown that expression of AMPA and NMDA receptor subunits is elevated in whole homogenates prepared from dentate gyrus 48 h after LTP induction in vivo. In the present study, we utilized laser microdissection (LMD) techniques to determine whether AMPA and NMDA receptor upregulation occurs specifically in the stimulated regions of the dentate gyrus dendritic arbor. Receptor proteins GluN1, GluA1 and GluA2, as well as postsynaptic density protein of 95 kDa and tubulin were detected by Western blot analysis in microdissected samples. Gradients of expression were observed for GluN1 and GluA2, decreasing from the inner to the outer zones of the molecular layer, and were independent of LTP. When induced at medial perforant path synapses, LTP was associated with an apparent specific redistribution of GluA1 and GluN1 to the middle molecular layer that contains these synapses. These data indicate that glutamate receptor proteins are delivered specifically to dendritic regions possessing LTP-expressing synapses, and that these changes are preserved for at least 48 h. PMID:24667777

  2. The effect of acute swim stress and training in the water maze on hippocampal synaptic activity as well as plasticity in the dentate gyrus of freely moving rats: revisiting swim-induced LTP reinforcement.

    PubMed

    Tabassum, Heena; Frey, Julietta U

    2013-12-01

    Hippocampal long-term potentiation (LTP) is a cellular model of learning and memory. An early form of LTP (E-LTP) can be reinforced into its late form (L-LTP) by various behavioral interactions within a specific time window ("behavioral LTP-reinforcement"). Depending on the type and procedure used, various studies have shown that stress differentially affects synaptic plasticity. Under low stress, such as novelty detection or mild foot shocks, E-LTP can be transformed into L-LTP in the rat dentate gyrus (DG). A reinforcing effect of a 2-min swim, however, has only been shown in (Korz and Frey (2003) J Neurosci 23:7281-7287; Korz and Frey (2005) J Neurosci 25:7393-7400; Ahmed et al. (2006) J Neurosci 26:3951-3958; Sajikumar et al., (2007) J Physiol 584.2:389-400) so far. We have reinvestigated these studies using the same as well as an improved recording technique which allowed the recording of field excitatory postsynaptic potentials (fEPSP) and the population spike amplitude (PSA) at their places of generation in freely moving rats. We show that acute swim stress led to a long-term depression (LTD) in baseline values of PSA and partially fEPSP. In contrast to earlier studies a LTP-reinforcement by swimming could never be reproduced. Our results indicate that 2-min swim stress influenced synaptic potentials as well as E-LTP negatively. PMID:23836535

  3. Reinforcement of Rat Hippocampal LTP by Holeboard Training

    ERIC Educational Resources Information Center

    Frey, Julietta U.; Korz, Volker; Uzakov, Shukhrat

    2005-01-01

    Hippocampal long-term potentiation (LTP) can be dissociated in early-LTP lasting 4-5 h and late-LTP with a duration of more than 8 h, the latter of which requires protein synthesis and heterosynaptic activity during its induction. Previous studies in vivo have shown that early-LTP in the dentate gyrus can protein synthesis-dependently be…

  4. Studies in Optimal Configuration of the LTP

    SciTech Connect

    McKinney, Wayne R.; Anders, Mark; Barber, Samuel K.; Domning, Edward E.; Lou, Yunian; Morrison, Gregory Y.; Salmassi, Farhad; Smith, Brian V.; Yashchuk, Valeriy V.

    2010-08-10

    Brightness preservation requirements for ever brighter synchrotron radiation and free electron laser beamlines require surface slope tolerances of x-ray optics on the order of 0.2 mu rad, or better. Hence, the accuracy of dedicated surface slope metrology must be 0.1 mu rad, or even less. Achieving this level of measurement accuracy with the flagship instrument at synchrotron radiation metrology laboratories, the Long Trace Profiler (LTP), requires all significant sources of systematic, random, and instrumental drift errors to be identified, and reduced or eliminated. In this respect, the performance of certain components of the Advanced Light Source LTP-II design [Kirschman, et al., Proc. SPIE, 7077, 70770A-12 (2008)] is analyzed, considering the principal justification for inclusion of each component, possible systematic error due to the quality of its optical material, and drift effects due to generated heat, etc. We investigate the effects of replacement of the existing diode laser with a fiber-coupled laser light source, and demonstrate that reducing the number of components by using a single beam on the surface under test (SUT), rather than an original double beam maintains, or even improves the accuracy of measurement with our LTP. Based on the performance of the upgraded LTP, we trace the further steps for improving of the LTP optical system.

  5. Isolation and Functional Analysis of ZmLTP3, a Homologue to Arabidopsis LTP3.

    PubMed

    Zou, Hua-Wen; Tian, Xiao-Hai; Ma, Guo-Hui; Li, Zhi-Xin

    2013-01-01

    Plant lipid transfer proteins (LTPs) are encoded by multigene families and play important roles in plant physiology. One full-length cDNA encoding an Arabidopsis LTP3 homologue was isolated from maize by RT-PCR and named as ZmLTP3. RT-PCR analysis indicated that the ZmLTP3 expression is induced by salicylic acid (SA), mannitol and salt. Furthermore, in different tissues the ZmLTP3 displayed different expression patterns, indicating that ZmLTP3 may play multiple roles in stress resistance. Over-expression of ZmLTP3 in wild-type Arabidopsis resulted in the increased salt tolerance. Under salt stress condition, compared to wild-type (WT) plants, transgenic Arabidopsis grew better, had higher seedling fresh (FW), dry weight (DW), seed yields, proline content and lower MDA content and relative electric conductivity level. Our results suggest that maize ZmLTP3 might encode a member of LTPs family and play roles in salt resistance. PMID:23455470

  6. Parameter estimation techniques for LTP system identification

    NASA Astrophysics Data System (ADS)

    Nofrarias Serra, Miquel

    LISA Pathfinder (LPF) is the precursor mission of LISA (Laser Interferometer Space Antenna) and the first step towards gravitational waves detection in space. The main instrument onboard the mission is the LTP (LISA Technology Package) whose scientific goal is to test LISA's drag-free control loop by reaching a differential acceleration noise level between two masses in √ geodesic motion of 3 × 10-14 ms-2 / Hz in the milliHertz band. The mission is not only challenging in terms of technology readiness but also in terms of data analysis. As with any gravitational wave detector, attaining the instrument performance goals will require an extensive noise hunting campaign to measure all contributions with high accuracy. But, opposite to on-ground experiments, LTP characterisation will be only possible by setting parameters via telecommands and getting a selected amount of information through the available telemetry downlink. These two conditions, high accuracy and high reliability, are the main restrictions that the LTP data analysis must overcome. A dedicated object oriented Matlab Toolbox (LTPDA) has been set up by the LTP analysis team for this purpose. Among the different toolbox methods, an essential part for the mission are the parameter estimation tools that will be used for system identification during operations: Linear Least Squares, Non-linear Least Squares and Monte Carlo Markov Chain methods have been implemented as LTPDA methods. The data analysis team has been testing those methods with a series of mock data exercises with the following objectives: to cross-check parameter estimation methods and compare the achievable accuracy for each of them, and to develop the best strategies to describe the physics underlying a complex controlled experiment as the LTP. In this contribution we describe how these methods were tested with simulated LTP-like data to recover the parameters of the model and we report on the latest results of these mock data exercises.

  7. DYNAMICS OF NASCENT AND ACTIVE ZONE ULTRASTRUCTURE AS SYNAPSES ENLARGE DURING LTP IN MATURE HIPPOCAMPUS

    PubMed Central

    Bell, Maria Elizabeth; Bourne, Jennifer N.; Chirillo, Michael A.; Mendenhall, John M.; Kuwajima, Masaaki; Harris, Kristen M.

    2014-01-01

    Nascent zones and active zones are adjacent synaptic regions that share a postsynaptic density, but nascent zones lack the presynaptic vesicles found at active zones. Here dendritic spine synapses were reconstructed through serial section electron microscopy (3DEM) and EM tomography to investigate nascent zone dynamics during long-term potentiation (LTP) in mature rat hippocampus. LTP was induced with theta-burst stimulation and comparisons were made to control stimulation in the same hippocampal slices at 5 minutes, 30 minutes, and 2 hours post-induction and to perfusion-fixed hippocampus in vivo. Nascent zones were present at the edges of ~35% of synapses in perfusion-fixed hippocampus and as many as ~50% of synapses in some hippocampal slice conditions. By 5 minutes, small dense core vesicles known to transport active zone proteins moved into more presynaptic boutons. By 30 minutes, nascent zone area decreased without significant change in synapse area, suggesting that presynaptic vesicles were recruited to pre-existing nascent zones. By 2 hours, both nascent and active zones were enlarged. Immunogold labeling revealed that glutamate receptors can be found in nascent zones; however, average distances from nascent zones to docked presynaptic vesicles ranged from 170±5 nm in perfusion-fixed hippocampus to 251±4 nm at enlarged synapses by 2 hours during LTP. Prior stochastic modeling suggests that falloff in glutamate concentration reduces the probability of glutamate receptor activation from 0.4 at the center of release to 0.1 just 200 nm away. Thus, conversion of nascent zones to functional active zones likely requires the recruitment of presynaptic vesicles during LTP. PMID:25043676

  8. LTP Induction Modifies Functional Relationship among Hippocampal Neurons

    ERIC Educational Resources Information Center

    Yun, Sung H.; Lee, Deok S.; Lee, Hyunjung; Baeg, Eun H.; Kim, Yun B.; Jung, Min W.

    2007-01-01

    To obtain evidence linking long-term potentiation (LTP) and memory, we examined whether LTP induction modifies functional relationship among neurons in the rat hippocampus. In contrast to neurons in low-frequency stimulated or AP5-treated slices, LTP induction altered "functional connectivity," as defined by the degree of synchronous firing, among…

  9. Postsynaptic potentiation of corticospinal projecting neurons in the anterior cingulate cortex after nerve injury

    PubMed Central

    2014-01-01

    Long-term potentiation (LTP) is the key cellular mechanism for physiological learning and pathological chronic pain. In the anterior cingulate cortex (ACC), postsynaptic recruitment or modification of AMPA receptor (AMPAR) GluA1 contribute to the expression of LTP. Here we report that pyramidal cells in the deep layers of the ACC send direct descending projecting terminals to the dorsal horn of the spinal cord (lamina I-III). After peripheral nerve injury, these projection cells are activated, and postsynaptic excitatory responses of these descending projecting neurons were significantly enhanced. Newly recruited AMPARs contribute to the potentiated synaptic transmission of cingulate neurons. PKA-dependent phosphorylation of GluA1 is important, since enhanced synaptic transmission was abolished in GluA1 phosphorylation site serine-845 mutant mice. Our findings provide strong evidence that peripheral nerve injury induce long-term enhancement of cortical-spinal projecting cells in the ACC. Direct top-down projection system provides rapid and profound modulation of spinal sensory transmission, including painful information. Inhibiting cortical top-down descending facilitation may serve as a novel target for treating neuropathic pain. PMID:24890933

  10. LTP enhances synaptogenesis in the developing hippocampus.

    PubMed

    Watson, Deborah J; Ostroff, Linnaea; Cao, Guan; Parker, Patrick H; Smith, Heather; Harris, Kristen M

    2016-05-01

    In adult hippocampus, long-term potentiation (LTP) produces synapse enlargement while preventing the formation of new small dendritic spines. Here, we tested how LTP affects structural synaptic plasticity in hippocampal area CA1 of Long-Evans rats at postnatal day 15 (P15). P15 is an age of robust synaptogenesis when less than 35% of dendritic spines have formed. We hypothesized that LTP might therefore have a different effect on synapse structure than in adults. Theta-burst stimulation (TBS) was used to induce LTP at one site and control stimulation was delivered at an independent site, both within s. radiatum of the same hippocampal slice. Slices were rapidly fixed at 5, 30, and 120 min after TBS, and processed for analysis by three-dimensional reconstruction from serial section electron microscopy (3DEM). All findings were compared to hippocampus that was perfusion-fixed (PF) in vivo at P15. Excitatory and inhibitory synapses on dendritic spines and shafts were distinguished from synaptic precursors, including filopodia and surface specializations. The potentiated response plateaued between 5 and 30 min and remained potentiated prior to fixation. TBS resulted in more small spines relative to PF by 30 min. This TBS-related spine increase lasted 120 min, hence, there were substantially more small spines with LTP than in the control or PF conditions. In contrast, control test pulses resulted in spine loss relative to PF by 120 min, but not earlier. The findings provide accurate new measurements of spine and synapse densities and sizes. The added or lost spines had small synapses, took time to form or disappear, and did not result in elevated potentiation or depression at 120 min. Thus, at P15 the spines formed following TBS, or lost with control stimulation, appear to be functionally silent. With TBS, existing synapses were awakened and then new spines formed as potential substrates for subsequent plasticity. © 2015 The Authors Hippocampus Published by Wiley

  11. Postsynaptic Assembly: A Role for Wnt Signaling

    PubMed Central

    Stamatakou, Eleanna; Salinas, Patricia C

    2014-01-01

    Synapse formation requires the coordinated formation of the presynaptic terminal, containing the machinery for neurotransmitter release, and the postsynaptic side that possesses the machinery for neurotransmitter reception. For coordinated pre- and postsynaptic assembly signals across the synapse are required. Wnt secreted proteins are well-known synaptogenic factors that promote the recruitment of presynaptic components in diverse organisms. However, recent studies demonstrate that Wnts act directly onto the postsynaptic side at both central and peripheral synapses to promote postsynaptic development and synaptic strength. This review focuses on the role of Wnts in postsynaptic development at central synapses and the neuromuscular junction. © 2013 The Authors. Developmental Neurobiology Published by Wiley Periodicals, Inc. Develop Neurobiol 74: 818–827, 2014 PMID:24105999

  12. N-methyl-D-aspartate receptors strongly regulate postsynaptic activity levels during optic nerve regeneration.

    PubMed

    Kolls, Brad J; Meyer, Ronald L

    2013-10-01

    During development, neuronal activity is used as a cue to guide synaptic rearrangements to refine connections. Many studies, especially in the visual system, have shown that the N-methyl-D-aspartate receptor (NMDAr) plays a key role in mediating activity-dependent refinement through long-term potentiation (LTP)-like processes. Adult goldfish can regenerate their optic nerve and utilize neuronal activity to generate precise topography in their projection onto tectum. Although the NMDAr has been implicated in this process, its precise role in regeneration has not been extensively studied. In examining NMDAr function during regeneration, we found salient differences compared with development. By using field excitatory postsynaptic potential (fEPSP) recordings, the contribution of the NMDAr at the primary optic synapse was measured. In contrast to development, no increase in NMDAr function was detectable during synaptic refinement. Unlike development, LTP could not be reliably elicited during regeneration. Unexpectedly, we found that NMDAr exerted a major effect on regulating ongoing tectal (postsynaptic) activity levels during regeneration. Blocking NMDAr strongly suppressed spontaneous activity during regeneration but had no significant effect in the normal projection. This difference could be attributed to an occlusion effect of strong optic drive in the normal projection, which dominated ongoing tectal activity. During regeneration, this optic drive is largely absent. Optic nerve stimulation further indicated that the NMDAr had little effect on the ability of optic fibers to evoke early postsynaptic impulse activity but was important for late network activity. These results indicate that, during regeneration, the NMDAr may play a critical role in the homeostatic regulation of ongoing activity and network excitability. PMID:23873725

  13. Modelling bidirectional modulations in synaptic plasticity: A biochemical pathway model to understand the emergence of long term potentiation (LTP) and long term depression (LTD).

    PubMed

    He, Yao; Kulasiri, Don; Samarasinghe, Sandhya

    2016-08-21

    Synaptic plasticity induces bidirectional modulations of the postsynaptic response following a synaptic transmission. The long term forms of synaptic plasticity, named long term potentiation (LTP) and long term depression (LTD), are critical for the antithetic functions of the memory system, memory formation and removal, respectively. A common Ca(2+) signalling upstream triggers both LTP and LTD, and the critical proteins and factors coordinating the LTP/LTD inductions are not well understood. We develop an integrated model based on the sub-models of the indispensable synaptic proteins in the emergence of synaptic plasticity to validate and understand their potential roles in the expression of synaptic plasticity. The model explains Ca(2+)/calmodulin (CaM) complex dependent coordination of LTP/LTD expressions by the interactions among the indispensable proteins using the experimentally estimated kinetic parameters. Analysis of the integrated model provides us with insights into the effective timescales of the key proteins and we conclude that the CaM pool size is critical for the coordination between LTP/LTD expressions. PMID:27185535

  14. The upgraded LTP-V at SLS

    NASA Astrophysics Data System (ADS)

    Flechsig, U.; Jaggi, A.; Krempaský, J.; Spielmann, S.; Thominet, V.

    2013-05-01

    Since 2005 the Swiss Light Source (SLS) has been operating a Long Trace Profiler (LTP)-V from Ocean Optics in its metrology laboratory to measure the synchrotron optics for SLS. In 2012 we finished a significant upgrade to improve the accuracy, reliability and measurement efficiency in particular for the calibration of adaptive optics. Folding mirrors with figure errors <λ/100 and an additional linear encoder have been installed, the 1d CCD detector with 2048 pixels has been replaced by a 16 mega-pixel CCD camera with gigabit ethernet interface GigE, the monolithic software has been replaced by a modular, full- EPICS compatible system based on a new LTP plugin for the areaDetector software for image processing. The plugin allows slope determination in real time i.e. per frame.

  15. Myosin IXa Binds AMPAR and Regulates Synaptic Structure, LTP, and Cognitive Function

    PubMed Central

    Folci, Alessandra; Murru, Luca; Vezzoli, Elena; Ponzoni, Luisa; Gerosa, Laura; Moretto, Edoardo; Longo, Fabiana; Zapata, Jonathan; Braida, Daniela; Pistillo, Francesco; Bähler, Martin; Francolini, Maura; Sala, Mariaelvina; Bassani, Silvia

    2016-01-01

    Myosin IXa (Myo9a) is a motor protein that is highly expressed in the brain. However, the role of Myo9a in neurons remains unknown. Here, we investigated Myo9a function in hippocampal synapses. In rat hippocampal neurons, Myo9a localizes to the postsynaptic density (PSD) and binds the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) GluA2 subunit. Myo9a+/- mice displayed a thicker PSD and increased levels of PSD95 and surface AMPAR expression. Furthermore, synaptic transmission, long-term potentiation (LTP) and cognitive functions were impaired in Myo9a+/- mice. Together, these results support a key role for Myo9a in controlling the molecular structure and function of hippocampal synapses. PMID:26834556

  16. Pim kinase expression is induced by LTP stimulation and required for the consolidation of enduring LTP.

    PubMed Central

    Konietzko, U; Kauselmann, G; Scafidi, J; Staubli, U; Mikkers, H; Berns, A; Schweizer, M; Waltereit, R; Kuhl, D

    1999-01-01

    In animals and several cellular models of synaptic plasticity, long-lasting changes in synaptic strength are dependent on gene transcription and translation. Here we demonstrate that Pim-1, a serine/threonine kinase closely related to Pim-2 and Pim-3, is induced in hippocampus in response to stimuli that evoke long-term potentiation (LTP). Mice deficient for Pim-1 show normal synaptic transmission and short-term plasticity. However, they fail to consolidate enduring LTP even though Pim-2 and Pim-3 are constitutively expressed in the hippocampus and Pim-3 expression is similarly induced by synaptic activity. Thus, expression of Pim-1 is required for LTP. Its level of expression and, consequently, its capacity to phosphorylate target proteins in dendritic and nuclear compartments of stimulated neurons might be a determining factor for the establishment of long-lasting changes in synaptic strength. PMID:10369676

  17. Synaptic Multivesicular Release in the Cerebellar Cortex: Its Mechanism and Role in Neural Encoding and Processing.

    PubMed

    Satake, Shin'Ichiro; Inoue, Tsuyoshi; Imoto, Keiji

    2016-04-01

    The number of synaptic vesicles released during fast release plays a major role in determining the strength of postsynaptic response. However, it remains unresolved how the number of vesicles released in response to action potentials is controlled at a single synapse. Recent findings suggest that the Cav2.1 subtype (P/Q-type) of voltage-gated calcium channels is responsible for inducing presynaptic multivesicular release (MVR) at rat cerebellar glutamatergic synapses from granule cells to molecular layer interneurons. The topographical distance from Cav2.1 channels to exocytotic Ca(2+) sensors is a critical determinant of MVR. In physiological trains of presynaptic neurons, MVR significantly impacts the excitability of postsynaptic neurons, not only by increasing peak amplitude but also by prolonging decay time of the postsynaptic currents. Therefore, MVR contributes additional complexity to neural encoding and processing in the cerebellar cortex. PMID:25971904

  18. [Pre- and Postsynaptic Mechanisms of the Deprivational Potentiation of Population Responses in Rat Hippocampal CA1 Neurons].

    PubMed

    Popov, V A

    2016-01-01

    Mechanisms of the deprivational potentiation (DeP) of the population responses in rat hippocampal CA1 neurons after 60-min period of the cessation of rare (0.05 Hz) test stimulation of Schaffer collaterals was investigated in vitro. It has been demonstrated that two independent mechanisms are involved in DeP induction: presynaptic component in initial phase of DeP and postsynaptic one responsible for the long-term phase of DeP. The competitive interference between mechanisms of the long-term phase of DeP and the protein phosphorylation phase of long-term potentiation (LTP) was confirmed. It was shown that not NMDA receptors, but purinergic P2 receptors participate in Ca(2+) -dependent mechanism of induction of the postsynaptic component of DeP. The common curve of dependence of synaptic strength on synaptic use/disuse, including the DeP, long-term depression (LTD) and LTP areas, is presented. PMID:27538284

  19. Cerebellar and Brainstem Malformations.

    PubMed

    Poretti, Andrea; Boltshauser, Eugen; Huisman, Thierry A G M

    2016-08-01

    The frequency and importance of the evaluation of the posterior fossa have increased significantly over the past 20 years owing to advances in neuroimaging. Conventional and advanced neuroimaging techniques allow detailed evaluation of the complex anatomic structures within the posterior fossa. A wide spectrum of cerebellar and brainstem malformations has been shown. Familiarity with the spectrum of cerebellar and brainstem malformations and their well-defined diagnostic criteria is crucial for optimal therapy, an accurate prognosis, and correct genetic counseling. This article discusses cerebellar and brainstem malformations, with emphasis on neuroimaging findings (including diagnostic criteria), neurologic presentation, systemic involvement, prognosis, and recurrence. PMID:27423798

  20. The Isolation, Primacy, and Recency Effects Predicted by an Adaptive LTD/LTP Threshold in Postsynaptic Cells

    ERIC Educational Resources Information Center

    Sikstrom, Sverker

    2006-01-01

    An item that stands out (is isolated) from its context is better remembered than an item consistent with the context. This isolation effect cannot be accounted for by increased attention, because it occurs when the isolated item is presented as the first item, or by impoverished memory of nonisolated items, because the isolated item is better…

  1. Diminished KCC2 confounds synapse specificity of LTP during senescence.

    PubMed

    Ferando, Isabella; Faas, Guido C; Mody, Istvan

    2016-09-01

    The synapse specificity of long-term potentiation (LTP) ensures that no interference arises from inputs irrelevant to the memory to be encoded. In hippocampi of aged (21-28 months) mice, LTP was relayed to unstimulated synapses, blemishing its synapse specificity. Diminished levels of the K(+)/Cl(-) cotransporter KCC2 and a depolarizing GABAA receptor-mediated synaptic component following LTP were the most likely causes for the spreading of potentiation, unveiling mechanisms hindering information storage in the aged brain and identifying KCC2 as a potential target for intervention. PMID:27500406

  2. Manifestations and possible sources of lunar transient phenomena /LTP/

    NASA Technical Reports Server (NTRS)

    Cameron, W. S.

    1975-01-01

    An observing program designed to monitor sites of lunar transient phenomena (LTP) is discussed in the context of the distribution of LTP sites and possible sources of the events. It is noted that the distribution of LTP sites shows a strong preference for the edges of maria and a paucity in the north and south highlands, suggesting a relationship with dark smooth material known to be volcanic and implying internal activity at the sites. The observing program, which is aimed at those LTP described as brightenings, has been conducted to determine the normal brightness of each observed feature for all phases of a lunation and to establish a quantified 'seeing' scale. The procedure for establishing the albedo scale of a given feature is outlined, and some observations of the crater Dawes are analyzed as an example.

  3. Neurotransmitters drive combinatorial multistate postsynaptic density networks.

    PubMed

    Coba, Marcelo P; Pocklington, Andrew J; Collins, Mark O; Kopanitsa, Maksym V; Uren, Rachel T; Swamy, Sajani; Croning, Mike D R; Choudhary, Jyoti S; Grant, Seth G N

    2009-01-01

    The mammalian postsynaptic density (PSD) comprises a complex collection of approximately 1100 proteins. Despite extensive knowledge of individual proteins, the overall organization of the PSD is poorly understood. Here, we define maps of molecular circuitry within the PSD based on phosphorylation of postsynaptic proteins. Activation of a single neurotransmitter receptor, the N-methyl-D-aspartate receptor (NMDAR), changed the phosphorylation status of 127 proteins. Stimulation of ionotropic and metabotropic glutamate receptors and dopamine receptors activated overlapping networks with distinct combinatorial phosphorylation signatures. Using peptide array technology, we identified specific phosphorylation motifs and switching mechanisms responsible for the integration of neurotransmitter receptor pathways and their coordination of multiple substrates in these networks. These combinatorial networks confer high information-processing capacity and functional diversity on synapses, and their elucidation may provide new insights into disease mechanisms and new opportunities for drug discovery. PMID:19401593

  4. CYLINDER LENS ALIGNMENT IN THE LTP

    SciTech Connect

    TAKACS, P.Z.

    2005-07-26

    The Long Trace Profiler (LTP), is well-suited for the measurement of the axial figure of cylindrical mirrors that usually have a long radius of curvature in the axial direction but have a short radius of curvature in the sagittal direction. The sagittal curvature causes the probe beam to diverge in the transverse direction without coming to a focus on the detector, resulting in a very weak signal. It is useful to place a cylinder lens into the optical system above the mirror under test to refocus the sagittal divergence and increase the signal level. A positive cylinder lens can be placed at two positions above the surface: the Cat's Eye reflection position and the Wavefront-Matching position. The Cat's Eye position, is very tolerant to mirror misalignment, which is not good if absolute axial radius of curvature is to be measured. Lateral positioning and rotational misalignments of lens and the mirror combine to produce unusual profile results. This paper looks at various alignment issues with measurements and by raytrace simulations to determine the best strategy to minimize radius of curvature errors in the measurement of cylindrical aspheres.

  5. Unilateral cerebellar aplasia.

    PubMed

    Boltshauser, E; Steinlin, M; Martin, E; Deonna, T

    1996-02-01

    We describe three children with unilateral cerebellar aplasia (UCA). Deliveries at term and neonatal periods were uneventful. Pregnancy was normal in one and complicated by mild bleeding (in second and fourth month respectively) in two instances. Presenting signs were delayed motor development with marked contralateral torticollis (n = 1), hemiplegia (n = 1) and unusual head nodding (n = 1). Neuroradiological investigations revealed complete aplasia (n = 1) and subtotal aplasia (n = 2) of one cerebellar hemisphere with only a residual wing-like structure below the tentorium. There was contralateral underdevelopment of the brainstem. The infant with hemiplegic cerebral palsy had an additional supratentorial periventricular parenchymal defect, contralateral to the cerebellar hypoplasia. In view of literature reports, describing similar neuroradiological or neuropathological findings in asymptomatic individuals, it is doubtful whether UCA is responsible for our patient's problems. In our cases UCA has presumably resulted from a prenatal destructive lesion, possibly an infarct, but the timing and exact nature are unknown. PMID:8677027

  6. Cerebellar-responsive neurons in the thalamic ventroanterior-ventrolateral complex of rats: in vivo electrophysiology.

    PubMed

    Sawyer, S F; Young, S J; Groves, P M; Tepper, J M

    1994-12-01

    In vivo intracellular recordings were obtained from identified thalamocortical neurons in the ventroanterior-ventrolateral complex in urethane-anesthetized rats. This thalamic nucleus has few interneurons. Neurons that responded to cerebellar stimulation were injected intracellularly with horseradish peroxidase or biocytin and examined with light and electron microscopy (see companion paper). Intrinsic membrane properties and voltage-dependent rhythmic activity of cerebellar-responsive ventroanterior-ventrolateral neurons were similar to those described previously for thalamic neurons. Thus, in addition to conventional "fast" Na(+)-dependent spikes, rat ventroanterior-ventrolateral neurons had "slow" Ca(2+)-mediated low-threshold spikes and membrane conductances that supported rhythmic oscillations. Two modes of spontaneous activity were observed: (i) a tonic firing pattern that consisted of irregularly occurring fast spikes that predominated when the membrane potential was more positive than about -60 mV, and (ii) a rhythmic firing pattern, observed when the membrane potential was more negative than about -65 mV, composed of periodic (4-8 Hz) membrane hyperpolarizations and ramp depolarizations that often produced a low-threshold spike and a burst of fast spikes. In some neurons, spontaneous fast prepotentials were also observed, often with a relatively constant rate (up to 70 Hz). Cerebellar stimulation elicited excitatory postsynaptic potentials that in some cases appeared to be all-or-none and were similar in form to fast prepotentials. Stimulation of ipsilateral motor cortex elicited a short-latency antidromic response followed by a monosynaptic excitatory postsynaptic potential, which had a slower rise time than excitatory postsynaptic potentials evoked from cerebellum, suggesting that cortical inputs were electrotonically distal to cerebellar inputs. In the presence of moderate membrane hyperpolarization, the cortically evoked excitatory postsynaptic

  7. Optimised purification and characterisation of lipid transfer protein 1 (LTP1) and its lipid-bound isoform LTP1b from barley malt.

    PubMed

    Nieuwoudt, Melanie; Lombard, Nicolaas; Rautenbach, Marina

    2014-08-15

    In beer brewing, brewers worldwide strive to obtain product consistency in terms of flavour, colour and foam. Important proteins contributing to beer foam are lipid transfer proteins (LTPs), in particular LTP1 and its lipid-bound isoform LTP1b, which are known to transport lipids in vivo and prevent lipids from destabilising the beer foam. LTP1 and LTP1b were successfully purified using only five purification steps with a high purified protein yield (160 mg LTP1 and LTP1b from 200 g barley). Circular dichroism of LTP1 and LTP1b confirmed that both proteins are highly tolerant to high temperatures (>90 °C) and are pH stable, particularly at a neutral to a more basic pH. Only LTP1 exhibited antiyeast and thermo-stable lytic activity, while LTP1b was inactive, indicating that the fatty acid moiety compromised the antimicrobial activity of LTP1. This lack in antiyeast activity and the positive foam properties of LTP1b would benefit beer fermentation and quality. PMID:24679818

  8. Nicotine recruits glutamate receptors to postsynaptic sites.

    PubMed

    Duan, Jing-Jing; Lozada, Adrian F; Gou, Chen-Yu; Xu, Jing; Chen, Yuan; Berg, Darwin K

    2015-09-01

    Cholinergic neurons project throughout the nervous system and activate nicotinic receptors to modulate synaptic function in ways that shape higher order brain function. The acute effects of nicotinic signaling on long-term synaptic plasticity have been well-characterized. Less well understood is how chronic exposure to low levels of nicotine, such as those encountered by habitual smokers, can alter neural connections to promote addiction and other lasting behavioral effects. We show here that chronic exposure of hippocampal neurons in culture to low levels of nicotine recruits AMPA and NMDA receptors to the cell surface and sequesters them at postsynaptic sites. The receptors include GluA2-containing AMPA receptors, which are responsible for most of the excitatory postsynaptic current mediated by AMPA receptors on the neurons, and include NMDA receptors containing GluN1 and GluN2B subunits. Moreover, we find that the nicotine treatment also increases expression of the presynaptic component synapsin 1 and arranges it in puncta juxtaposed to the additional AMPA and NMDA receptor puncta, suggestive of increases in synaptic contacts. Consistent with increased synaptic input, we find that the nicotine treatment leads to an increase in the excitatory postsynaptic currents mediated by AMPA and NMDA receptors. Further, the increases skew the ratio of excitatory-to-inhibitory input that the cell receives, and this holds both for pyramidal neurons and inhibitory neurons in the hippocampal CA1 region. The GluN2B-containing NMDA receptor redistribution at synapses is associated with a significant increase in GluN2B phosphorylation at Tyr1472, a site known to prevent GluN2B endocytosis. These results suggest that chronic exposure to low levels of nicotine not only alters functional connections but also is likely to change excitability levels across networks. Further, it may increase the propensity for synaptic plasticity, given the increase in synaptic NMDA receptors. PMID

  9. KCNQ/Kv7 channel activator flupirtine protects against acute stress-induced impairments of spatial memory retrieval and hippocampal LTP in rats.

    PubMed

    Li, C; Huang, P; Lu, Q; Zhou, M; Guo, L; Xu, X

    2014-11-01

    Spatial memory retrieval and hippocampal long-term potentiation (LTP) are impaired by stress. KCNQ/Kv7 channels are closely associated with memory and the KCNQ/Kv7 channel activator flupirtine represents neuroprotective effects. This study aims to test whether KCNQ/Kv7 channel activation prevents acute stress-induced impairments of spatial memory retrieval and hippocampal LTP. Rats were placed on an elevated platform in the middle of a bright room for 30 min to evoke acute stress. The expression of KCNQ/Kv7 subunits was analyzed at 1, 3 and 12 h after stress by Western blotting. Spatial memory was examined by the Morris water maze (MWM) and the field excitatory postsynaptic potential (fEPSP) in the hippocampal CA1 area was recorded in vivo. Acute stress transiently decreased the expression of KCNQ2 and KCNQ3 in the hippocampus. Acute stress impaired the spatial memory retrieval and hippocampal LTP, the KCNQ/Kv7 channel activator flupirtine prevented the impairments, and the protective effects of flupirtine were blocked by XE-991 (10,10-bis(4-Pyridinylmethyl)-9(10H)-anthracenone), a selective KCNQ channel blocker. Furthermore, acute stress decreased the phosphorylation of glycogen synthase kinase-3β (GSK-3β) at Ser9 in the hippocampus, and flupirtine inhibited the reduction. These results suggest that the KCNQ/Kv7 channels may be a potential target for protecting both hippocampal synaptic plasticity and spatial memory retrieval from acute stress influences. PMID:25234320

  10. BDNF mechanisms in late LTP formation: A synthesis and breakdown.

    PubMed

    Panja, Debabrata; Bramham, Clive R

    2014-01-01

    Unraveling the molecular mechanisms governing long-term synaptic plasticity is a key to understanding how the brain stores information in neural circuits and adapts to a changing environment. Brain-derived neurotrophic factor (BDNF) has emerged as a regulator of stable, late phase long-term potentiation (L-LTP) at excitatory glutamatergic synapses in the adult brain. However, the mechanisms by which BDNF triggers L-LTP are controversial. Here, we distill and discuss the latest advances along three main lines: 1) TrkB receptor-coupled translational control underlying dendritic protein synthesis and L-LTP, 2) Mechanisms for BDNF-induced rescue of L-LTP when protein synthesis is blocked, and 3) BDNF-TrkB regulation of actin cytoskeletal dynamics in dendritic spines. Finally, we explore the inter-relationships between BDNF-regulated mechanisms, how these mechanisms contribute to different forms of L-LTP in the hippocampus and dentate gyrus, and outline outstanding issues for future research. This article is part of the Special Issue entitled 'BDNF Regulation of Synaptic Structure, Function, and Plasticity'. PMID:23831365

  11. Consensus Paper: Neuroimmune Mechanisms of Cerebellar Ataxias.

    PubMed

    Mitoma, Hiroshi; Adhikari, Keya; Aeschlimann, Daniel; Chattopadhyay, Partha; Hadjivassiliou, Marios; Hampe, Christiane S; Honnorat, Jérôme; Joubert, Bastien; Kakei, Shinji; Lee, Jongho; Manto, Mario; Matsunaga, Akiko; Mizusawa, Hidehiro; Nanri, Kazunori; Shanmugarajah, Priya; Yoneda, Makoto; Yuki, Nobuhiro

    2016-04-01

    In the last few years, a lot of publications suggested that disabling cerebellar ataxias may develop through immune-mediated mechanisms. In this consensus paper, we discuss the clinical features of the main described immune-mediated cerebellar ataxias and address their presumed pathogenesis. Immune-mediated cerebellar ataxias include cerebellar ataxia associated with anti-GAD antibodies, the cerebellar type of Hashimoto's encephalopathy, primary autoimmune cerebellar ataxia, gluten ataxia, Miller Fisher syndrome, ataxia associated with systemic lupus erythematosus, and paraneoplastic cerebellar degeneration. Humoral mechanisms, cell-mediated immunity, inflammation, and vascular injuries contribute to the cerebellar deficits in immune-mediated cerebellar ataxias. PMID:25823827

  12. Glutamatergic postsynaptic block by Pamphobeteus spider venoms in crayfish.

    PubMed

    Araque, A; Ferreira, W; Lucas, S; Buño, W

    1992-01-31

    The effects of toxins from venom glands of two south american spiders (Pamphobeteus platyomma and P. soracabae) on glutamatergic excitatory synaptic transmission were studied in the neuromuscular junction of the opener muscle of crayfish. The toxins selectively and reversibly blocked both excitatory postsynaptic currents and potentials in a dose-dependent manner. They also reversibly abolished glutamate-induced postsynaptic membrane depolarization. They had no effect on resting postsynaptic membrane conductance nor on postsynaptic voltage-gated currents. The synaptic facilitation and the frequency of miniature postsynaptic potentials were unaffected by the toxins, indicating that presynaptic events were not modified. Picrotoxin, a selective antagonist of the gamma-aminobutyric acid (GABA)A receptor, did not modify toxin effects. We conclude that both toxins specifically block the postsynaptic glutamate receptor-channel complex. PMID:1319261

  13. Postsynaptic Signal Transduction Models for Long-Term Potentiation and Depression

    PubMed Central

    Manninen, Tiina; Hituri, Katri; Kotaleski, Jeanette Hellgren; Blackwell, Kim T.; Linne, Marja-Leena

    2010-01-01

    More than a hundred biochemical species, activated by neurotransmitters binding to transmembrane receptors, are important in long-term potentiation (LTP) and long-term depression (LTD). To investigate which species and interactions are critical for synaptic plasticity, many computational postsynaptic signal transduction models have been developed. The models range from simple models with a single reversible reaction to detailed models with several hundred kinetic reactions. In this study, more than a hundred models are reviewed, and their features are compared and contrasted so that similarities and differences are more readily apparent. The models are classified according to the type of synaptic plasticity that is modeled (LTP or LTD) and whether they include diffusion or electrophysiological phenomena. Other characteristics that discriminate the models include the phase of synaptic plasticity modeled (induction, expression, or maintenance) and the simulation method used (deterministic or stochastic). We find that models are becoming increasingly sophisticated, by including stochastic properties, integrating with electrophysiological properties of entire neurons, or incorporating diffusion of signaling molecules. Simpler models continue to be developed because they are computationally efficient and allow theoretical analysis. The more complex models permit investigation of mechanisms underlying specific properties and experimental verification of model predictions. Nonetheless, it is difficult to fully comprehend the evolution of these models because (1) several models are not described in detail in the publications, (2) only a few models are provided in existing model databases, and (3) comparison to previous models is lacking. We conclude that the value of these models for understanding molecular mechanisms of synaptic plasticity is increasing and will be enhanced further with more complete descriptions and sharing of the published models. PMID:21188161

  14. Relative and absolute quantification of postsynaptic density proteome isolated from rat forebrain and cerebellum.

    PubMed

    Cheng, Dongmei; Hoogenraad, Casper C; Rush, John; Ramm, Elizabeth; Schlager, Max A; Duong, Duc M; Xu, Ping; Wijayawardana, Sameera R; Hanfelt, John; Nakagawa, Terunaga; Sheng, Morgan; Peng, Junmin

    2006-06-01

    The postsynaptic density (PSD) of central excitatory synapses is essential for postsynaptic signaling, and its components are heterogeneous among different neuronal subtypes and brain structures. Here we report large scale relative and absolute quantification of proteins in PSDs purified from adult rat forebrain and cerebellum. PSD protein profiles were determined using the cleavable ICAT strategy and LC-MS/MS. A total of 296 proteins were identified and quantified with 43 proteins exhibiting statistically significant abundance change between forebrain and cerebellum, indicating marked molecular heterogeneity of PSDs between different brain regions. Moreover we utilized absolute quantification strategy, in which synthetic isotope-labeled peptides were used as internal standards, to measure the molar abundance of 32 key PSD proteins in forebrain and cerebellum. These data confirm the abundance of calcium/calmodulin-dependent protein kinase II and PSD-95 and reveal unexpected stoichiometric ratios between glutamate receptors, scaffold proteins, and signaling molecules in the PSD. Our data also demonstrate that the absolute quantification method is well suited for targeted quantitative proteomic analysis. Overall this study delineates a crucial molecular difference between forebrain and cerebellar PSDs and provides a quantitative framework for measuring the molecular stoichiometry of the PSD. PMID:16507876

  15. Genetic perturbation of postsynaptic activity regulates synapse elimination in developing cerebellum

    PubMed Central

    Lorenzetto, Erika; Caselli, Luana; Feng, Guoping; Yuan, Weilong; Nerbonne, Jeanne M.; Sanes, Joshua R.; Buffelli, Mario

    2009-01-01

    In many parts of the vertebrate nervous system, synaptic connections are remodeled during early postnatal life. Neural activity plays an important role in regulating one such rearrangement, synapse elimination, in the developing neuromuscular system, but there is little direct evidence on roles of pre- or postsynaptic activity in regulating synapse elimination in the developing brain. To address this issue, we expressed a chloride channel-yellow fluorescent protein fusion in cerebellar Purkinje cells (PCs) of transgenic mice to decrease their excitability. We then assessed elimination of supernumerary climbing fiber inputs to PCs. Individual PCs are innervated by multiple climbing fibers at birth; all but one are eliminated during the first three postnatal weeks in wild-type mice, but multiple innervation persists for at least three months in the transgenic mice. The normal redistribution of climbing fiber synapses from PC somata to proximal dendrites was also blunted in transgenics. These results show that normal electrical activity of the postsynaptic cell is required for it to attain a mature innervation pattern. PMID:19805323

  16. Metronidazole induced cerebellar ataxia

    PubMed Central

    Hari, Aditya; Srikanth, B. Akshaya; Lakshmi, G. Sriranga

    2013-01-01

    Metronidazole is a widely used antimicrobial usually prescribed by many specialist doctors for a short duration of 10-15 days. Prolonged use of metronidazole is rare. The present case is of a patient who used the drug for 4 months and developed peripheral neuropathy, convulsions, and cerebellar ataxia. He was treated with diazepam and levetiracetam. The patient recovered completely following discontinuation of metronidazole. PMID:23833378

  17. LTP3 contributes to disease susceptibility in Arabidopsis by enhancing abscisic acid (ABA) biosynthesis.

    PubMed

    Gao, Shan; Guo, Wenya; Feng, Wen; Liu, Liang; Song, Xiaorui; Chen, Jian; Hou, Wei; Zhu, Hongxia; Tang, Saijun; Hu, Jian

    2016-04-01

    Several plant lipid transfer proteins (LTPs) act positively in plant disease resistance. Here, we show that LTP3 (At5g59320), a pathogen and abscisic acid (ABA)-induced gene, negatively regulates plant immunity in Arabidopsis. The overexpression of LTP3 (LTP3-OX) led to an enhanced susceptibility to virulent bacteria and compromised resistance to avirulent bacteria. On infection of LTP3-OX plants with Pseudomonas syringae pv. tomato, genes involved in ABA biosynthesis, NCED3 and AAO3, were highly induced, whereas salicylic acid (SA)-related genes, ICS1 and PR1, were down-regulated. Accordingly, in LTP3-OX plants, we observed increased ABA levels and decreased SA levels relative to the wild-type. We also showed that the LTP3 overexpression-mediated enhanced susceptibility was partially dependent on AAO3. Interestingly, loss of function of LTP3 (ltp3-1) did not affect ABA pathways, but resulted in PR1 gene induction and elevated SA levels, suggesting that LTP3 can negatively regulate SA in an ABA-independent manner. However, a double mutant consisting of ltp3-1 and silent LTP4 (ltp3/ltp4) showed reduced susceptibility to Pseudomonas and down-regulation of ABA biosynthesis genes, suggesting that LTP3 acts in a redundant manner with its closest homologue LTP4 by modulating the ABA pathway. Taken together, our data show that LTP3 is a novel negative regulator of plant immunity which acts through the manipulation of the ABA-SA balance. PMID:26123657

  18. The initiation of post-synaptic protrusions

    PubMed Central

    Hotulainen, Pirta; Saarikangas, Juha

    2016-01-01

    ABSTRACT The post-synaptic spines of neuronal dendrites are highly elaborate membrane protrusions. Their anatomy, stability and density are intimately linked to cognitive performance. The morphological transitions of spines are powered by coordinated polymerization of actin filaments against the plasma membrane, but how the membrane-associated polymerization is spatially and temporally regulated has remained ill defined. Here, we discuss our recent findings showing that dendritic spines can be initiated by direct membrane bending by the I-BAR protein MIM/Mtss1. This lipid phosphatidylinositol (PI(4,5)P2) signaling-activated membrane bending coordinated spatial actin assembly and promoted spine formation. From recent advances, we formulate a general model to discuss how spatially concentrated protein-lipid microdomains formed by multivalent interactions between lipids and actin/membrane regulatory proteins might launch cell protrusions. PMID:27489575

  19. Flavoprotein imaging in the cerebellar cortex in vivo: cellular and metabolic basis and insights into cerebellar function

    NASA Astrophysics Data System (ADS)

    Gao, Wangcai; Chen, Gang; Ebner, Timothy J.

    2009-02-01

    Flavoprotein autofluorescence is an activity dependent intrinsic signal. Flavoproteins are involved in the electron transport chain and change their fluorescence according to the cellular redox state. We have been using flavoprotein autofluorescence in the cerebellum to examine properties of cerebellar circuits. Studies have also focused on understanding the cellular and metabolic origins of this intrinsic optical signal. Parallel fiber stimulation evokes a beamlike response intersected by bands of decreased fluorescence. The beam response is biphasic, with an early fluorescence increase (light phase) followed by a slower decrease (dark phase). We show this signal originates from flavoproteins as determined by its wavelength selectivity and sensitivity to blockers of the electron transport chain. Selectively blocking glutamate receptors abolished the on-beam light phase with the dark phase remaining intact. This demonstrates that the light phase is due to postsynaptic neuronal activation and suggests the dark phase is primarily due to glial activation. The bands of reduced fluorescence intersecting the beam are primarily neuronal in origin, mediated by GABAergic transmission, and due to the inhibitory action of molecular layer interneurons on Purkinje cells and the interneurons themselves. This parasagittally organized molecular layer inhibition differentially modulates the spatial pattern of cerebellar cortical activity. Flavoprotein imaging also reveals the functional architectures underlying the responses to inferior olive and peripheral whisker pad stimulation. Therefore, flavoprotein autofluorescence imaging is providing new insights into cerebellar cortical function and neurometabolic coupling.

  20. R-Ras contributes to LTP and contextual discrimination.

    PubMed

    Darcy, M J; Jin, S-X; Feig, L A

    2014-09-26

    The ability to discriminate between closely related contexts is a specific form of hippocampal-dependent learning that may be impaired in certain neurodegenerative disorders such as Alzheimer's and Down Syndrome. However, signaling pathways regulating this form of learning are poorly understood. Previous studies have shown that the calcium-dependent exchange factor Ras-GRF1, an activator of Rac, Ras and R-Ras GTPases, is important for this form of learning and memory. Moreover, the ability to discriminate contexts was linked to the ability of Ras-GRF1 to promote high-frequency stimulation long-term potentiation (HFS-LTP) via the activation of p38 Map kinase. Here, we show that R-Ras is involved in this form of learning by using virally-delivered miRNAs targeting R-Ras into the CA1 region of the dorsal hippocampus and observing impaired contextual discrimination. Like the loss of GRF1, knockdown of R-Ras in the CA1 also impairs the induction of HFS-LTP and p38 Map kinase. Nevertheless, experiments indicate that this involvement of R-Ras in HFS-LTP that is required for contextual discrimination is independent of Ras-GRF1. Thus, R-Ras is a novel regulator of a form of hippocampal-dependent LTP as well as learning and memory that is affected in certain forms of neurodegenerative diseases. PMID:25043327

  1. Decoding BDNF-LTP coupling in cocaine addiction

    PubMed Central

    Mao, Li-Min; Fibuch, Eugene E; Wang, John Q.

    2010-01-01

    BDNF is a neurotrophic peptide that regulates synaptic plasticity. New work by Lu and coworkers in this issue of Neuron now identifies BDNF as a gatekeeper of synaptic and behavioral plasticity in cocaine sensitization. In the medial prefrontal cortex, upregulated BDNF facilitates LTP and contributes to neurobehavioral adaptations to psychostimulants. PMID:20890399

  2. Identification of an elaborate complex mediating postsynaptic inhibition.

    PubMed

    Uezu, Akiyoshi; Kanak, Daniel J; Bradshaw, Tyler W A; Soderblom, Erik J; Catavero, Christina M; Burette, Alain C; Weinberg, Richard J; Soderling, Scott H

    2016-09-01

    Inhibitory synapses dampen neuronal activity through postsynaptic hyperpolarization. The composition of the inhibitory postsynapse and the mechanistic basis of its regulation, however, remain poorly understood. We used an in vivo chemico-genetic proximity-labeling approach to discover inhibitory postsynaptic proteins. Quantitative mass spectrometry not only recapitulated known inhibitory postsynaptic proteins but also revealed a large network of new proteins, many of which are either implicated in neurodevelopmental disorders or are of unknown function. Clustered regularly interspaced short palindromic repeats (CRISPR) depletion of one of these previously uncharacterized proteins, InSyn1, led to decreased postsynaptic inhibitory sites, reduced the frequency of miniature inhibitory currents, and increased excitability in the hippocampus. Our findings uncover a rich and functionally diverse assemblage of previously unknown proteins that regulate postsynaptic inhibition and might contribute to developmental brain disorders. PMID:27609886

  3. [Cerebellar cognitive affective syndrome secondary to a cerebellar tumour].

    PubMed

    Domínguez-Carral, J; Carreras-Sáez, I; García-Peñas, J J; Fournier-Del Castillo, C; Villalobos-Reales, J

    2015-01-01

    Cerebellar cognitive affective syndrome is characterized by disturbances of executive function, impaired spatial cognition, linguistic difficulties, and personality change. The case of an 11 year old boy is presented, with behavior problems, learning difficulties and social interaction problems. In the physical examination he had poor visual contact, immature behavior, reduced expressive language and global motor disability with gait dyspraxia, with no defined cerebellar motor signs. In the neuropsychological evaluation he has a full scale overall intellectual quotient of 84, with signs of cerebellar cognitive affective syndrome. A tumour affecting inferior cerebellar vermis was observed in the magnetic resonance imaging, which had not significantly grown during 5 years of follow up. The cerebellum participates in controlling cognitive and affective functions. Cerebellar pathology must be considered in the differential diagnosis of children with cognitive or learning disorder with associated behavioral and emotional components. PMID:24954915

  4. Clinical manifestations of cerebellar disease.

    PubMed

    Javalkar, Vijayakumar; Khan, Misbba; Davis, Debra E

    2014-11-01

    Clinical manifestations of cerebellar disease include ataxia and tremor, as well as nystagmus, dysarthria, and cognitive dysfunction. Recognition of the cerebellar pattern of disease can aid in the prompt and correct diagnosis and lead to appropriate treatment and rehabilitation to minimize disability. PMID:25439285

  5. Expression of LTP genes in response to saline stress in rice seedlings.

    PubMed

    Moraes, G P; Benitez, L C; do Amaral, M N; Vighi, I L; Auler, P A; da Maia, L C; Bianchi, V J; Braga, E J B

    2015-01-01

    Saline stress is one of the primary factors limiting increased rice productivity in the southern region of Brazil. Farming can be affected by salinity that is due to both the origin of the soils as well as the irrigation water. Lipid transfer proteins (LTPs) have many physiological functions, including in the response to saline stress. Therefore, the objective of this study was to quantify the relative expression of 11 genetic isoforms that encode LTP1-type proteins in rice genotypes tolerant and sensitive to saline stress in the vegetative period. When the plants reached development stage V4, alternating irrigation was started with nutritive solution and water containing 150 mM NaCl. The LTP7 gene showed an increase in expression by 13.81-fold after 96 h of stress exposure in the saline-tolerant group, whereas the LTP10 gene expression level was increased by 71.10-fold after 96 h in the saline-sensitive group. The LTP26, LTP23, and LTP18 genes showed increased expression in both genotypes; however, the expression levels and response times were different. Thus, LTP7 and LTP10 showed the highest response to salinity. The LTP18, LTP23, and LTP26 genes were negatively correlated with the response to salinity. PMID:26345756

  6. Dopamine Induces LTP Differentially in Apical and Basal Dendrites through BDNF and Voltage-Dependent Calcium Channels

    ERIC Educational Resources Information Center

    Navakkode, Sheeja; Sajikumar, Sreedharan; Korte, Martin; Soong, Tuck Wah

    2012-01-01

    The dopaminergic modulation of long-term potentiation (LTP) has been studied well, but the mechanism by which dopamine induces LTP (DA-LTP) in CA1 pyramidal neurons is unknown. Here, we report that DA-LTP in basal dendrites is dependent while in apical dendrites it is independent of activation of L-type voltage-gated calcium channels (VDCC).…

  7. Distinct Single but Not Necessarily Repeated Tetanization Is Required to Induce Hippocampal Late-LTP in the Rat CA1

    ERIC Educational Resources Information Center

    Sajikumar, Sreedharan; Navakkode, Sheeja; Frey, Julietta U.

    2008-01-01

    The protein synthesis-dependent form of hippocampal long-term potentiation (late-LTP) is thought to underlie memory. Its induction requires a distinct stimulation strength, and the common opinion is that only repeated tetani result in late-LTP whereas as single tetanus only reveals a transient early-LTP. Properties of LTP induction were compared…

  8. Unexpected Magnetic Domain Behavior in LTP-MnBi

    SciTech Connect

    Nguyen, PK; Jin, S; Berkowitz, AE

    2013-07-01

    Low-temperature-phase MnBi (LTP-MnBi) has attracted much interest as a potential rare-earth-free permanent magnet material because of its high uniaxial magnetocrystalline anisotropy at room temperature, K approximate to 10(7) ergs/cc, and the unusual increase of anisotropy with increasing temperature, with an accompanying increasing coercive force (H-C) with temperature. However, due to the complex Mn-Bi phase diagram, bulk samples of LTP-MnBi with the optimum saturation moment, similar to 75-76 emu/g have been achieved only with zone-refined single crystals. We have prepared polycrystalline samples of LTP-MnBi by induction melting and annealing at 300 degrees C. The moment in 70 kOe is 73.5 emu/g, but H-C is only 50 Oe. This is quite surprising-the high saturation moment indicates the dominating presence of LTP-MnBi. Therefore, an H-C c of some significant fraction of 2K/M-S approximate to 30 kOe would seem reasonable in this polycrystalline sample. By examining "Bitter" patterns, we show that the sample is composed of similar to 50 - 100 mu m crystallites. The randomly oriented crystallites exhibit the variety of magnetic domain structures and orientations expected from the hexagonal-structured MnBi with its strong uniaxial anisotropy. Clearly, the reversal of magnetization in the sample proceeds by the low-field nucleation of reversed magnetization in each crystallite, rather than by a wall-pinning mechanism. When the annealed sample was milled into fine particles, H-C increased by several orders of magnitude, as expected.

  9. MULTIPLE FUNCTIONS LONG TRACE PROFILER (LTP-MF) FOR NATIONAL SYNCHROTRON RADIATION LABORATORY OF CHINA.

    SciTech Connect

    QIAN, S.; WANG, Q.; HONG, Y.; TAKACS, P.

    2005-07-31

    The Long Trace Profiler (LTP) is a useful optical metrology instrument for measuring the figure and slope error of cylindrical aspheres commonly used as synchrotron radiation (SR) optics. It is used extensively at a number of synchrotron radiation laboratories around the world. In order to improve SR beam line quality and resolution, the National Synchrotron Radiation Laboratory (NSRL) of China is developing a versatile LTP that can be used to measure both SR optics and more conventional ''normal'' optical surfaces. The optical metrology laboratories at Brookhaven National Laboratory (BNL) and NSRL are collaborating in developing a multiple functions LTP (LTP-MF). Characteristics of the LTP-MF are: a very compact and lightweight optical head, a large angular test range ({+-} 16 mad) and high accuracy. The LTP-MF can be used in various configurations: as a laboratory-based LTP, an in-situ LTP or penta-prism LTP, as an angle monitor, a portable LTP, and a small radius of curvature test instrument. The schematic design of the compact optical head and a new compact slide are introduced. Analysis of different measurements modes and systematic error correction methods are introduced.

  10. Regulatory function of Arabidopsis lipid transfer protein 1 (LTP1) in ethylene response and signaling.

    PubMed

    Wang, Honglin; Sun, Yue; Chang, Jianhong; Zheng, Fangfang; Pei, Haixia; Yi, Yanjun; Chang, Caren; Dong, Chun-Hai

    2016-07-01

    Ethylene as a gaseous plant hormone is directly involved in various processes during plant growth and development. Much is known regarding the ethylene receptors and regulatory factors in the ethylene signal transduction pathway. In Arabidopsis thaliana, REVERSION-TO-ETHYLENE SENSITIVITY1 (RTE1) can interact with and positively regulates the ethylene receptor ETHYLENE RESPONSE1 (ETR1). In this study we report the identification and characterization of an RTE1-interacting protein, a putative Arabidopsis lipid transfer protein 1 (LTP1) of unknown function. Through bimolecular fluorescence complementation, a direct molecular interaction between LTP1 and RTE1 was verified in planta. Analysis of an LTP1-GFP fusion in transgenic plants and plasmolysis experiments revealed that LTP1 is localized to the cytoplasm. Analysis of ethylene responses showed that the ltp1 knockout is hypersensitive to 1-aminocyclopropanecarboxylic acid (ACC), while LTP1 overexpression confers insensitivity. Analysis of double mutants etr1-2 ltp1 and rte1-3 ltp1 demonstrates a regulatory function of LTP1 in ethylene receptor signaling through the molecular association with RTE1. This study uncovers a novel function of Arabidopsis LTP1 in the regulation of ethylene response and signaling. PMID:27097903

  11. Automated cerebellar lobule segmentation with application to cerebellar structural analysis in cerebellar disease.

    PubMed

    Yang, Zhen; Ye, Chuyang; Bogovic, John A; Carass, Aaron; Jedynak, Bruno M; Ying, Sarah H; Prince, Jerry L

    2016-02-15

    The cerebellum plays an important role in both motor control and cognitive function. Cerebellar function is topographically organized and diseases that affect specific parts of the cerebellum are associated with specific patterns of symptoms. Accordingly, delineation and quantification of cerebellar sub-regions from magnetic resonance images are important in the study of cerebellar atrophy and associated functional losses. This paper describes an automated cerebellar lobule segmentation method based on a graph cut segmentation framework. Results from multi-atlas labeling and tissue classification contribute to the region terms in the graph cut energy function and boundary classification contributes to the boundary term in the energy function. A cerebellar parcellation is achieved by minimizing the energy function using the α-expansion technique. The proposed method was evaluated using a leave-one-out cross-validation on 15 subjects including both healthy controls and patients with cerebellar diseases. Based on reported Dice coefficients, the proposed method outperforms two state-of-the-art methods. The proposed method was then applied to 77 subjects to study the region-specific cerebellar structural differences in three spinocerebellar ataxia (SCA) genetic subtypes. Quantitative analysis of the lobule volumes shows distinct patterns of volume changes associated with different SCA subtypes consistent with known patterns of atrophy in these genetic subtypes. PMID:26408861

  12. Autosomal recessive cerebellar ataxias

    PubMed Central

    Palau, Francesc; Espinós, Carmen

    2006-01-01

    Autosomal recessive cerebellar ataxias (ARCA) are a heterogeneous group of rare neurological disorders involving both central and peripheral nervous system, and in some case other systems and organs, and characterized by degeneration or abnormal development of cerebellum and spinal cord, autosomal recessive inheritance and, in most cases, early onset occurring before the age of 20 years. This group encompasses a large number of rare diseases, the most frequent in Caucasian population being Friedreich ataxia (estimated prevalence 2–4/100,000), ataxia-telangiectasia (1–2.5/100,000) and early onset cerebellar ataxia with retained tendon reflexes (1/100,000). Other forms ARCA are much less common. Based on clinicogenetic criteria, five main types ARCA can be distinguished: congenital ataxias (developmental disorder), ataxias associated with metabolic disorders, ataxias with a DNA repair defect, degenerative ataxias, and ataxia associated with other features. These diseases are due to mutations in specific genes, some of which have been identified, such as frataxin in Friedreich ataxia, α-tocopherol transfer protein in ataxia with vitamin E deficiency (AVED), aprataxin in ataxia with oculomotor apraxia (AOA1), and senataxin in ataxia with oculomotor apraxia (AOA2). Clinical diagnosis is confirmed by ancillary tests such as neuroimaging (magnetic resonance imaging, scanning), electrophysiological examination, and mutation analysis when the causative gene is identified. Correct clinical and genetic diagnosis is important for appropriate genetic counseling and prognosis and, in some instances, pharmacological treatment. Due to autosomal recessive inheritance, previous familial history of affected individuals is unlikely. For most ARCA there is no specific drug treatment except for coenzyme Q10 deficiency and abetalipoproteinemia. PMID:17112370

  13. How Ca2+-permeable AMPA receptors, the kinase PKA, and the phosphatase PP2B are intertwined in synaptic LTP and LTD.

    PubMed

    Hell, Johannes W

    2016-01-01

    Both synaptic long-term potentiation (LTP) and long-term depression (LTD) are thought to be critical for memory formation. Dell'Acqua and co-workers now demonstrate that transient postsynaptic incorporation of Ca(2+)-permeable (CP) α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) is required for LTD in the exemplary hippocampal CA1 region in 2-week-old mice. Mechanistically, LTD depends on AKAP150-anchored protein kinase A (PKA) to promote the initial functional recruitment of CP-AMPARs during LTD induction and on AKAP150-anchored protein phosphatase 2B (PP2B) to trigger their subsequent removal as part of the lasting depression of synaptic transmission. PMID:27117250

  14. Speech prosody in cerebellar ataxia

    NASA Astrophysics Data System (ADS)

    Casper, Maureen

    The present study sought an acoustic signature for the speech disturbance recognized in cerebellar degeneration. Magnetic resonance imaging was used for a radiological rating of cerebellar involvement in six cerebellar ataxic dysarthric speakers. Acoustic measures of the [pap] syllables in contrastive prosodic conditions and of normal vs. brain-damaged patients were used to further our understanding both of the speech degeneration that accompanies cerebellar pathology and of speech motor control and movement in general. Pair-wise comparisons of the prosodic conditions within the normal group showed statistically significant differences for four prosodic contrasts. For three of the four contrasts analyzed, the normal speakers showed both longer durations and higher formant and fundamental frequency values in the more prominent first condition of the contrast. The acoustic measures of the normal prosodic contrast values were then used as a model to measure the degree of speech deterioration for individual cerebellar subjects. This estimate of speech deterioration as determined by individual differences between cerebellar and normal subjects' acoustic values of the four prosodic contrasts was used in correlation analyses with MRI ratings. Moderate correlations between speech deterioration and cerebellar atrophy were found in the measures of syllable duration and f0. A strong negative correlation was found for F1. Moreover, the normal model presented by these acoustic data allows for a description of the flexibility of task- oriented behavior in normal speech motor control. These data challenge spatio-temporal theory which explains movement as an artifact of time wherein longer durations predict more extreme movements and give further evidence for gestural internal dynamics of movement in which time emerges from articulatory events rather than dictating those events. This model provides a sensitive index of cerebellar pathology with quantitative acoustic

  15. Peel LTP (Pru p 3)--the major allergen of peach--is methylated. A proteomic study.

    PubMed

    Larocca, Marilena; Martelli, Giuseppe; Grossi, Gerarda; Padula, Maria Carmela; Riccio, Paolo; Rossano, Rocco

    2013-12-01

    Lipid transfer protein (LTP, Pru p 3) is the major allergen of peach (Prunus persica), and is in a greater abundance in the peel than in the pulp of the fruit. Peel LTP is more allergenic than pulp LTP, but it is not clear whether this is due to its specific allergenic properties or to its higher concentration. In this study, we have used a new one-step, rapid procedure for the purification of LTP from peel and pulp of four peach varieties [Gladys (white flesh), California (nectarine yellow flesh), Plusplus (yellow flesh), Red Fair (nectarine yellow flesh)] harvested in a field grown in Southern Italy. Purification was based on miniature reversed-phase chromatography, a procedure suitable for proteomic study. Proteomic analysis of purified LTPs revealed that the amino acid sequence of LTP was identical in all peach genotypes but, for the first time, peel LTP was found to be methylated. PMID:23871022

  16. The Characteristics of LTP Induced in Hippocampal Slices Are Dependent on Slice-Recovery Conditions

    ERIC Educational Resources Information Center

    Godaux, Emile; Ris, Laurence; Capron, Brigitte; Sindic, Christian

    2006-01-01

    In area CA1 of hippocampal slices which are allowed to recover from slicing "in interface" and where recordings are carried out in interface, a single 1-sec train of 100-Hz stimulation triggers a short-lasting long-term potentiation (S-LTP), which lasts 1-2 h, whereas multiple 1-sec trains induce a long-lasting LTP (L-LTP), which lasts several…

  17. NsLTP1 and NsLTP2 isoforms in soft wheat (Triticum aestivum Cv. Centauro) and farro (Triticum dicoccon Schrank) bran.

    PubMed

    Capocchi, Antonella; Fontanini, Debora; Muccilli, Vera; Cunsolo, Vincenzo; Saviozzi, Franco; Saletti, Rosaria; Lorenzi, Roberto; Foti, Salvatore; Galleschi, Luciano

    2005-10-01

    Isoforms of nonspecific lipid-transfer protein 1 (nsLTP1) and nonspecific lipid-transfer protein 2 (nsLTP2) were investigated in bran tissues isolated from caryopses of two cereal crops quite relevant for the Italian market, the cultivar Centauro of soft wheat (Triticum aestivum) and Italian emmer or farro (Triticum dicoccon Schrank). By sequential separation of the bran extracts on cation-exchange and gel filtration chromatographies, fractions containing only proteins belonging to the nsLTP1 and nsLTP2 classes were obtained. The proteins were roughly identified by SDS-PAGE and by immunoreactions in Western blotting experiments. By MALDI-MS and RP-HPLC/ESI-MS analyses we were able to show the presence of several LTP1 and LTP2 isoforms in the investigated species. Bioinformatic searches based on the determined Mr indicated that (i) two nsLTP1s already identified in T. aestivum have Mr and number of Cys residues identical to that of a 9.6 kDa protein present both in soft wheat cv. Centauro and in farro; (ii) two isoforms of nsLTP2 detected in T. aestivum have the same Mr and number of Cys residues of two 7 kDa proteins found in Centauro; and (iii) a nsLTP1 detected in Ambrosia artemisiifolia has Mr and number of Cys residues coincident to that of a 9.9 kDa protein found both in soft wheat cv. Centauro and in farro. PMID:16190659

  18. 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

  19. Dysfunctional cerebellar Purkinje cells contribute to autism-like behaviour in Shank2-deficient mice.

    PubMed

    Peter, Saša; Ten Brinke, Michiel M; Stedehouder, Jeffrey; Reinelt, Claudia M; Wu, Bin; Zhou, Haibo; Zhou, Kuikui; Boele, Henk-Jan; Kushner, Steven A; Lee, Min Goo; Schmeisser, Michael J; Boeckers, Tobias M; Schonewille, Martijn; Hoebeek, Freek E; De Zeeuw, Chris I

    2016-01-01

    Loss-of-function mutations in the gene encoding the postsynaptic scaffolding protein SHANK2 are a highly penetrant cause of autism spectrum disorders (ASD) involving cerebellum-related motor problems. Recent studies have implicated cerebellar pathology in the aetiology of ASD. Here we evaluate the possibility that cerebellar Purkinje cells (PCs) represent a critical locus of ASD-like pathophysiology in mice lacking Shank2. Absence of Shank2 impairs both PC intrinsic plasticity and induction of long-term potentiation at the parallel fibre to PC synapse. Moreover, inhibitory input onto PCs is significantly enhanced, most prominently in the posterior lobe where simple spike (SS) regularity is most affected. Using PC-specific Shank2 knockouts, we replicate alterations of SS regularity in vivo and establish cerebellar dependence of ASD-like behavioural phenotypes in motor learning and social interaction. These data highlight the importance of Shank2 for PC function, and support a model by which cerebellar pathology is prominent in certain forms of ASD. PMID:27581745

  20. Speech prosody in cerebellar ataxia.

    PubMed

    Casper, Maureen A; Raphael, Lawrence J; Harris, Katherine S; Geibel, Jennifer M

    2007-01-01

    Persons with cerebellar ataxia exhibit changes in physical coordination and speech and voice production. Previously, these alterations of speech and voice production were described primarily via perceptual coordinates. In this study, the spatial-temporal properties of syllable production were examined in 12 speakers, six of whom were healthy speakers and six with ataxia. The speaking task was designed to elicit six different prosodic conditions and four contrastive prosodic events. Distinct prosodic patterns were elicited by the examiner for cerebellar patients and healthy speakers. These utterances were digitally recorded and analysed acoustically and statistically. The healthy speakers showed statistically significant differences among all four prosodic contrasts. The normal model described by the prosodic contrasts provided a sensitive index of cerebellar pathology with quantitative acoustic analyses. A significant interaction between subject groups and prosodic conditions revealed a compromised prosody in cerebellar patients. Significant differences were found for durational parameters, F0 and formant frequencies. The cerebellar speakers demonstrated different patterns of syllable lengthening and syllable reduction from that of the healthy speakers. PMID:17613097

  1. Subcellular compartment-specific molecular diversity of pre- and postsynaptic GABAB-activated GIRK channels in Purkinje cells

    PubMed Central

    Fernández-Alacid, Laura; Aguado, Carolina; Ciruela, Francisco; Martín, Ricardo; Colón, José; Cabañero, María José; Gassmann, Martin; Watanabe, Masahiko; Shigemoto, Ryuichi; Wickman, Kevin; Bettler, Bernhard; Sánchez-Prieto, José; Luján, Rafael

    2009-01-01

    Activation of G protein-gated inwardly-rectifying K+ (GIRK or Kir3) channels by metabotropic gamma-aminobutyric acid (B) (GABAB) receptors is an essential signalling pathway controlling neuronal excitability and synaptic transmission in the brain. To investigate the relationship between GIRK channel subunits and GABAB receptors in cerebellar Purkinje cells at post- and pre-synaptic sites, we used biochemical, functional and immunohistochemical techniques. Co-immunoprecipitation analysis demonstrated that GIRK subunits are co-assembled with GABAB receptors in the cerebellum. Immunoelectron microscopy showed that the subunit composition of GIRK channels in Purkinje cell spines is compartment-dependent. Thus, at extrasynaptic sites GIRK channels are formed by GIRK1/GIRK2/GIRK3, postsynaptic densities contain GIRK2/GIRK3 and dendritic shafts contain GIRK1/GIRK3. The postsynaptic association of GIRK subunits with GABAB receptors in Purkinje cells is supported by the subcellular regulation of the ion channel and the receptor in mutant mice. At presynaptic sites, GIRK channels localized to parallel fibre terminals are formed by GIRK1/GIRK2/GIRK3 and co-localize with GABAB receptors. Consistent with this morphological evidence we demonstrate their functional interaction at axon terminals in the cerebellum by showing that GIRK channels play a role in the inhibition of glutamate release by GABAB receptors. The association of GIRK channels and GABAB receptors with excitatory synapses at both post- and presynaptic sites indicates their intimate involvement in the modulation of glutamatergic neurotransmission in the cerebellum. PMID:19558451

  2. Ataxias and Cerebellar or Spinocerebellar Degeneration

    MedlinePlus

    ... Awards Enhancing Diversity Find People About NINDS NINDS Ataxias and Cerebellar or Spinocerebellar Degeneration Information Page Synonym(s): ... Publications and Information Publicaciones en Español What are Ataxias and Cerebellar or Spinocerebellar Degeneration? Ataxia often occurs ...

  3. Temperate Streptococcus thermophilus phages expressing superinfection exclusion proteins of the Ltp type

    PubMed Central

    Ali, Yahya; Koberg, Sabrina; Heßner, Stefanie; Sun, Xingmin; Rabe, Björn; Back, Angela; Neve, Horst; Heller, Knut J.

    2014-01-01

    Lipoprotein Ltp encoded by temperate Streptococcus thermophilus phage TP-J34 is the prototype of the wide-spread family of host cell surface-exposed lipoproteins involved in superinfection exclusion (sie). When screening for other S. thermophilus phages expressing this type of lipoprotein, three temperate phages—TP-EW, TP-DSM20617, and TP-778—were isolated. In this communication we present the total nucleotide sequences of TP-J34 and TP-778L. For TP-EW, a phage almost identical to TP-J34, besides the ltp gene only the two regions of deviation from TP-J34 DNA were analyzed: the gene encoding the tail protein causing an assembly defect in TP-J34 and the gene encoding the lysin, which in TP-EW contains an intron. For TP-DSM20617 only the sequence of the lysogeny module containing the ltp gene was determined. The region showed high homology to the same region of TP-778. For TP-778 we could show that absence of the attR region resulted in aberrant excision of phage DNA. The amino acid sequence of mature LtpTP-EW was shown to be identical to that of mature LtpTP-J34, whereas the amino acid sequence of mature LtpTP-778 was shown to differ from mature LtpTP-J34 in eight amino acid positions. LtpTP-DSM20617 was shown to differ from LtpTP-778 in just one amino acid position. In contrast to LtpTP-J34, LtpTP-778 did not affect infection of lactococcal phage P008 instead increased activity against phage P001 was noticed. PMID:24659988

  4. Neuroligin-2 accelerates GABAergic synapse maturation in cerebellar granule cells.

    PubMed

    Fu, Zhanyan; Vicini, Stefano

    2009-09-01

    Neuroligins (NLGs) are postsynaptic cell adhesion molecules that are thought to function in synaptogenesis. To investigate the role of NLGs on synaptic transmission once the synapse is formed, we transfected neuroligin-2 (NLG-2) in cultured mouse cerebellar granule cells (CGCs), and recorded GABA(A) (gamma-aminobutyric acid) receptor mediated miniature postsynaptic currents (mIPSCs). NLG-2 transfected cells had mIPSCs with faster decay than matching GFP expressing controls at young culture ages (days in vitro, DIV7-8). Down-regulation of NLG-2 by the isoform specific shRNA-NLG-2 resulted in an opposite effect. We and others have shown that the switch of alpha subunits of GABA(A)Rs from alpha2/3 to alpha1 underlies developmental speeding of the IPSC decay in various CNS regions, including the cerebellum. To assess whether the reduced decay time of mIPSCs by NLG-2 is due to the recruitment of more alpha1 containing GABA(A)Rs at the synapses, we examined the prolongation of current decay by the Zolpidem, which has been shown to preferentially enhance the activity of alpha1 subunit-containing GABA channel. The application of Zolpidem resulted in a significantly greater prolongation kinetics of synaptic currents in NLG-2 over-expressing cells than control cells, suggesting that NLG-2 over-expression accelerates synapse maturation by promoting incorporation of the alpha1 subunit-containing GABA(A)Rs at postsynaptic sites in immature cells. In addition, the effect of NLG-2 on the speeding of decay time course of synaptic currents was abolished when we used CGC cultures from alpha1-/- mice. Lastly, to exclude the possibility that the fast decay of mIPSCs induced by NLG-2 could be also due to the impacts of NLG-2 on the GABA transient in synaptic cleft, we measured the sensitivity of mIPSCs to the fast-off competitive antagonists TPMPA. We found that TPMPA similarly inhibits mIPSCs in control and NLG-2 over-expressing CGCs both at young age (DIV8) and old age (DIV14) of

  5. Alcohol Withdrawal and Cerebellar Mitochondria.

    PubMed

    Jung, Marianna E

    2015-08-01

    Cerebellar disorders trigger the symptoms of movement problems, imbalance, incoordination, and frequent fall. Cerebellar disorders are shown in various CNS illnesses including a drinking disorder called alcoholism. Alcoholism is manifested as an inability to control drinking in spite of adverse consequences. Human and animal studies have shown that cerebellar symptoms persist even after complete abstinence from drinking. In particular, the abrupt termination (ethanol withdrawal) of long-term excessive ethanol consumption has shown to provoke a variety of neuronal and mitochondrial damage to the cerebellum. Upon ethanol withdrawal, excitatory neurotransmitter molecules such as glutamate are overly released in brain areas including cerebellum. This is particularly relevant to the cerebellar neuronal network as glutamate signals are projected to Purkinje neurons through granular cells that are the most populated neuronal type in CNS. This excitatory neuronal signal may be elevated by ethanol withdrawal stress, which promotes an increase in intracellular Ca(2+) level and a decrease in a Ca(2+)-binding protein, both of which result in the excessive entry of Ca(2+) to the mitochondria. Subsequently, mitochondria undergo a prolonged opening of mitochondrial permeability transition pore and the overproduction of harmful free radicals, impeding adenosine triphosphate (ATP)-generating function. This in turn provokes the leakage of mitochondrial molecule cytochrome c to the cytosol, which triggers a cascade of adverse cytosol reactions. Upstream to this pathway, cerebellum under the condition of ethanol withdrawal has shown aberrant gene modifications through altered DNA methylation, histone acetylation, or microRNA expression. Interplay between these events and molecules may result in functional damage to cerebellar mitochondria and consequent neuronal degeneration, thereby contributing to motoric deficit. Mitochondria-targeting research may help develop a powerful new

  6. Visual experience induces long-term potentiation (LTP) in the primary visual cortex

    PubMed Central

    Cooke, Sam F.; Bear, Mark F.

    2010-01-01

    Stimulus-specific response potentiation (SRP) is a robust form of experience-dependent plasticity that occurs in primary visual cortex. In awake mice, visual evoked potentials (VEPs) recorded in layer 4 of binocular visual cortex undergo increases in amplitude with repeated presentation of a sinusoidal grating stimulus over days. This effect is highly specific to the experienced stimulus. Here, we test whether the mechanisms of thalamocortical LTP, induced with a theta-burst electrical stimulation (TBS) of the dorsal lateral geniculate nucleus (dLGN), are sufficient to account for SRP. First, we demonstrate that LTP similarly enhances the amplitude of VEPs, but in a way that generalizes across multiple stimuli, spatial frequencies, and contrasts. Second, we show that LTP occludes the subsequent expression of SRP. Third, we reveal that prior SRP occludes TBS-induced LTP of the VEP evoked by the experienced stimulus, but not by unfamiliar stimuli. Finally, we show that SRP is rapidly and selectively reversed by local cortical infusion of a peptide that inhibits PKMζ, a constitutively active kinase known to maintain NMDA receptor-dependent LTP and memory. Thus, SRP is expressed by the same core mechanisms as LTP. SRP therefore provides a simple assay to assess the integrity of LTP in the intact nervous system. Moreover, the results suggest that LTP of visual cortex, like SRP, can potentially be exploited to improve vision. PMID:21123576

  7. Effects of Ketamine on Neuronal Spontaneous Excitatory Postsynaptic Currents and Miniature Excitatory Postsynaptic Currents in the Somatosensory Cortex of Rats

    PubMed Central

    Yuan, Chengdong; Zhang, Yajun; Zhang, Yu; Cao, Song; Wang, Yuan; Fu, Bao; Yu, Tian

    2016-01-01

    Background: Ketamine is a commonly used intravenous anesthetic which produces dissociation anesthesia, analgesia, and amnesia. The mechanism of ketamine-induced synaptic inhibition in high-level cortical areas is still unknown. We aimed to elucidate the effects of different concentrations of ketamine on the glutamatergic synaptic transmission of the neurons in the primary somatosensory cortex by using the whole-cell patch-clamp method. Methods: Sprague-Dawley rats (11–19 postnatal days, n=36) were used to obtain brain slices (300 μM). Spontaneous excitatory postsynaptic currents (data from 40 neurons) were recorded at a command potential of -70 mV in the presence of bicuculline (a competitive antagonist of GABAA receptors, 30 μM) and strychnine (glycine receptor antagonist, 30 μM). Miniature excitatory postsynaptic currents (data from 40 neurons) were also recorded when 1 μM of tetrodotoxin was added into the artificial cerebrospinal fluid. We used GraphPad Prism5for statistical analysis. Significant differences in the mean amplitude and frequency were tested using the Student paired 2-tailed t test. Values of P<0.05 were considered significant. Results: Different concentrations of ketamine inhibited the frequency and amplitude of the spontaneous excitatory postsynaptic currents as well as the amplitude of the miniature excitatory postsynaptic currents in a concentration-dependent manner, but they exerted no significant effect on the frequency of the miniature excitatory postsynaptic currents. Conclusion: Ketamine inhibited the excitatory synaptic transmission of the neurons in the primary somatosensory cortex. The inhibition may have been mediated by a reduction in the sensitivity of the postsynaptic glutamatergic receptors. PMID:27365548

  8. The late maintenance of hippocampal LTP: requirements, phases, 'synaptic tagging', 'late-associativity' and implications.

    PubMed

    Reymann, Klaus G; Frey, Julietta U

    2007-01-01

    Our review focuses on the mechanisms which enable the late maintenance of hippocampal long-term potentiation (LTP; >3h), a phenomenon which is thought to underlie prolonged memory. About 20 years ago we showed for the first time that the maintenance of LTP - like memory storage--depends on intact protein synthesis and thus, consists of at least two temporal phases. Here we concentrate on mechanisms required for the induction of the transient early-LTP and of the protein synthesis-dependent late-LTP. Our group has shown that the induction of late-LTP requires the associative activation of heterosynaptic inputs, i.e. the synergistic activation of glutamatergic and modulatory, reinforcing inputs within specific, effective time windows. The induction of late-LTP is characterized by novel, late-associative properties such as 'synaptic tagging' and 'late-associative reinforcement'. Both phenomena require the associative setting of synaptic tags as well as the availability of plasticity-related proteins (PRPs) and they are restricted to functional dendritic compartments, in general. 'Synaptic tagging' guarantees input specificity and thus the specific processing of afferent signals for the establishment of late-LTP. 'Late-associative reinforcement' describes a process where early-LTP by the co-activation of modulatory inputs can be transformed into late-LTP in activated synapses where a tag is set. Recent evidence from behavioral experiments, which studied processes of emotional and cognitive reinforcement of LTP, point to the physiological relevance of the above mechanisms during cellular and system's memory formation. PMID:16919684

  9. The postsynaptic spectrin/4.1 membrane protein "accumulation machine".

    PubMed

    Baines, A J; Keating, L; Phillips, G W; Scott, C

    2001-01-01

    An important aspect of the function of the membrane-associated cytoskeleton has been suggested to be to trap and retain selected transmembrane proteins at points on the cell surface specified by cell adhesion molecules. In the process, cell adhesion molecules are cross-linked to each other, and so junctional complexes are strengthened. In this short review, we will discuss recent advances in understanding the role of this "accumulation machine" in postsynaptic structures. Function in the brain depends on correct ordering of synaptic intercellular junctions, and in particular the recruitment of receptors and other apparatus of the signalling system to postsynaptic membranes. Spectrin has long been known to be a component of postsynaptic densities, and recent advances in molecular cloning indicate that beta spectrins at PSDs are all "long" C-terminal isoforms characterised by pleckstrin homology domains. Isoforms of protein 4.1 are also present at synapses. All four 4.1 proteins are represented in PSD preparations, but it is 4.1R that is most enriched in PSDs. 4.1R binds to several proteins enriched in PSDs, including the characteristic PSD intermediate filament, alpha-internexin. Both 4.1 and spectrin interact with ionotropic glutamate receptors (AMPA and NMDA receptors, respectively): 4.1 stabilises AMPA receptors on the cell surface. By linking these receptors to the cytoskeletal and cell adhesion molecules that specify glutamatergic synapses, the membrane protein accumulation machine is suggested to direct the formation of postsynaptic signalling complexes. PMID:11598642

  10. [Clinical manifestations of cerebellar ataxias].

    PubMed

    Abdulkerimov, Kh T

    2003-01-01

    The analysis of clinical manifestations and focal symptoms in 18 patients with cerebellar ataxia (CA) has shown that these markers are not sufficient for making an accurate diagnosis in all CA cases. It is recommended to verify an ataxia form with objective methods, computed stabilography, in particular. PMID:12958853

  11. Orthostatic tremor: a cerebellar pathology?

    PubMed Central

    Popa, Traian; García-Lorenzo, Daniel; Valabregue, Romain; Legrand, André-Pierre; Apartis, Emmanuelle; Marais, Lea; Degos, Bertrand; Hubsch, Cecile; Fernández-Vidal, Sara; Bardinet, Eric; Roze, Emmanuel; Lehéricy, Stéphane; Meunier, Sabine; Vidailhet, Marie

    2016-01-01

    See Muthuraman et al. (doi:10.1093/aww164) for a scientific commentary on this article. Primary orthostatic tremor is characterized by high frequency tremor affecting the legs and trunk during the standing position. Cerebellar defects were suggested in orthostatic tremor without direct evidence. We aimed to characterize the anatomo-functional defects of the cerebellar motor pathways in orthostatic tremor. We used multimodal neuroimaging to compare 17 patients with orthostatic tremor and 17 age- and gender-matched healthy volunteers. Nine of the patients with orthostatic tremor underwent repetitive transcranial stimulation applied over the cerebellum during five consecutive days. We quantified the duration of standing position and tremor severity through electromyographic recordings. Compared to healthy volunteers, grey matter volume in patients with orthostatic tremor was (i) increased in the cerebellar vermis and correlated positively with the duration of the standing position; and (ii) increased in the supplementary motor area and decreased in the lateral cerebellum, which both correlated with the disease duration. Functional connectivity between the lateral cerebellum and the supplementary motor area was abnormally increased in patients with orthostatic tremor, and correlated positively with tremor severity. After repetitive transcranial stimulation, tremor severity and functional connectivity between the lateral cerebellum and the supplementary motor area were reduced. We provide an explanation for orthostatic tremor pathophysiology, and demonstrate the functional relevance of cerebello-thalamo-cortical connections in tremor related to cerebellar defects. PMID:27329770

  12. Speech Prosody in Cerebellar Ataxia

    ERIC Educational Resources Information Center

    Casper, Maureen A.; Raphael, Lawrence J.; Harris, Katherine S.; Geibel, Jennifer M.

    2007-01-01

    Persons with cerebellar ataxia exhibit changes in physical coordination and speech and voice production. Previously, these alterations of speech and voice production were described primarily via perceptual coordinates. In this study, the spatial-temporal properties of syllable production were examined in 12 speakers, six of whom were healthy…

  13. Theta Frequency Stimulation Induces a Local Form of Late Phase LTP in the CA1 Region of the Hippocampus

    ERIC Educational Resources Information Center

    Huang, Yan-You; Kandel, Eric R.

    2005-01-01

    The late phase of LTP (L-LTP) is typically induced by repeated high-frequency stimulation. This form of LTP requires activation of transcription and translation and results in the cell-wide distribution of gene products that can be captured by other marked synapses. Here we report that theta frequency stimulation (5 Hz, 30 sec) applied to the…

  14. The compartmental restriction of cerebellar interneurons

    PubMed Central

    Consalez, G. Giacomo; Hawkes, Richard

    2013-01-01

    The Purkinje cells (PC's) of the cerebellar cortex are subdivided into multiple different molecular phenotypes that form an elaborate array of parasagittal stripes. This array serves as a scaffold around which afferent topography is organized. The ways in which cerebellar interneurons may be restricted by this scaffolding are less well-understood. This review begins with a brief survey of cerebellar topography. Next, it reviews the development of stripes in the cerebellum with a particular emphasis on the embryological origins of cerebellar interneurons. These data serve as a foundation to discuss the hypothesis that cerebellar compartment boundaries also restrict cerebellar interneurons, both excitatory [granule cells, unipolar brush cells (UBCs)] and inhibitory (e.g., Golgi cells, basket cells). Finally, it is proposed that the same PC scaffold that restricts afferent terminal fields to stripes may also act to organize cerebellar interneurons. PMID:23346049

  15. Differential distribution of Shank and GKAP at the postsynaptic density.

    PubMed

    Tao-Cheng, Jung-Hwa; Yang, Yijung; Reese, Thomas S; Dosemeci, Ayse

    2015-01-01

    Shank and GKAP are scaffold proteins and binding partners at the postsynaptic density (PSD). The distribution and dynamics of Shank and GKAP were studied in dissociated hippocampal cultures by pre-embedding immunogold electron microscopy. Antibodies against epitopes containing their respective mutual binding sites were used to verify the expected juxtapositioning of Shank and GKAP. If all Shank and GKAP molecules at the PSD were bound to each other, the distribution of label for the two proteins should coincide. However, labels for the mutual binding sites showed significant differences in distribution, with a narrow distribution for GKAP located close to the postsynaptic membrane, and a wider distribution for Shank extending deeper into the cytoplasm. Upon depolarization with high K+, neither the intensity nor distribution of label for GKAP changed, but labeling intensity for Shank at the PSD increased to ~150% of controls while the median distance of label from postsynaptic membrane increased by 7.5 nm. These results indicate a preferential recruitment of Shank to more distal parts of the PSD complex. Conversely, upon incubation in Ca2+-free medium containing EGTA, the labeling intensity of Shank at the PSD decreased to ~70% of controls and the median distance of label from postsynaptic membrane decreased by 9 nm, indicating a preferential loss of Shank molecules in more distal parts of the PSD complex. These observations identify two pools of Shank at the PSD complex, one relatively stable pool, closer to the postsynaptic membrane that can bind to GKAP, and another more dynamic pool at a location too far away to bind to GKAP. PMID:25775468

  16. Differential Distribution of Shank and GKAP at the Postsynaptic Density

    PubMed Central

    Tao-Cheng, Jung-Hwa; Yang, Yijung; Reese, Thomas S.; Dosemeci, Ayse

    2015-01-01

    Shank and GKAP are scaffold proteins and binding partners at the postsynaptic density (PSD). The distribution and dynamics of Shank and GKAP were studied in dissociated hippocampal cultures by pre-embedding immunogold electron microscopy. Antibodies against epitopes containing their respective mutual binding sites were used to verify the expected juxtapositioning of Shank and GKAP. If all Shank and GKAP molecules at the PSD were bound to each other, the distribution of label for the two proteins should coincide. However, labels for the mutual binding sites showed significant differences in distribution, with a narrow distribution for GKAP located close to the postsynaptic membrane, and a wider distribution for Shank extending deeper into the cytoplasm. Upon depolarization with high K+, neither the intensity nor distribution of label for GKAP changed, but labeling intensity for Shank at the PSD increased to ~150% of controls while the median distance of label from postsynaptic membrane increased by 7.5 nm. These results indicate a preferential recruitment of Shank to more distal parts of the PSD complex. Conversely, upon incubation in Ca2+-free medium containing EGTA, the labeling intensity of Shank at the PSD decreased to ~70% of controls and the median distance of label from postsynaptic membrane decreased by 9 nm, indicating a preferential loss of Shank molecules in more distal parts of the PSD complex. These observations identify two pools of Shank at the PSD complex, one relatively stable pool, closer to the postsynaptic membrane that can bind to GKAP, and another more dynamic pool at a location too far away to bind to GKAP. PMID:25775468

  17. Long-Term Spatiotemporal Reconfiguration of Neuronal Activity Revealed by Voltage-Sensitive Dye Imaging in the Cerebellar Granular Layer.

    PubMed

    Gandolfi, Daniela; Mapelli, Jonathan; D'Angelo, Egidio

    2015-01-01

    Understanding the spatiotemporal organization of long-term synaptic plasticity in neuronal networks demands techniques capable of monitoring changes in synaptic responsiveness over extended multineuronal structures. Among these techniques, voltage-sensitive dye imaging (VSD imaging) is of particular interest due to its good spatial resolution. However, improvements of the technique are needed in order to overcome limits imposed by its low signal-to-noise ratio. Here, we show that VSD imaging can detect long-term potentiation (LTP) and long-term depression (LTD) in acute cerebellar slices. Combined VSD imaging and patch-clamp recordings revealed that the most excited regions were predominantly associated with granule cells (GrCs) generating EPSP-spike complexes, while poorly responding regions were associated with GrCs generating EPSPs only. The correspondence with cellular changes occurring during LTP and LTD was highlighted by a vector representation obtained by combining amplitude with time-to-peak of VSD signals. This showed that LTP occurred in the most excited regions lying in the core of activated areas and increased the number of EPSP-spike complexes, while LTD occurred in the less excited regions lying in the surround. VSD imaging appears to be an efficient tool for investigating how synaptic plasticity contributes to the reorganization of multineuronal activity in neuronal circuits. PMID:26294979

  18. Destabilization of the Postsynaptic Density by PSD-95 Serine 73 Phosphorylation Inhibits Spine Growth and Synaptic Plasticity

    PubMed Central

    Steiner, Pascal; Higley, Michael J.; Xu, Weifeng; Czervionke, Brian L.; Malenka, Robert C.; Sabatini, Bernardo L.

    2009-01-01

    SUMMARY Long-term potentiation (LTP) is accompanied by dendritic spine growth and changes in the composition of the postsynaptic density (PSD). We find that activity-dependent growth of apical spines of CA1 pyramidal neurons is accompanied by destabilization of the PSD that results in transient loss and rapid replacement of PSD-95 and SHANK2. Signaling through PSD-95 is required for activity-dependent spine growth and trafficking of SHANK2. N-terminal PDZ and C-terminal guanylate kinase domains of PSD-95 are required for both processes, indicating that PSD-95 coordinates multiple signals to regulate morphological plasticity. Activity-dependent trafficking of PSD-95 is triggered by phosphorylation at serine 73, a conserved calcium/calmodulin-dependent protein kinase II (CaMKII) consensus phosphorylation site, which negatively regulates spine growth and potentiation of synaptic currents. We propose that PSD-95 and CaMKII act at multiple steps during plasticity induction to initially trigger and later terminate spine growth by trafficking growth-promoting PSD proteins out of the active spine. PMID:19081375

  19. Early postnatal nicotine exposure causes hippocampus-dependent memory impairments in adolescent mice: association with altered nicotinic cholinergic modulation of LTP, but not impaired LTP

    PubMed Central

    Nakauchi, Sakura; Malvaez, Melissa; Su, Hailing; Kleeman, Elise; Dang, Richard; Wood, Marcelo A.; Sumikawa, Katumi

    2014-01-01

    Fetal nicotine exposure from smoking during pregnancy causes long-lasting cognitive impairments in offspring, yet little is known about the mechanisms that underlie this effect. Here we demonstrate that early postnatal exposure of mouse pups to nicotine via maternal milk impairs long-term, but not short-term, hippocampus-dependent memory during adolescence. At the Schaffer collateral (SC) pathway, the most widely studied synapses for a cellular correlate of hippocampus-dependent memory, the induction of N-methyl-d-aspartate receptor-dependent transient long-term potentiation (LTP) and protein synthesis-dependent long-lasting LTP are not diminished by nicotine exposure, but rather unexpectedly the threshold for LTP induction becomes lower after nicotine treatment. Using voltage sensitive dye to visualize hippocampal activity, we found that early postnatal nicotine exposure also results in enhanced CA1 depolarization and hyperpolarization after SC stimulation. Furthermore, we show that postnatal nicotine exposure induces pervasive changes to the nicotinic modulation of CA1 activity: activation of nicotinic receptors no longer increases CA1 network depolarization, acute nicotine inhibits rather than facilitates the induction of LTP at the SC pathway by recruiting an additional nicotinic receptor subtype, and acute nicotine no longer blocks LTP induction at the temporoammonic pathway. These findings reflect the pervasive impact of nicotine exposure during hippocampal development, and demonstrate an association of hippocampal memory impairments with altered nicotinic cholinergic modulation of LTP, but not impaired LTP. The implication of our results is that nicotinic cholinergic-dependent plasticity is required for long-term memory formation and that postnatal nicotine exposure disrupts this form of plasticity. PMID:25545599

  20. Tobacco NtLTP1, a glandular-specific lipid transfer protein, is required for lipid secretion from glandular trichomes.

    PubMed

    Choi, Yong Eui; Lim, Soon; Kim, Hyun-Jung; Han, Jung Yeon; Lee, Mi-Hyun; Yang, Yanyan; Kim, Ji-Ah; Kim, Yun-Soo

    2012-05-01

    Glandular trichomes are the phytochemical factories of plants, and they secrete a wide range of commercially important natural products such as lipids, terpenes and flavonoids. Herein, we report that the Nicotiana tabacum LTP1 (NtLTP1) gene, which is specifically expressed in long glandular trichomes, plays a role in lipid secretion from trichome heads. NtLTP1 mRNA is abundantly transcribed in trichomes, but NtLTP3, NtLTP4 and NtLTP5 are not. In situ hybridization revealed that NtLTP1 mRNAs accumulate specifically in long trichomes and not in short trichomes or epidermal cells. X-gluc staining of leaves from a transgenic plant expressing the NtLTP1 promoter fused to a GUS gene revealed that NtLTP1 protein accumulated preferentially on the tops of long glandular trichomes. GFP fluorescence from transgenic tobacco plants expressing an NtLTP1-GFP fusion protein was localized at the periphery of cells and in the excreted liquid droplets from the glandular trichome heads. In vitro assays using a fluorescent 2-p-toluidinonaphthalene-6-sulfonate probe indicated that recombinant NtLTP1 had lipid-binding activity. The overexpression of NtLTP1 in transgenic tobacco plants resulted in the increased secretion of trichome exudates, including epicuticular wax. In transgenic NtLTP1-RNAi lines, liquid secretion from trichomes was strongly reduced, but epicuticular wax secretion was not altered. Moreover, transgenic tobacco plants overexpressing NtLTP1 showed increased protection against aphids. Taken together, these data suggest that NtLTP1 is abundantly expressed in long glandular trichomes, and may play a role in lipid secretion from long glandular trichomes. PMID:22171964

  1. Drosophila Lipophorin Receptors Recruit the Lipoprotein LTP to the Plasma Membrane to Mediate Lipid Uptake

    PubMed Central

    Rodríguez-Vázquez, Míriam; Mejía-Morales, John E.; Culi, Joaquim

    2015-01-01

    Lipophorin, the main Drosophila lipoprotein, circulates in the hemolymph transporting lipids between organs following routes that must adapt to changing physiological requirements. Lipophorin receptors expressed in developmentally dynamic patterns in tissues such as imaginal discs, oenocytes and ovaries control the timing and tissular distribution of lipid uptake. Using an affinity purification strategy, we identified a novel ligand for the lipophorin receptors, the circulating lipoprotein Lipid Transfer Particle (LTP). We show that specific isoforms of the lipophorin receptors mediate the extracellular accumulation of LTP in imaginal discs and ovaries. The interaction requires the LA-1 module in the lipophorin receptors and is strengthened by a contiguous region of 16 conserved amino acids. Lipophorin receptor variants that do not interact with LTP cannot mediate lipid uptake, revealing an essential role of LTP in the process. In addition, we show that lipophorin associates with the lipophorin receptors and with the extracellular matrix through weak interactions. However, during lipophorin receptor-mediated lipid uptake, LTP is required for a transient stabilization of lipophorin in the basolateral plasma membrane of imaginal disc cells. Together, our data suggests a molecular mechanism by which the lipophorin receptors tether LTP to the plasma membrane in lipid acceptor tissues. LTP would interact with lipophorin particles adsorbed to the extracellular matrix and with the plasma membrane, catalyzing the exchange of lipids between them. PMID:26121667

  2. State-Dependent Partial Occlusion of Cortical LTP-Like Plasticity in Major Depression.

    PubMed

    Kuhn, Marion; Mainberger, Florian; Feige, Bernd; Maier, Jonathan G; Mall, Volker; Jung, Nicolai H; Reis, Janine; Klöppel, Stefan; Normann, Claus; Nissen, Christoph

    2016-05-01

    The synaptic plasticity hypothesis of major depressive disorder (MDD) posits that alterations in synaptic plasticity represent a final common pathway underlying the clinical symptoms of the disorder. This study tested the hypotheses that patients with MDD show an attenuation of cortical synaptic long-term potentiation (LTP)-like plasticity in comparison with healthy controls, and that this attenuation recovers after remission. Cortical synaptic LTP-like plasticity was measured using a transcranial magnetic stimulation protocol, ie, paired associative stimulation (PAS), in 27 in-patients with MDD according to ICD-10 criteria and 27 sex- and age-matched healthy controls. The amplitude of motor-evoked potentials was measured before and after PAS. Patients were assessed during the acute episode and at follow-up to determine the state- or trait-character of LTP-like changes. LTP-like plasticity, the PAS-induced increase in motor-evoked potential amplitudes, was significantly attenuated in patients with an acute episode of MDD compared with healthy controls. Patients with remission showed a restoration of synaptic plasticity, whereas the deficits persisted in patients without remission, indicative for a state-character of impaired LTP-like plasticity. The results provide first evidence for a state-dependent partial occlusion of cortical LTP-like plasticity in MDD. This further identifies impaired LTP-like plasticity as a potential pathomechanism and treatment target of the disorder. PMID:26442602

  3. Expression of GFP-tagged neuronal glutamate transporters in cerebellar Purkinje neurons.

    PubMed

    Meera, Pratap; Dodson, Paul D; Karakossian, Movses H; Otis, Thomas S

    2005-11-01

    Of the five excitatory amino acid transporters (EAATs) identified, two genes are expressed by neurons (EAAT3 and EAAT4) and give rise to transporters confined to neuronal cell bodies and dendrites. At an ultrastructural level, EAAT3 and EAAT4 proteins are clustered at the edges of postsynaptic densities of excitatory synapses. This pattern of localization suggests that postsynaptic EAATs may help to limit spillover of glutamate from excitatory synapses. In an effort to study transporter localization in living neurons and ultimately to manipulate uptake at intact synapses, we have developed viral reagents encoding neuronal EAATs tagged with GFP. We demonstrate that these fusion proteins are capable of Na(+)-dependent glutamate uptake, that they generate ionic conductances indistinguishable from their wild-type counterparts, and that GFP does not alter their glutamate dose-dependence. Two-photon microscopy was used to examine fusion protein expression in Purkinje neurons in acute cerebellar slices. Both EAAT3-GFP and EAAT4-GFP were observed at high levels in the dendritic spines of transfected Purkinje neurons. These findings indicate that functional EAAT fusion proteins can be synthesized and appropriately trafficked to postsynaptic compartments. Furthermore, they validate a powerful system for looking at EAAT function in situ. PMID:16212990

  4. Improved immunohistochemical detection of postsynaptically located PSD-95/SAP90 protein family by protease section pretreatment: a study in the adult mouse brain.

    PubMed

    Fukaya, M; Watanabe, M

    2000-10-30

    Postsynaptic density (PSD)-95, SAP102, and Chapsyn-110 are members of the PSD-95/SAP90 protein family, which interact with the C-terminus of N-methyl-D-aspartate (NMDA) receptor and shaker-type potassium channel subunits. Here we report that appropriate section pretreatment with pepsin has led to qualitative and quantitative changes in light microscopic immunohistochemical detection of the protein family. First, pepsin pretreatment lowered the concentration of affinity-purified primary antibodies, while it greatly increased the intensity of immunoreactions. Second, the resulting overall distributions of PSD-95, SAP102, and Chapsyn-110 in the adult mouse brain were consistent with their mRNA distributions. Third, instead of the reported patterns of somatodendritic labeling, tiny punctate staining in the neuropil became overwhelming. Fourth, many PSD-95-immunopositive puncta were apposed closely to synaptophysin-positive nerve terminals and overlapped with NMDA receptor subunits. By postembedding immunogold, the PSD-95 antibody was shown to label exclusively the postsynaptic density at asymmetrical synapses. Based on these results, we conclude that antibody access and binding to the postsynaptically located PSD-95/SAP90 protein family are hindered when conventional immunohistochemistry is adopted, and that pepsin pretreatment effectively unmasks the postsynaptic epitopes. On the other hand, PSD-95 in axon terminals of cerebellar basket cells, where high levels of potassium channels are present, was detectable irrespective of pepsin pretreatment, suggesting that PSD-95 antibody is readily accessible to the presynaptic epitopes. Consequently, the present immunohistochemical results have provided light microscopic evidence supporting the prevailing notion that the PSD-95/SAP90 protein family interacts with NMDA receptor subunits and potassium channel subunits. PMID:11027400

  5. Cerebellar mature teratoma in adulthood.

    PubMed

    Zavanone, M; Alimehmeti, R; Campanella, R; Ram-Pini, P; Locatelli, M; Egidi, M; Righini, A; Bauer, D

    2002-03-01

    Mature teratoma of the posterior cranial fossa in adults is extremely rare. We report a particularly rare case of medio-lateral cerebellar mature teratoma that became symptomatic in a middle-aged man. The CT revealed the lesion of heterogeneous density with calcifications in the solid medial portion. Only the MRI could reliably define the borders of the cystic component extending into the left cerebellar lobe. Histologically the presence of fully matured representative tissues of the 3 germ layers ensured the diagnosis of mature teratoma. We suggest that the cyst formation from progressive latent hemorrhage and/or secretion from the gland cells of the tumor, may be responsible for the clinical decompensation even in adulthood. PMID:12118223

  6. The Postsynaptic Density: There Is More than Meets the Eye.

    PubMed

    Dosemeci, Ayse; Weinberg, Richard J; Reese, Thomas S; Tao-Cheng, Jung-Hwa

    2016-01-01

    The postsynaptic density (PSD), apparent in electron micrographs as a dense lamina just beneath the postsynaptic membrane, includes a deeper layer, the "pallium", containing a scaffold of Shank and Homer proteins. Though poorly defined in traditionally prepared thin-section electron micrographs, the pallium becomes denser and more conspicuous during intense synaptic activity, due to the reversible addition of CaMKII and other proteins. In this Perspective article, we review the significance of CaMKII-mediated recruitment of proteins to the pallium with respect to both the trafficking of receptors and the remodeling of spine shape that follow synaptic stimulation. We suggest that the level and duration of CaMKII translocation and activation in the pallium will shape activity-induced changes in the spine. PMID:27594834

  7. The Postsynaptic Density: There Is More than Meets the Eye

    PubMed Central

    Dosemeci, Ayse; Weinberg, Richard J.; Reese, Thomas S.; Tao-Cheng, Jung-Hwa

    2016-01-01

    The postsynaptic density (PSD), apparent in electron micrographs as a dense lamina just beneath the postsynaptic membrane, includes a deeper layer, the “pallium”, containing a scaffold of Shank and Homer proteins. Though poorly defined in traditionally prepared thin-section electron micrographs, the pallium becomes denser and more conspicuous during intense synaptic activity, due to the reversible addition of CaMKII and other proteins. In this Perspective article, we review the significance of CaMKII-mediated recruitment of proteins to the pallium with respect to both the trafficking of receptors and the remodeling of spine shape that follow synaptic stimulation. We suggest that the level and duration of CaMKII translocation and activation in the pallium will shape activity-induced changes in the spine. PMID:27594834

  8. Cerebellar neurocognition and Korsakoff's syndrome: an hypothesis.

    PubMed

    Wijnia, Jan W; Goossensen, Anne

    2010-08-01

    In literature, the cerebellum is given a substantial role in cognitive processes, in addition to traditional views on cerebellar function of regulating motor behaviour. The phenomenon of cerebellar damage causing impairments in memory and executive functioning was observed in various cerebellar disorders. Cerebellar cognitive dysfunction can be interpreted as a disturbance of cerebello-cerebral connections to areas of the cerebral cortex involved in cognitive processing, but the exact nature of the cognitive dysregulation is not known. Memory and executive dysfunction are important clinical features of Korsakoff's syndrome. We hypothesize that the Korsakoff syndrome might be an example of cerebellar neurocognitive dysfunctioning, caused by cerebello-cerebral pathways being disconnected in brain areas that are classically affected in Wernicke's encephalopathy. Further research is needed to support the possibility of cerebellar neurocognitive disturbances in Korsakoff's syndrome. If correct, this hypothesis may contribute to a better understanding of the clinical and neuropsychological profile of Korsakoff's syndrome. PMID:20303220

  9. Serotoninergic dorsal raphe neurons possess functional postsynaptic nicotinic acetylcholine receptors.

    PubMed

    Galindo-Charles, Luis; Hernandez-Lopez, Salvador; Galarraga, Elvira; Tapia, Dagoberto; Bargas, José; Garduño, Julieta; Frías-Dominguez, Carmen; Drucker-Colin, René; Mihailescu, Stefan

    2008-08-01

    Very few neurons in the telencephalon have been shown to express functional postsynaptic nicotinic acetylcholine receptors (nAChRs), among them, the noradrenergic and dopaminergic neurons. However, there is no evidence for postsynaptic nAChRs on serotonergic neurons. In this study, we asked if functional nAChRs are present in serotonergic (5-HT) and nonserotonergic (non-5-HT) neurons of the dorsal raphe nucleus (DRN). In rat midbrain slices, field stimulation at the tegmental pedunculopontine (PPT) nucleus evoked postsynaptic currents (eEPSCs) with different components in DRN neurons. After blocking the glutamatergic and GABAergic components, the remaining eEPSCs were blocked by mecamylamine and reduced by either the selective alpha7 nAChR antagonist methyllycaconitine (MLA) or the selective alpha4beta2 nAChR antagonist dihydro-beta-eritroidine (DHbetaE). Simultaneous addition of MLA and DHbetaE blocked all eEPSCs. Integrity of the PPT-DRN pathway was assessed by both anterograde biocytin tracing and antidromic stimulation from the DRN. Inward currents evoked by the direct application of acetylcholine (ACh), in the presence of atropine and tetrodotoxin, consisted of two kinetically different currents: one was blocked by MLA and the other by DHbetaE; in both 5-HT and non-5-HT DR neurons. Analysis of spontaneous (sEPSCs) and evoked (eEPSCs) synaptic events led to the conclusion that nAChRs were located at the postsynaptic membrane. The possible implications of these newly described nAChRs in various physiological processes and behavioral events, such as the wake-sleep cycle, are discussed. PMID:18512214

  10. Towards a quantitative model of the post-synaptic proteome.

    PubMed

    Sorokina, Oksana; Sorokin, Anatoly; Armstrong, J Douglas

    2011-10-01

    The postsynaptic compartment of the excitatory glutamatergic synapse contains hundreds of distinct polypeptides with a wide range of functions (signalling, trafficking, cell-adhesion, etc.). Structural dynamics in the post-synaptic density (PSD) are believed to underpin cognitive processes. Although functionally and morphologically diverse, PSD proteins are generally enriched with specific domains, which precisely define the mode of clustering essential for signal processing. We applied a stochastic calculus of domain binding provided by a rule-based modelling approach to formalise the highly combinatorial signalling pathway in the PSD and perform the numerical analysis of the relative distribution of protein complexes and their sizes. We specified the combinatorics of protein interactions in the PSD by rules, taking into account protein domain structure, specific domain affinity and relative protein availability. With this model we interrogated the critical conditions for the protein aggregation into large complexes and distribution of both size and composition. The presented approach extends existing qualitative protein-protein interaction maps by considering the quantitative information for stoichiometry and binding properties for the elements of the network. This results in a more realistic view of the postsynaptic proteome at the molecular level. PMID:21874189

  11. Spino-olivary projections in the rat are anatomically separate from postsynaptic dorsal column projections.

    PubMed

    Flavell, Charlotte R; Cerminara, Nadia L; Apps, Richard; Lumb, Bridget M

    2014-06-15

    The gracile nucleus (GN) and lateral part of rostral dorsal accessory olive (rDAO) are important relays for indirect, postsynaptic dorsal column, and direct ascending pathways, respectively, that terminate as climbing fibers in the "hindlimb-receiving" parts of the C1 and C3 zones in the cerebellar cortex. While the spinal cells of origin of that project to GN and rDAO are from largely separate territories in the spinal cord, previous studies have indicated that there could be an area of overlap between these two populations in the medial dorsal horn. Given the access of these two ascending tracts to sensory (thalamic) versus sensorimotor (precerebellar) pathways, the present study therefore addresses the important question of whether or not individual neurons have the potential to contribute axons to both ascending pathways. A double-fluorescent tracer strategy was used in rats (red Retrobeads and Fluoro-Ruby or green Retrobeads and Fluoro-Emerald) to map the spatial distribution of cells of origin of the two projections in the lumbar spinal cord. The two pathways were found to receive input from almost entirely separate territories within the lumbar cord (levels L3-L5). GN predominantly receives input from lamina IV, while rDAO receives its input from three cell populations: medial laminae V-VI, lateral lamina V, and medial laminae VII-VIII. Cells that had axons that branched to supply both GN and rDAO represented only about 1% of either single-labeled cell population. Overall, the findings therefore suggest functional independence of the two ascending pathways. PMID:24357064

  12. Frequency dependent activation of a slow N-methyl-D-aspartate-dependent excitatory postsynaptic potential in turtle cerebellum by mossy fibre afferents.

    PubMed

    Larson-Prior, L J; Morrison, P D; Bushey, R M; Slater, N T

    1995-08-01

    The synaptic responses of turtle cerebellar Purkinje cells to stimulation of localized mossy fibre systems have been studied by use of intrasomatic and intradendritic recordings in a brainstem-cerebellum preparation in vitro. Activation of mossy fibre inputs from the spinocerebellar pathway evoked fast, disynaptic postsynaptic potentials which were graded in amplitude with stimulus intensity and elicited at latencies consistent with those reported for peripheral nerve stimulation. Repetitive activation (50-100 Hz, 2-10 stimuli) of both spinocerebellar and trigeminocerebellar pathways evoked a slow, long-lasting excitatory postsynaptic potential regardless of whether single stimuli resulted in excitatory, inhibitory, or no postsynaptic responses. This slow potential was capable of triggering dendritic pacemaker discharges in recorded Purkinje cells in addition to volleys of simple spikes when activated at or near resting membrane potential. The fast excitatory synaptic potentials evoked by spinocerebellar stimulation were blocked by the glutamate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione, consistent with the hypothesis that they are mediated by activation of ionotropic glutamate receptors of the alpha-amino-3-hydroxy-5-methylisox-azole-4-proprionic acid subtype at the mossy fibre-granule cell synapse and the subsequent parallel fibre-Purkinje cell synapse. The slow excitatory synaptic potential evoked by repetitive stimulation of either the spinocerebellar tract or trigeminal nerve was blocked by DL-2-amino-5-phosphonvalerate, indicating that this potential is primarily dependent upon N-methyl-D-aspartate receptors at the mossy fibre-granule cell synapse for its expression. This slow potential was reversibly potentiated by L-2-amino-4-phosphonobutyrate and bicuculline; the metabotropic glutamate antagonist (+)-alpha-methyl-4-carboxyphenylglycine did not block this potentiation. The ability of mossy fibre inputs to drive long, slow excitatory events in

  13. Late-associativity, synaptic tagging, and the role of dopamine during LTP and LTD.

    PubMed

    Sajikumar, Sreedharan; Frey, Julietta U

    2004-07-01

    Protein synthesis-dependent, synapse input-specific late phases of long-term potentiation (LTP) and depression (LTD) may underlie memory formation at the cellular level. Recently, it was described that the induction of LTP can mark a specifically activated synapse by a synaptic tag to capture synapse non-specific plasticity-related proteins (PRPs) and thus maintaining input-specific LTP for prolonged periods. Here we show in rat hippocampal slices in vitro, that the induction of protein synthesis-dependent late-LTD is also characterized by synaptic tagging and that heterosynaptic induction of either LTD or LTP on two sets of independent synaptic inputs S1 and S2 can lead to late-associative interactions: early-LTD in S2 was transformed into a late-LTD, if late-LTP was induced in S1. The synthesis of process-independent PRPs by late-LTP in S1 was sufficient to transform early- into late-LTD in S2 when process-specific synaptic tags were set. We name this new associative property of cellular information processing 'cross-tagging.' PMID:15183167

  14. Learning of Sensory Sequences in Cerebellar Patients

    ERIC Educational Resources Information Center

    Frings, Markus; Boenisch, Raoul; Gerwig, Marcus; Diener, Hans-Christoph; Timmann, Dagmar

    2004-01-01

    A possible role of the cerebellum in detecting and recognizing event sequences has been proposed. The present study sought to determine whether patients with cerebellar lesions are impaired in the acquisition and discrimination of sequences of sensory stimuli of different modalities. A group of 26 cerebellar patients and 26 controls matched for…

  15. Consensus Paper: Management of Degenerative Cerebellar Disorders

    PubMed Central

    Ilg, W.; Bastian, A. J.; Boesch, S.; Burciu, R. G.; Celnik, P.; Claaßen, J.; Feil, K.; Kalla, R.; Miyai, I.; Nachbauer, W.; Schöls, L.; Strupp, M.; Synofzik, M.; Teufel, J.

    2015-01-01

    Treatment of motor symptoms of degenerative cerebellar ataxia remains difficult. Yet there are recent developments that are likely to lead to significant improvements in the future. Most desirable would be a causative treatment of the underlying cerebellar disease. This is currently available only for a very small subset of cerebellar ataxias with known metabolic dysfunction. However, increasing knowledge of the pathophysiology of hereditary ataxia should lead to an increasing number of medically sensible drug trials. In this paper, data from recent drug trials in patients with recessive and dominant cerebellar ataxias will be summarized. There is consensus that up to date, no medication has been proven effective. Aminopyridines and acetazolamide are the only exception, which are beneficial in patients with episodic ataxia type 2. Aminopyridines are also effective in a subset of patients presenting with downbeat nystagmus. As such, all authors agreed that the mainstays of treatment of degenerative cerebellar ataxia are currently physiotherapy, occupational therapy, and speech therapy. For many years, well-controlled rehabilitation studies in patients with cerebellar ataxia were lacking. Data of recently published studies show that coordinative training improves motor function in both adult and juvenile patients with cerebellar degeneration. Given the well-known contribution of the cerebellum to motor learning, possible mechanisms underlying improvement will be outlined. There is consensus that evidence-based guidelines for the physiotherapy of degenerative cerebellar ataxia need to be developed. Future developments in physiotherapeutical interventions will be discussed including application of non-invasive brain stimulation. PMID:24222635

  16. Metronidazole-Induced Cerebellar Toxicity

    PubMed Central

    Agarwal, Amit; Kanekar, Sangam; Sabat, Shyam; Thamburaj, Krishnamurthy

    2016-01-01

    Metronidazole is a very common antibacterial and antiprotozoal with wide usage across the globe, including the least developed countries. It is generally well-tolerated with a low incidence of serious side-effects. Neurological toxicity is fairly common with this drug, however majority of these are peripheral neuropathy with very few cases of central nervous toxicity reported. We report the imaging findings in two patients with cerebellar dysfunction after Metronidazole usage. Signal changes in the dentate and red nucleus were seen on magnetic resonance imaging in these patients. Most of the cases reported in literature reported similar findings, suggesting high predilection for the dentate nucleus in metronidazole induced encephalopathy. PMID:27127600

  17. Cerebellar Stroke-manifesting as Mania.

    PubMed

    Jagadesan, Venkatesan; Thiruvengadam, Kannapiran R; Muralidharan, Rengarajalu

    2014-07-01

    Secondary mania resulting from cerebral Cortex are described commonly. But secondary mania produced by cerebellar lesions are relatively uncommon. This case report describes a patient who developed cerebellar stoke and manic features simultaneously. 28 years old male developed giddiness and projectile vomiting. Then he would lie down for about an hour only to find that he could not walk. He became quarrelsome. His Psycho motor activities and speech were increased. He was euphoric and was expressing grandiose ideas. Bender Gestalt Test showed signs of organicity. Score in Young mania relating scale was 32; productivity was low in Rorschach. Neurological examination revealed left cerebellar signs like ataxia and slurring of speech. Computed tomography of brain showed left cerebellar infarct. Relationship between Psychiatric manifestations and cerebellar lesion are discussed. PMID:25035567

  18. Cerebellar Stroke-manifesting as Mania

    PubMed Central

    Jagadesan, Venkatesan; Thiruvengadam, Kannapiran R.; Muralidharan, Rengarajalu

    2014-01-01

    Secondary mania resulting from cerebral Cortex are described commonly. But secondary mania produced by cerebellar lesions are relatively uncommon. This case report describes a patient who developed cerebellar stoke and manic features simultaneously. 28 years old male developed giddiness and projectile vomiting. Then he would lie down for about an hour only to find that he could not walk. He became quarrelsome. His Psycho motor activities and speech were increased. He was euphoric and was expressing grandiose ideas. Bender Gestalt Test showed signs of organicity. Score in Young mania relating scale was 32; productivity was low in Rorschach. Neurological examination revealed left cerebellar signs like ataxia and slurring of speech. Computed tomography of brain showed left cerebellar infarct. Relationship between Psychiatric manifestations and cerebellar lesion are discussed. PMID:25035567

  19. Cellular and molecular basis of cerebellar development

    PubMed Central

    Martinez, Salvador; Andreu, Abraham; Mecklenburg, Nora; Echevarria, Diego

    2013-01-01

    Historically, the molecular and cellular mechanisms of cerebellar development were investigated through structural descriptions and studying spontaneous mutations in animal models and humans. Advances in experimental embryology, genetic engineering, and neuroimaging techniques render today the possibility to approach the analysis of molecular mechanisms underlying histogenesis and morphogenesis of the cerebellum by experimental designs. Several genes and molecules were identified to be involved in the cerebellar plate regionalization, specification, and differentiation of cerebellar neurons, as well as the establishment of cellular migratory routes and the subsequent neuronal connectivity. Indeed, pattern formation of the cerebellum requires the adequate orchestration of both key morphogenetic signals, arising from distinct brain regions, and local expression of specific transcription factors. Thus, the present review wants to revisit and discuss these morphogenetic and molecular mechanisms taking place during cerebellar development in order to understand causal processes regulating cerebellar cytoarchitecture, its highly topographically ordered circuitry and its role in brain function. PMID:23805080

  20. Asymptomatic cerebellar atrophy after acute enteroviral encephalitis.

    PubMed

    Vitaszil, Edina; Kamondi, Anita; Csillik, Anita; Velkey, Imre; Szirmai, Imre

    2005-07-01

    We report on a 13-year-old male who had acute enteroviral encephalitis causing cerebellar symptoms at the age of 10 years. Magnetic resonance imaging (MRI) showed no abnormalities. Clinically he appeared to be recovered completely after 6 months. Twenty-three months after the recovery, MRI was performed because he presented with slight lower-limb and truncal ataxia experienced as lack of foot coordination while playing football or riding a bicycle. MRI demonstrated severe cerebellar atrophy. Clinically he recovered completely in 10 days. Only sophisticated electrophysiological methods revealed cerebellar dysfunction. The case provides evidence for the plasticity of cerebellar regulatory structures involved in the coordination of fine movements. It seems that in childhood the slow, isolated disintegration of cerebellar systems can be compensated for by upper thalamic or telencephalic connections, in a similar way to a congenital deficit of the cerebellum. PMID:15991870

  1. Effects of chronic cocaine abuse on postsynaptic dopamine receptors

    SciTech Connect

    Volkow, N.D.; Fowler, J.S.; Wolf, A.P.; Schlyer, D.; Shiue, C.Y.; Alpert, R.; Dewey, S.L.; Logan, J.; Bendriem, B.; Christman, D. )

    1990-06-01

    To assess the effects of chronic cocaine intoxication on dopamine receptors in human subjects, the authors evaluated ({sup 18}F)N-methylspiroperidol binding using positron emission tomography in 10 cocaine abusers and 10 normal control subjects. Cocaine abusers who had been detoxified for 1 week or less showed significantly lower values for uptake of ({sup 18}F)N-methylspiroperidol in striatum than the normal subjects, whereas the cocaine abusers who had been detoxified for 1 month showed values comparable to those obtained from normal subjects. The authors conclude that postsynaptic dopamine receptor availability decreases with chronic cocaine abuse but may recover after a drug-free interval.

  2. Differential effects of subtype-specific nicotinic acetylcholine receptor agonists on early and late hippocampal LTP.

    PubMed

    Kroker, Katja S; Rast, Georg; Rosenbrock, Holger

    2011-12-01

    Brain nicotinic acetylcholine receptors are involved in several neuropsychiatric disorders, e.g. Alzheimer's and Parkinson's diseases, Tourette's syndrome, schizophrenia, depression, autism, attention deficit hyperactivity disorder, and anxiety. Currently, approaches selectively targeting the activation of specific nicotinic acetylcholine receptors are in clinical development for treatment of memory impairment of Alzheimer's disease patients. These are α4β2 and α7 nicotinic acetylcholine receptor agonists which are believed to enhance cholinergic and glutamatergic neurotransmission, respectively. In order to gain a better insight into the mechanistic role of these two nicotinic acetylcholine receptors in learning and memory, we investigated the effects of the α4β2 nicotinic acetylcholine receptor agonist TC-1827 and the α7 nicotinic acetylcholine receptor partial agonist SSR180711 on hippocampal long-term potentiation (LTP), a widely accepted cellular experimental model of memory formation. Generally, LTP is distinguished in an early and a late form, the former being protein-synthesis independent and the latter being protein-synthesis dependent. TC-1827 was found to increase early LTP in a bell-shaped dose dependent manner, but did not affect late LTP. In contrast, the α7 nicotinic acetylcholine receptor partial agonist SSR180711 showed enhancing effects on both early and late LTP in a bell-shaped manner. Furthermore, SSR180711 not only increased early LTP, but also transformed it into late LTP, which was not observed with the α4β2 nicotinic acetylcholine receptor agonist. Therefore, based on these findings α7 nicotinic acetylcholine receptor (partial) agonists appear to exhibit stronger efficacy on memory improvement than α4β2 nicotinic acetylcholine receptor agonists. PMID:21968142

  3. Deleterious effects of a low amount of ethanol on LTP-like plasticity in human cortex.

    PubMed

    Lücke, Caroline; Heidegger, Tonio; Röhner, Mirjam; Toennes, Stefan W; Krivanekova, Lucia; Müller-Dahlhaus, Florian; Ziemann, Ulf

    2014-05-01

    Ingesting ethanol (EtOH) at low doses during social drinking is a common human behavior for its facilitating effects on social interactions. However, low-dose EtOH may have also detrimental effects that so far are underexplored. Here we sought to test the effects of low-dose EtOH on long-term potentiation (LTP)-like plasticity in human motor cortex. Previous cellular experiments showed that low-dose EtOH potentiates extrasynaptic GABAAR and reduces NMDAR-mediated currents, processes that would limit the expression of LTP. Paired associative transcranial magnetic stimulation (PASLTP) was employed in nine healthy subjects for induction of LTP-like plasticity, indexed by a long-term increase in motor-evoked potential input-output curves. Synaptic α1-GABAAR function was measured by saccadic peak velocity (SPV). Very low doses of EtOH (resulting in blood concentrations of <5 mM) suppressed LTP-like plasticity but did not affect SPV when compared with a placebo condition. In contrast, 1 mg of alprazolam, a classical benzodiazepine, or 10 mg of zolpidem, a non-benzodiazepine hypnotic, decreased SPV but did not significantly affect LTP-like plasticity when compared with placebo. This double dissociation of low-dose EtOH vs alprazolam/zolpidem effects is best explained by the putatively high affinity of EtOH but not alprazolam/zolpidem to extrasynaptic GABAARs and to NMDARs. Findings suggest that enhancement of extrasynaptic GABAAR-mediated tonic inhibition and/or reduction of NMDAR-mediated neurotransmission by EtOH blocks LTP-like plasticity in human cortex at very low doses that are easily reached during social drinking. Therefore, low-dose EtOH may jeopardize LTP-dependent processes, such as learning and memory formation. PMID:24385131

  4. β2-Adrenergic receptor supports prolonged theta tetanus-induced LTP.

    PubMed

    Qian, Hai; Matt, Lucas; Zhang, Mingxu; Nguyen, Minh; Patriarchi, Tommaso; Koval, Olha M; Anderson, Mark E; He, Kaiwen; Lee, Hey-Kyoung; Hell, Johannes W

    2012-05-01

    The widespread noradrenergic innervation in the brain promotes arousal and learning by molecular mechanisms that remain largely undefined. Recent work shows that the β(2)-adrenergic receptor (β(2)AR) is linked to the AMPA-type glutamate receptor subunit GluA1 via stargazin and PSD-95 (Joiner ML, Lise MF, Yuen EY, Kam AY, Zhang M, Hall DD, Malik ZA, Qian H, Chen Y, Ulrich JD, Burette AC, Weinberg RJ, Law PY, El-Husseini A, Yan Z, Hell JW. EMBO J 29: 482-495, 2010). We now demonstrate that the β(2)AR plays a prominent role in long-term potentiation (LTP) induced by a train of 900 stimuli at 5 Hz (prolonged theta-tetanus-LTP, or PTT-LTP) in the hippocampal CA1 region in mice, which requires simultaneous β-adrenergic stimulation. Although PTT-LTP was impaired in hippocampal slices from β(1)AR and β(2)AR knockout (KO) mice, only β(2)AR-selective stimulation with salbutamol supported this PTT-LTP in wild-type (WT) slices, whereas β(1)AR-selective stimulation with dobutamine (+ prazosin) did not. Furthermore, only the β(2)AR-selective antagonist ICI-118551 and not the β(1)AR-selective antagonist CGP-20712 inhibited PTT-LTP and phosphorylation of GluA1 on its PKA site S845 in WT slices. Our analysis of S845A knockin (KI) mice indicates that this phosphorylation is relevant for PTT-LTP. These results identify the β(2)AR-S845 signaling pathway as a prominent regulator of synaptic plasticity. PMID:22338020

  5. Developmental Cerebellar Cognitive Affective Syndrome in Ex-preterm Survivors Following Cerebellar Injury

    PubMed Central

    Brossard-Racine, Marie; du Plessis, Adre J.; Limperopoulos, Catherine

    2015-01-01

    Cerebellar injury is increasingly recognized as an important complication of very preterm birth. However, the neurodevelopmental consequences of early life cerebellar injury in prematurely born infants have not been well elucidated. We performed a literature search of studies published between 1997 and 2014 describing neurodevelopmental outcomes of preterm infants following direct cerebellar injury or indirect cerebellar injury/underdevelopment. Available data suggests that both direct and indirect mechanisms of cerebellar injury appear to stunt cerebellar growth and adversely affect neurodevelopment. This review also provides important insights into the highly integrated cerebral-cerebellar structural and functional correlates. Finally, this review highlights that early life impairment of cerebellar growth extends far beyond motor impairments and plays a critical, previously underrecognized role in the long-term cognitive, behavioral, and social deficits associated with brain injury among premature infants. These data point to a developmental form of the cerebellar cognitive affective syndrome previously described in adults. Longitudinal prospective studies using serial advanced magnetic resonance imaging techniques are needed to better delineate the full extent of the role of prematurity-related cerebellar injury and topography in the genesis of cognitive, social-behavioral dysfunction. PMID:25241880

  6. Neurobeachin is required postsynaptically for electrical and chemical synapse formation

    PubMed Central

    Miller, Adam C.; Voelker, Lisa H.; Shah, Arish N.; Moens, Cecilia B.

    2014-01-01

    Summary Background Neural networks and their function are defined by synapses, which are adhesions specialized for intercellular communication that can be either chemical or electrical. At chemical synapses transmission between neurons is mediated by neurotransmitters, while at electrical synapses direct ionic and metabolic coupling occurs via gap junctions between neurons. The molecular pathways required for electrical synaptogenesis are not well understood and whether they share mechanisms of formation with chemical synapses is not clear. Results Here, using a forward genetic screen in zebrafish we find that the autism-associated gene neurobeachin (nbea), which encodes a BEACH-domain containing protein implicated in endomembrane trafficking, is required for both electrical and chemical synapse formation. Additionally, we find that nbea is dispensable for axonal formation and early dendritic outgrowth, but is required to maintain dendritic complexity. These synaptic and morphological defects correlate with deficiencies in behavioral performance. Using chimeric animals in which individually identifiable neurons are either mutant or wildtype we find that Nbea is necessary and sufficient autonomously in the postsynaptic neuron for both synapse formation and dendritic arborization. Conclusions Our data identify a surprising link between electrical and chemical synapse formation and show that Nbea acts as a critical regulator in the postsynaptic neuron for the coordination of dendritic morphology with synaptogenesis. PMID:25484298

  7. SNAP-25, a Known Presynaptic Protein with Emerging Postsynaptic Functions

    PubMed Central

    Antonucci, Flavia; Corradini, Irene; Fossati, Giuliana; Tomasoni, Romana; Menna, Elisabetta; Matteoli, Michela

    2016-01-01

    A hallmark of synaptic specializations is their dependence on highly organized complexes of proteins that interact with each other. The loss or modification of key synaptic proteins directly affects the properties of such networks, ultimately impacting synaptic function. SNAP-25 is a component of the SNARE complex, which is central to synaptic vesicle exocytosis, and, by directly interacting with different calcium channels subunits, it negatively modulates neuronal voltage-gated calcium channels, thus regulating intracellular calcium dynamics. The SNAP-25 gene has been associated with distinct brain diseases, including Attention Deficit Hyperactivity Disorder (ADHD), schizophrenia and bipolar disorder, indicating that the protein may act as a shared biological substrate among different “synaptopathies”. The mechanisms by which alterations in SNAP-25 may concur to these psychiatric diseases are still undefined, although alterations in neurotransmitter release have been indicated as potential causative processes. This review summarizes recent work showing that SNAP-25 not only controls exo/endocytic processes at the presynaptic terminal, but also regulates postsynaptic receptor trafficking, spine morphogenesis, and plasticity, thus opening the possibility that SNAP-25 defects may contribute to psychiatric diseases by impacting not only presynaptic but also postsynaptic functions. PMID:27047369

  8. NMDA receptors amplify mossy fiber synaptic inputs at frequencies up to at least 750 Hz in cerebellar granule cells.

    PubMed

    Baade, Carolin; Byczkowicz, Niklas; Hallermann, Stefan

    2016-07-01

    Neuronal integration of high-frequency signals is important for rapid information processing. Cerebellar mossy fiber axons (MFs) can fire action potentials (APs) at frequencies of more than one kilohertz. However, it is unclear whether and how the postsynaptic cerebellar granule cells (GCs) are able to process these high-frequency MF inputs. Here, we measured AP firing in GCs during high-frequency MF stimulation and show that GC firing frequency increased non-linearly when MF stimulation frequency was increased from 100 to 750 Hz. To investigate the mechanisms enabling such high-frequency signaling, we analyzed the role of N-methyl-d-aspartate receptors (NMDARs), which have been implicated in synaptic signaling at lower frequencies. Application of D-2-amino-5-phosphonopentanoic acid (APV), a potent inhibitor of NMDARs, strongly impaired the GC firing frequency during high-frequency MF stimulation. APV had no significant effect on single excitatory postsynaptic potentials (EPSPs) or currents (EPSCs) evoked at 1 Hz at resting membrane potentials. However, the time course of EPSCs evoked at 1 Hz at depolarized potentials or following high-frequency MF stimulation was accelerated by APV. Thus, our results show that NMDAR-mediated currents amplify high-frequency MF inputs by prolonging the time courses of synaptic inputs, thereby causing greater synaptic summation of inputs. Hence, NMDARs support the integration of MF synaptic input at frequencies up to at least 750 Hz. Synapse 70:269-276, 2016. © 2016 Wiley Periodicals, Inc. PMID:26887562

  9. Cerebellar Motor Function in Spina Bifida Meningomyelocele

    PubMed Central

    Dennis, Maureen; Salman, Michael S.; Juranek, Jenifer; Fletcher, Jack M.

    2010-01-01

    Spina bifida meningomyelocele (SBM), a congenital neurodevelopmental disorder, involves dysmorphology of the cerebellum, and its most obvious manifestations are motor deficits. This paper reviews cerebellar neuropathology and motor function across several motor systems well studied in SBM in relation to current models of cerebellar motor and timing function. Children and adults with SBM have widespread motor deficits in trunk, upper limbs, eyes, and speech articulators that are broadly congruent with those observed in adults with cerebellar lesions. The structure and function of the cerebellum are correlated with a range of motor functions. While motor learning is generally preserved in SBM, those motor functions requiring predictive signals and precise calibration of the temporal features of movement are impaired, resulting in deficits in smooth movement coordination as well as in the classical cerebellar triad of dysmetria, ataxia, and dysarthria. That motor function in individuals with SBM is disordered in a manner phenotypically similar to that in adult cerebellar lesions, and appears to involve similar deficits in predictive cerebellar motor control, suggests that age-based cerebellar motor plasticity is limited in individuals with this neurodevelopmental disorder. PMID:20652468

  10. X-linked disorders with cerebellar dysgenesis

    PubMed Central

    2011-01-01

    X-linked disorders with cerebellar dysgenesis (XLCD) are a genetically heterogeneous and clinically variable group of disorders in which the hallmark is a cerebellar defect (hypoplasia, atrophy or dysplasia) visible on brain imaging, caused by gene mutations or genomic imbalances on the X-chromosome. The neurological features of XLCD include hypotonia, developmental delay, intellectual disability, ataxia and/or other cerebellar signs. Normal cognitive development has also been reported. Cerebellar dysgenesis may be isolated or associated with other brain malformations or multiorgan involvement. There are at least 15 genes on the X-chromosome that have been constantly or occasionally associated with a pathological cerebellar phenotype. 8 XLCD loci have been mapped and several families with X-linked inheritance have been reported. Recently, two recurrent duplication syndromes in Xq28 have been associated with cerebellar hypoplasia. Given the report of several forms of XLCD and the excess of males with ataxia, this group of conditions is probably underestimated and families of patients with neuroradiological and clinical evidence of a cerebellar disorder should be counseled for high risk of X-linked inheritance. PMID:21569638

  11. SynArfGEF is a guanine nucleotide exchange factor for Arf6 and localizes preferentially at post-synaptic specializations of inhibitory synapses.

    PubMed

    Fukaya, Masahiro; Kamata, Akifumi; Hara, Yoshinobu; Tamaki, Hideaki; Katsumata, Osamu; Ito, Naoki; Takeda, Shin'ichi; Hata, Yutaka; Suzuki, Tatsuo; Watanabe, Masahiko; Harvey, Robert J; Sakagami, Hiroyuki

    2011-03-01

    SynArfGEF, also known as BRAG3 or IQSEC3, is a member of the brefeldin A-resistant Arf-GEF/IQSEC family and was originally identified by screening for mRNA species associated with the post-synaptic density fraction. In this study, we demonstrate that synArfGEF activates Arf6, using Arf pull down and transferrin incorporation assays. Immunohistochemical analysis reveals that synArfGEF is present in somata and dendrites as puncta in close association with inhibitory synapses, whereas immunoelectron microscopic analysis reveals that synArfGEF localizes preferentially at post-synaptic specializations of symmetric synapses. Using yeast two-hybrid and pull down assays, we show that synArfGEF is able to bind utrophin/dystrophin and S-SCAM/MAGI-2 scaffolding proteins that localize at inhibitory synapses. Double immunostaining reveals that synArfGEF co-localizes with dystrophin and S-SCAM in cultured hippocampal neurons and cerebellar cortex, respectively. Both β-dystroglycan and S-SCAM were immunoprecipitated from brain lysates using anti-synArfGEF IgG. Taken together, these findings suggest that synArfGEF functions as a novel regulator of Arf6 at inhibitory synapses and associates with the dystrophin-associated glycoprotein complex and S-SCAM. PMID:21198641

  12. Optogenetic mapping of cerebellar inhibitory circuitry reveals spatially biased coordination of interneurons via electrical synapses.

    PubMed

    Kim, Jinsook; Lee, Soojung; Tsuda, Sachiko; Zhang, Xuying; Asrican, Brent; Gloss, Bernd; Feng, Guoping; Augustine, George J

    2014-06-12

    We used high-speed optogenetic mapping technology to examine the spatial organization of local inhibitory circuits formed by cerebellar interneurons. Transgenic mice expressing channelrhodopsin-2 exclusively in molecular layer interneurons allowed us to focally photostimulate these neurons, while measuring resulting responses in postsynaptic Purkinje cells. This approach revealed that interneurons converge upon Purkinje cells over a broad area and that at least seven interneurons form functional synapses with a single Purkinje cell. The number of converging interneurons was reduced by treatment with gap junction blockers, revealing that electrical synapses between interneurons contribute substantially to the spatial convergence. Remarkably, gap junction blockers affected convergence in sagittal slices, but not in coronal slices, indicating a sagittal bias in electrical coupling between interneurons. We conclude that electrical synapse networks spatially coordinate interneurons in the cerebellum and may also serve this function in other brain regions. PMID:24857665

  13. Sonic hedgehog patterning during cerebellar development.

    PubMed

    De Luca, Annarita; Cerrato, Valentina; Fucà, Elisa; Parmigiani, Elena; Buffo, Annalisa; Leto, Ketty

    2016-01-01

    The morphogenic factor sonic hedgehog (Shh) actively orchestrates many aspects of cerebellar development and maturation. During embryogenesis, Shh signaling is active in the ventricular germinal zone (VZ) and represents an essential signal for proliferation of VZ-derived progenitors. Later, Shh secreted by Purkinje cells sustains the amplification of postnatal neurogenic niches: the external granular layer and the prospective white matter, where excitatory granule cells and inhibitory interneurons are produced, respectively. Moreover, Shh signaling affects Bergmann glial differentiation and promotes cerebellar foliation during development. Here we review the most relevant functions of Shh during cerebellar ontogenesis, underlying its role in physiological and pathological conditions. PMID:26499980

  14. Pediatric Neurocutaneous Syndromes with Cerebellar Involvement.

    PubMed

    Bosemani, Thangamadhan; Huisman, Thierry A G M; Poretti, Andrea

    2016-08-01

    Neurocutaneous syndromes encompasses a broad group of genetic disorders with different clinical, genetic, and pathologic features that share developmental lesions of the skin as well as central and peripheral nervous system. Cerebellar involvement has been shown in numerous types of neurocutaneous syndrome. It may help or be needed for the diagnosis and to explain the cognitive and behavioral phenotype of affected children. This article describes various types of neurocutaneous syndrome with cerebellar involvement. For each neurocutaneous disease or syndrome, clinical features, genetic, neuroimaging findings, and the potential role of the cerebellar involvement is discussed. PMID:27423801

  15. The upregulation of NR2A-containing N-methyl-D-aspartate receptor function by tyrosine phosphorylation of postsynaptic density 95 via facilitating Src/proline-rich tyrosine kinase 2 activation.

    PubMed

    Zhao, Chao; Du, Cai-Ping; Peng, Yan; Xu, Zhen; Sun, Chang-Cheng; Liu, Yong; Hou, Xiao-Yu

    2015-04-01

    The activation of postsynaptic N-methyl-D-aspartate (NMDA) receptors is required for long-term potentiation (LTP) of synaptic transmission. Postsynaptic density 95 (PSD-95) serves as a scaffold protein that tethers NMDA receptor subunits, kinases, and signal molecules. Our previous study proves that PSD-95 is a substrate of Src/Fyn and identifies Y523 on PSD-95 as a principal phosphorylation site. In this paper, we try to define an involvement and molecular consequences of PSD-95 phosphorylation by Src in NMDA receptor regulation. We found that either NMDA or chemical LTP induction leads to rapid phosphorylation of PSD-95 by Src in cultured cortical neurons. The phosphorylation of Y523 on PSD-95 potentiates NR2A-containing NMDA receptor current amplitude, implying an important role of Src-mediated PSD-95 phosphorylation in NMDA receptor activation. Comparing to wild-type PSD-95, overexpression of nonphosphorylatable mutant PSD-95Y523F attenuated the NMDA-stimulated NR2A tyrosine phosphorylation that enhances electrophysiological responses of NMDA receptor channels, while did not affect the membrane localization of NR2A subunits. PSD-95Y523D, a phosphomimetic mutant of PSD-95, induced NR2A tyrosine phosphorylation even if there was no NMDA treatment. In addition, the deficiency of Y523 phosphorylation on PSD-95 impaired the facilitatory effect of PSD-95 on the activation of Src and proline-rich tyrosine kinase 2 (Pyk2) and decreased the binding of Pyk2 with PSD-95. These results indicate that PSD-95 phosphorylation by Src facilitates the integration of Pyk2 to PSD-95 signal complex, the activation of Pyk2/Src, as well as the subsequent tyrosine phosphorylation of NR2A, which ultimately results in the upregulation of NMDA receptor function and synaptic transmission. PMID:24981431

  16. A Reinforcing Circuit Action of Extrasynaptic GABAA Receptor Modulators on Cerebellar Granule Cell Inhibition

    PubMed Central

    Santhakumar, Vijayalakshmi; Otis, Thomas S.

    2013-01-01

    GABAA receptors (GABARs) are the targets of a wide variety of modulatory drugs which enhance chloride flux through GABAR ion channels. Certain GABAR modulators appear to acutely enhance the function of δ subunit-containing GABAR subtypes responsible for tonic forms of inhibition. Here we identify a reinforcing circuit mechanism by which these drugs, in addition to directly enhancing GABAR function, also increase GABA release. Electrophysiological recordings in cerebellar slices from rats homozygous for the ethanol-hypersensitive (α6100Q) allele show that modulators and agonists selective for δ-containing GABARs such as THDOC, ethanol and THIP (gaboxadol) increased the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) in granule cells. Ethanol fails to augment granule cell sIPSC frequency in the presence of glutamate receptor antagonists, indicating that circuit mechanisms involving granule cell output contribute to ethanol-enhancement of synaptic inhibition. Additionally, GABAR antagonists decrease ethanol-induced enhancement of Golgi cell firing. Consistent with a role for glutamatergic inputs, THIP-induced increases in Golgi cell firing are abolished by glutamate receptor antagonists. Moreover, THIP enhances the frequency of spontaneous excitatory postsynaptic currents in Golgi cells. Analyses of knockout mice indicate that δ subunit-containing GABARs are required for enhancing GABA release in the presence of ethanol and THIP. The limited expression of the GABAR δ subunit protein within the cerebellar cortex suggests that an indirect, circuit mechanism is responsible for stimulating Golgi cell GABA release by drugs selective for extrasynaptic isoforms of GABARs. Such circuit effects reinforce direct actions of these positive modulators on tonic GABAergic inhibition and are likely to contribute to the potent effect of these compounds as nervous system depressants. PMID:23977374

  17. A reinforcing circuit action of extrasynaptic GABAA receptor modulators on cerebellar granule cell inhibition.

    PubMed

    Santhakumar, Vijayalakshmi; Meera, Pratap; Karakossian, Movses H; Otis, Thomas S

    2013-01-01

    GABAA receptors (GABARs) are the targets of a wide variety of modulatory drugs which enhance chloride flux through GABAR ion channels. Certain GABAR modulators appear to acutely enhance the function of δ subunit-containing GABAR subtypes responsible for tonic forms of inhibition. Here we identify a reinforcing circuit mechanism by which these drugs, in addition to directly enhancing GABAR function, also increase GABA release. Electrophysiological recordings in cerebellar slices from rats homozygous for the ethanol-hypersensitive (α6100Q) allele show that modulators and agonists selective for δ-containing GABARs such as THDOC, ethanol and THIP (gaboxadol) increased the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) in granule cells. Ethanol fails to augment granule cell sIPSC frequency in the presence of glutamate receptor antagonists, indicating that circuit mechanisms involving granule cell output contribute to ethanol-enhancement of synaptic inhibition. Additionally, GABAR antagonists decrease ethanol-induced enhancement of Golgi cell firing. Consistent with a role for glutamatergic inputs, THIP-induced increases in Golgi cell firing are abolished by glutamate receptor antagonists. Moreover, THIP enhances the frequency of spontaneous excitatory postsynaptic currents in Golgi cells. Analyses of knockout mice indicate that δ subunit-containing GABARs are required for enhancing GABA release in the presence of ethanol and THIP. The limited expression of the GABAR δ subunit protein within the cerebellar cortex suggests that an indirect, circuit mechanism is responsible for stimulating Golgi cell GABA release by drugs selective for extrasynaptic isoforms of GABARs. Such circuit effects reinforce direct actions of these positive modulators on tonic GABAergic inhibition and are likely to contribute to the potent effect of these compounds as nervous system depressants. PMID:23977374

  18. Tetraploid and hexaploid wheats express identical isoforms of nsLTP1.

    PubMed

    Capocchi, Antonella; Fontanini, Debora; Muccilli, Vera; Cunsolo, Vincenzo; Saviozzi, Franco; Saletti, Rosaria; Foti, Salvatore; Galleschi, Luciano

    2006-03-22

    Nonspecific lipid-transfer proteins (nsLTPs) have been recognized as allergens in several plant species among which are cereals important in human nutrition. In this report, we purified a 9600 +/- 1 Da protein from both soft wheat and farro bran. Mass spectrometric analyses revealed that these proteins are identical, belong to the nsLTP1 class, and have high sequence homology with nsLTP1 isolated from other cereal species. Their identification was further supported by the ability of the soft wheat nsLTP1 to transfer pyrene-labeled lipids between donor and acceptor membranes. The results are discussed in view of the increasing diffusion on the markets of bran-rich products. PMID:16536621

  19. Ryanodine-mediated conversion of STP to LTP is lacking in synaptopodin-deficient mice.

    PubMed

    Grigoryan, Gayane; Segal, Menahem

    2016-05-01

    In previous studies we and others have found that activation of ryanodine receptors (RyRs) facilitate expression of long-term potentiation (LTP) of reactivity to afferent stimulation in hippocampal slices, with a more pronounced action in the ventral hippocampus. We have also been able to link the involvement of synaptopodin (SP), an actin-binding protein, with neuronal plasticity via its interaction with RyRs. To test this link more directly, we have now compared the ability of ryanodine to convert short-term to LTP in hippocampal slices taken from normal and SP-knockout (SPKO) mice. Indeed, SPKO hippocampus expresses lower concentrations of RyRs and in slices of these mice ryanodine is unable to facilitate conversion of short-term to LTP. These observations link functionally SP with calcium stores. PMID:25772508

  20. Screening of agrochemicals in foodstuffs using low-temperature plasma (LTP) ambient ionization mass spectrometry.

    PubMed

    Wiley, Joshua S; García-Reyes, Juan F; Harper, Jason D; Charipar, Nicholas A; Ouyang, Zheng; Cooks, R Graham

    2010-05-01

    Low-temperature plasma (LTP) permits direct ambient ionization and mass analysis of samples in their native environment with minimal or no prior preparation. LTP utilizes dielectric barrier discharges (DBDs) to create a low power plasma which is guided by gas flow onto the sample from which analytes are desorbed and ionized. In this study, the potential of LTP-MS for the detection of pesticide residues in food is demonstrated. Thirteen multi-class agricultural chemicals were studied (ametryn, amitraz, atrazine, buprofezin, DEET, diphenylamine, ethoxyquin, imazalil, isofenphos-methyl, isoproturon, malathion, parathion-ethyl and terbuthylazine). To evaluate the potential of the proposed approach, LTP-MS experiments were performed directly on fruit peels as well as on fruit/vegetable extracts. Most of the agrochemicals examined displayed remarkable sensitivity in the positive ion mode, giving limits of detection (LOD) for the direct measurement in the low picogram range. Tandem mass spectrometry (MS/MS) was used to confirm identification of selected pesticides by using for these experiments spiked fruit/vegetable extracts (QuEChERS, a standard sample treatment protocol) at levels as low as 1 pg, absolute, for some of the analytes. Comparisons of the data obtained by direct LTP-MS were made with the slower but more accurate conventional LC-MS/MS procedure. Herbicides spiked in aqueous solutions were detectable at LODs as low as 0.5 microg L(-1) without the need for any sample preparation. The results demonstrate that ambient LTP-MS can be applied for the detection and confirmation of traces of agrochemicals in actual market-purchased produce and in natural water samples. Quantitative analysis was also performed in a few selected cases and displayed a relatively high degree of linearity over four orders of magnitude. PMID:20419245

  1. Crystallization of DIR1, a LTP2-like resistance signalling protein from Arabidopsis thaliana

    SciTech Connect

    Lascombe, Marie-Bernard; Buhot, Nathalie; Bakan, Bénédicte; Marion, Didier; Blein, Jean Pierre; Lamb, Chris J.; Prangé, Thierry

    2006-07-01

    DIR1, a putative LTP2 protein from Arabidopsis thaliana implicated in systemic acquired resistance in planta, has been crystallized in space group P2{sub 1}2{sub 1}2{sub 1} with one molecule per asymmetric unit. DIR1, a putative LTP2 protein from Arabidopsis thaliana implicated in systemic acquired resistance in planta, has been crystallized in space group P2{sub 1}2{sub 1}2{sub 1} with one molecule per asymmetric unit. The crystals diffract to a resolution of 1.6 Å.

  2. Isoliquiritigenin, a Chalcone Compound, Enhances Spontaneous Inhibitory Postsynaptic Response

    PubMed Central

    Woo, Junsung; Cho, Suengmok

    2014-01-01

    Isoliquiritigenin (ILTG) is a chalcone compound and shows various pharmacological properties, including antioxidant and anti-inflammatory activities. In recent study, we have reported a novel role of ILTG in sleep through a positive allosteric modulation of gamma-aminobutyric acid type A (GABAA)-benzodiazepine (BZD) receptors. However, the effect of ILTG in GABAAR-mediated synaptic response in brain has not been tested yet. Here we report that ILTG significantly prolonged the decay of spontaneous inhibitory postsynaptic currents (sIPSCs) mediated by GABAAR in mouse hippocampal CA1 pyramidal neurons without affecting amplitude and frequency of sIPSCs. This enhancement was fully inhibited by flumazenil (FLU), a specific GABAA-BZD receptor antagonist. These results suggest a potential role of ILTG as a modulator of GABAergic synaptic transmission. PMID:24963281

  3. A Computational Model for the AMPA Receptor Phosphorylation Master Switch Regulating Cerebellar Long-Term Depression

    PubMed Central

    Gallimore, Andrew R.; Aricescu, A. Radu; Yuzaki, Michisuke; Calinescu, Radu

    2016-01-01

    The expression of long-term depression (LTD) in cerebellar Purkinje cells results from the internalisation of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors (AMPARs) from the postsynaptic membrane. This process is regulated by a complex signalling pathway involving sustained protein kinase C (PKC) activation, inhibition of serine/threonine phosphatase, and an active protein tyrosine phosphatase, PTPMEG. In addition, two AMPAR-interacting proteins–glutamate receptor-interacting protein (GRIP) and protein interacting with C kinase 1 (PICK1)–regulate the availability of AMPARs for trafficking between the postsynaptic membrane and the endosome. Here we present a new computational model of these overlapping signalling pathways. The model reveals how PTPMEG cooperates with PKC to drive LTD expression by facilitating the effect of PKC on the dissociation of AMPARs from GRIP and thus their availability for trafficking. Model simulations show that LTD expression is increased by serine/threonine phosphatase inhibition, and negatively regulated by Src-family tyrosine kinase activity, which restricts the dissociation of AMPARs from GRIP under basal conditions. We use the model to expose the dynamic balance between AMPAR internalisation and reinsertion, and the phosphorylation switch responsible for the perturbation of this balance and for the rapid plasticity initiation and regulation. Our model advances the understanding of PF-PC LTD regulation and induction, and provides a validated extensible platform for more detailed studies of this fundamental synaptic process. PMID:26807999

  4. A Computational Model for the AMPA Receptor Phosphorylation Master Switch Regulating Cerebellar Long-Term Depression.

    PubMed

    Gallimore, Andrew R; Aricescu, A Radu; Yuzaki, Michisuke; Calinescu, Radu

    2016-01-01

    The expression of long-term depression (LTD) in cerebellar Purkinje cells results from the internalisation of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors (AMPARs) from the postsynaptic membrane. This process is regulated by a complex signalling pathway involving sustained protein kinase C (PKC) activation, inhibition of serine/threonine phosphatase, and an active protein tyrosine phosphatase, PTPMEG. In addition, two AMPAR-interacting proteins-glutamate receptor-interacting protein (GRIP) and protein interacting with C kinase 1 (PICK1)-regulate the availability of AMPARs for trafficking between the postsynaptic membrane and the endosome. Here we present a new computational model of these overlapping signalling pathways. The model reveals how PTPMEG cooperates with PKC to drive LTD expression by facilitating the effect of PKC on the dissociation of AMPARs from GRIP and thus their availability for trafficking. Model simulations show that LTD expression is increased by serine/threonine phosphatase inhibition, and negatively regulated by Src-family tyrosine kinase activity, which restricts the dissociation of AMPARs from GRIP under basal conditions. We use the model to expose the dynamic balance between AMPAR internalisation and reinsertion, and the phosphorylation switch responsible for the perturbation of this balance and for the rapid plasticity initiation and regulation. Our model advances the understanding of PF-PC LTD regulation and induction, and provides a validated extensible platform for more detailed studies of this fundamental synaptic process. PMID:26807999

  5. LTP-1, a novel antimitotic agent and Stat3 inhibitor, inhibits human pancreatic carcinomas in vitro and in vivo

    PubMed Central

    Huang, Han-Li; Chao, Min-Wu; Chen, Chung-Chun; Cheng, Chun-Chun; Chen, Mei-Chuan; Lin, Chao-Feng; Liou, Jing-Ping; Teng, Che-Ming; Pan, Shiow-Lin

    2016-01-01

    Pancreatic cancer is the leading cause of cancer death worldwide with a poor survival rate. The objective of this study was to determine the mechanism of action of a novel antimitotic and Stat3 inhibitor, LTP-1, on human pancreatic cancer in vitro and in vivo. We found that LTP-1 inhibited pancreatic cancer cell growth and viability with significant G2/M arrest and disruption of microtubule dynamics. LTP-1 also caused G2/M arrest-independent Stat3 dephosphorylation along with ERK activation, which indicated the possible dual function of LTP-1. Long-term treatment of LTP-1 also induced polyploidy, activated caspases, induced subG1 cell population, and therefore, triggered pancreatic cancer cell apoptosis. Finally, we used an in vivo xenograft model to demonstrate that LTP-1 suppressed the growth of pancreatic adenocarcinoma. In summary, our data suggest that LTP-1 may alter microtubule dynamics, which ultimately causes polyploidy and apoptosis, thereby inhibiting pancreatic cancer growth in vitro and in vivo. This study provides evidence that LTP-1 could be a potential therapeutic agent for further development of pancreatic cancer treatment. PMID:27278358

  6. A wheat lipid transfer protein (TdLTP4) promotes tolerance to abiotic and biotic stress in Arabidopsis thaliana.

    PubMed

    Safi, Hela; Saibi, Walid; Alaoui, Meryem Mrani; Hmyene, Abdelaziz; Masmoudi, Khaled; Hanin, Moez; Brini, Faïçal

    2015-04-01

    Lipid transfer proteins (LTPs) are members of the family of pathogenesis-related proteins (PR-14) that are believed to be involved in plant defense responses. In this study, we report the isolation and characterization of a novel gene TdLTP4 encoding an LTP protein from durum wheat [Triticum turgidum L. subsp. Durum Desf.]. Molecular Phylogeny analyses of wheat TdLTP4 gene showed a high identity to other plant LTPs. Predicted three-dimensional structural model revealed the presence of six helices and nine loop turns. Expression analysis in two local durum wheat varieties with marked differences in salt and drought tolerance, revealed a higher transcript accumulation of TdLTP4 under different stress conditions in the tolerant variety, compared to the sensitive one. The overexpression of TdLTP4 in Arabidopsis resulted in a promoted plant growth under various stress conditions including NaCl, ABA, JA and H2O2 treatments. Moreover, the LTP-overexpressing lines exhibit less sensitivity to jasmonate than wild-type plants. Furthermore, detached leaves from transgenic Arabidopsis expressing TdLTP4 gene showed enhanced fungal resistance against Alternaria solani and Botrytis cinerea. Together, these data provide the evidence for the involvement of TdLTP4 gene in the tolerance to both abiotic and biotic stresses in crop plants. PMID:25703105

  7. Involvement of IP3 Receptors in LTP and LTD Induction in Guinea Pig Hippocampal CA1 Neurons

    ERIC Educational Resources Information Center

    Taufiq, Ahmed Mostafa; Fujii, Satoshi; Yamazaki, Yoshihiko; Sasaki, Hiroshi; Kaneko, Kenya; Li, Jianmin; Kato, Hiroshi; Mikoshiba, Katsuhiko

    2005-01-01

    The role of inositol 1, 4, 5-trisphosphate receptors (IP3Rs) in long-term potentiation (LTP) and long-term depression (LTD) was studied in CA1 neurons in guinea pig hippocampal slices. In standard solution, short tetanic stimulation consisting of 15 pulses at 100 Hz induced LTP, while three short trains of low-frequency stimulation (LFS; 200…

  8. Mutation at the TrkB PLC[gamma]-Docking Site Affects Hippocampal LTP and Associative Learning in Conscious Mice

    ERIC Educational Resources Information Center

    Valenzuela-Harrington, Mauricio; Delgado-Garcia, Jose M.; Minichiello, Liliana; Gruart, Agnes; Sciarretta, Carla

    2007-01-01

    Previous in vitro studies have characterized the electrophysiological properties and molecular events associated with long-term potentiation (LTP), but as yet there are no in vivo data from molecular-level dissection that directly identify LTP as the biological substrate for learning and memory. Understanding whether the molecular pathways…

  9. LTP-1, a novel antimitotic agent and Stat3 inhibitor, inhibits human pancreatic carcinomas in vitro and in vivo.

    PubMed

    Huang, Han-Li; Chao, Min-Wu; Chen, Chung-Chun; Cheng, Chun-Chun; Chen, Mei-Chuan; Lin, Chao-Feng; Liou, Jing-Ping; Teng, Che-Ming; Pan, Shiow-Lin

    2016-01-01

    Pancreatic cancer is the leading cause of cancer death worldwide with a poor survival rate. The objective of this study was to determine the mechanism of action of a novel antimitotic and Stat3 inhibitor, LTP-1, on human pancreatic cancer in vitro and in vivo. We found that LTP-1 inhibited pancreatic cancer cell growth and viability with significant G2/M arrest and disruption of microtubule dynamics. LTP-1 also caused G2/M arrest-independent Stat3 dephosphorylation along with ERK activation, which indicated the possible dual function of LTP-1. Long-term treatment of LTP-1 also induced polyploidy, activated caspases, induced subG1 cell population, and therefore, triggered pancreatic cancer cell apoptosis. Finally, we used an in vivo xenograft model to demonstrate that LTP-1 suppressed the growth of pancreatic adenocarcinoma. In summary, our data suggest that LTP-1 may alter microtubule dynamics, which ultimately causes polyploidy and apoptosis, thereby inhibiting pancreatic cancer growth in vitro and in vivo. This study provides evidence that LTP-1 could be a potential therapeutic agent for further development of pancreatic cancer treatment. PMID:27278358

  10. 5-HT1a Receptor Antagonists Block Perforant Path-Dentate LTP Induced in Novel, but Not Familiar, Environments

    ERIC Educational Resources Information Center

    Sanberg, Cyndy Davis; Jones, Floretta L.; Do, Viet H.; Dieguez, Dario, Jr.; Derrick, Brian E.

    2006-01-01

    Numerous studies suggest roles for monoamines in modulating long-term potentiation (LTP). Previously, we reported that both induction and maintenance of perforant path-dentate gyrus LTP is enhanced when induced while animals explore novel environments. Here we investigate the contribution of serotonin and 5-HT1a receptors to the novelty-mediated…

  11. Distribution of SNAP25, VAMP1 and VAMP2 in mature and developing deep cerebellar nuclei after estrogen administration.

    PubMed

    Manca, P; Mameli, O; Caria, M A; Torrejón-Escribano, B; Blasi, J

    2014-04-25

    Synaptosomal-associated protein of 25kDa (SNAP25), vesicle-associated membrane protein 1 (VAMP1) and 2 (VAMP2) are components of soluble N-ethylmaleimide-sensitive fusion attachment protein receptors (SNARE) complex which is involved in synaptic vesicle exocytosis, a fundamental step in neurotransmitter release. SNARE expression in cerebellum correlates with specific neurotransmitter pathways underlying synaptic diversification and defined synaptic properties. In this study we firstly characterized the distribution of SNAP25, VAMP1 and VAMP2 in the nerve terminals of a defined cerebellar region, the deep cerebellar nuclei (DCN), of adult and newborn rats. Then, given the pivotal role of estradiol (E2) in the synaptic organization of the cerebellar circuitry in early postnatal life, we examined whether administration of E2 in the newborn DCN affected synaptic density and changed the distribution of the presynaptic proteins SNAP25, VAMP1 and VAMP2, together with post synaptic density protein 95 (PSD95). Results showed that: (1) distribution of SNAP25, VAMP1 and VAMP2 in adult DCN differs significantly from that found in newborn DCN; (2) administration of E2 in the newborn DCN affected synaptic density and also changed the distribution of the pre- and postsynaptic proteins. The differential distribution of SNAP25, VAMP1 and VAMP2 in nerve terminals of adult and newborn rats may correlate with specific stages of neuronal phenotypic differentiation. The effects of E2 on SNAP25, VAMP1, VAMP2, PDS95 and synaptic density suggest that pre- and postsynaptic proteins are under estrogenic control during development and that synaptic maturation can also be related with the activity of this steroid. PMID:24534378

  12. Impact of single-site axonal GABAergic synaptic events on cerebellar interneuron activity

    PubMed Central

    Zorrilla de San Martin, Javier; Jalil, Abdelali

    2015-01-01

    Axonal ionotropic receptors are present in a variety of neuronal types, and their function has largely been associated with the modulation of axonal activity and synaptic release. It is usually assumed that activation of axonal GABAARs comes from spillover, but in cerebellar molecular layer interneurons (MLIs) the GABA source is different: in these cells, GABA release activates presynaptic GABAA autoreceptors (autoRs) together with postsynaptic targets, producing an autoR-mediated synaptic event. The frequency of presynaptic, autoR-mediated miniature currents is twice that of their somatodendritic counterparts, suggesting that autoR-mediated responses have an important effect on interneuron activity. Here, we used local Ca2+ photolysis in MLI axons of juvenile rats to evoke GABA release from individual varicosities to study the activation of axonal autoRs in single release sites. Our data show that single-site autoR conductances are similar to postsynaptic dendritic conductances. In conditions of high [Cl−]i, autoR-mediated conductances range from 1 to 5 nS; this corresponds to ∼30–150 GABAA channels per presynaptic varicosity, a value close to the number of channels in postsynaptic densities. Voltage responses produced by the activation of autoRs in single varicosities are amplified by a Nav-dependent mechanism and propagate along the axon with a length constant of 91 µm. Immunolabeling determination of synapse location shows that on average, one third of the synapses produce autoR-mediated signals that are large enough to reach the axon initial segment. Finally, we show that single-site activation of presynaptic GABAA autoRs leads to an increase in MLI excitability and thus conveys a strong feedback signal that contributes to spiking activity. PMID:26621773

  13. Consensus Paper: Radiological Biomarkers of Cerebellar Diseases

    PubMed Central

    Baldarçara, Leonardo; Currie, Stuart; Hadjivassiliou, M.; Hoggard, Nigel; Jack, Allison; Jackowski, Andrea P.; Mascalchi, Mario; Parazzini, Cecilia; Reetz, Kathrin; Righini, Andrea; Schulz, Jörg B.; Vella, Alessandra; Webb, Sara Jane; Habas, Christophe

    2016-01-01

    Hereditary and sporadic cerebellar ataxias represent a vast and still growing group of diseases whose diagnosis and differentiation cannot only rely on clinical evaluation. Brain imaging including magnetic resonance (MR) and nuclear medicine techniques allows for characterization of structural and functional abnormalities underlying symptomatic ataxias. These methods thus constitute a potential source of radiological biomarkers, which could be used to identify these diseases and differentiate subgroups of them, and to assess their severity and their evolution. Such biomarkers mainly comprise qualitative and quantitative data obtained from MR including proton spectroscopy, diffusion imaging, tractography, voxel-based morphometry, functional imaging during task execution or in a resting state, and from SPETC and PET with several radiotracers. In the current article, we aim to illustrate briefly some applications of these neuroimaging tools to evaluation of cerebellar disorders such as inherited cerebellar ataxia, fetal developmental malformations, and immune-mediated cerebellar diseases and of neurodegenerative or early-developing diseases, such as dementia and autism in which cerebellar involvement is an emerging feature. Although these radiological biomarkers appear promising and helpful to better understand ataxia-related anatomical and physiological impairments, to date, very few of them have turned out to be specific for a given ataxia with atrophy of the cerebellar system being the main and the most usual alteration being observed. Consequently, much remains to be done to establish sensitivity, specificity, and reproducibility of available MR and nuclear medicine features as diagnostic, progression and surrogate biomarkers in clinical routine. PMID:25382714

  14. Dendritic patch-clamp recordings from cerebellar granule cells demonstrate electrotonic compactness

    PubMed Central

    Delvendahl, Igor; Straub, Isabelle; Hallermann, Stefan

    2015-01-01

    Cerebellar granule cells (GCs), the smallest neurons in the brain, have on average four short dendrites that receive high-frequency mossy fiber inputs conveying sensory information. The short length of the dendrites suggests that GCs are electrotonically compact allowing unfiltered integration of dendritic inputs. The small average diameter of the dendrites (~0.7 µm), however, argues for dendritic filtering. Previous studies based on somatic recordings and modeling indicated that GCs are electrotonically extremely compact. Here, we performed patch-clamp recordings from GC dendrites in acute brain slices of mice to directly analyze the electrotonic properties of GCs. Strikingly, the input resistance did not differ significantly between dendrites and somata of GCs. Furthermore, spontaneous excitatory postsynaptic potentials (EPSP) were similar in amplitude at dendritic and somatic recording sites. From the dendritic and somatic input resistances we determined parameters characterizing the electrotonic compactness of GCs. These data directly demonstrate that cerebellar GCs are electrotonically compact and thus ideally suited for efficient high-frequency information transfer. PMID:25852483

  15. Age-Related Enhancement of a Protein Synthesis-Dependent Late Phase of LTP Induced by Low Frequency Paired-Pulse Stimulation in Hippocampus

    ERIC Educational Resources Information Center

    Huang, Yan-You; Kandel, Eric R.

    2006-01-01

    Protein synthesis-dependent late phase of LTP (L-LTP) is typically induced by repeated high-frequency stimulation (HFS). This form of L-LTP is reduced in the aged animal and is positively correlated with age-related memory loss. Here we report a novel form of protein synthesis-dependent late phase of LTP in the CA1 region of hippocampus induced by…

  16. REM Sleep-Dependent Bidirectional Regulation of Hippocampal-Based Emotional Memory and LTP.

    PubMed

    Ravassard, Pascal; Hamieh, Al Mahdy; Joseph, Mickaël Antoine; Fraize, Nicolas; Libourel, Paul-Antoine; Lebarillier, Léa; Arthaud, Sébastien; Meissirel, Claire; Touret, Monique; Malleret, Gaël; Salin, Paul-Antoine

    2016-04-01

    Prolonged rapid-eye-movement (REM) sleep deprivation has long been used to study the role of REM sleep in learning and memory processes. However, this method potentially induces stress and fatigue that may directly affect cognitive functions. Here, by using a short-term and nonstressful REM sleep deprivation (RSD) method we assessed in rats the bidirectional influence of reduced and increased REM sleep amount on hippocampal-dependent emotional memory and plasticity. Our results indicate that 4 h RSD impaired consolidation of contextual fear conditioning (CFC) and induction of long-term potentiation (LTP), while decreasing density of Egr1/Zif268-expressing neurons in the CA1 region of the dorsal hippocampus. LTP and Egr1 expression were not affected in ventral CA1. Conversely, an increase in REM sleep restores and further facilitates CFC consolidation and LTP induction, and also increases Egr1 expression in dorsal CA1. Moreover, CFC consolidation, Egr1 neuron density, and LTP amplitude in dorsal CA1 show a positive correlation with REM sleep amount. Altogether, these results indicate that mild changes in REM sleep amount bidirectionally affect memory and synaptic plasticity mechanisms occurring in the CA1 area of the dorsal hippocampus. PMID:25585510

  17. Reevaluation of the Beam and Radial Hypotheses of Parallel Fiber Action in the Cerebellar Cortex

    PubMed Central

    Cramer, Samuel W.; Gao, Wangcai; Chen, Gang

    2013-01-01

    The role of parallel fibers (PFs) in cerebellar physiology remains controversial. Early studies inspired the “beam” hypothesis whereby granule cell (GC) activation results in PF-driven, postsynaptic excitation of beams of Purkinje cells (PCs). However, the “radial” hypothesis postulates that the ascending limb of the GC axon provides the dominant input to PCs and generates patch-like responses. Using optical imaging and single-cell recordings in the mouse cerebellar cortex in vivo, this study reexamines the beam versus radial controversy. Electrical stimulation of mossy fibers (MFs) as well as microinjection of NMDA in the granular layer generates beam-like responses with a centrally located patch-like response. Remarkably, ipsilateral forepaw stimulation evokes a beam-like response in Crus I. Discrete molecular layer lesions demonstrate that PFs contribute to the peripherally generated responses in Crus I. In contrast, vibrissal stimulation induces patch-like activation of Crus II and GABAA antagonists fail to convert this patch-like activity into a beam-like response, implying that molecular layer inhibition does not prevent beam-like responses. However, blocking excitatory amino acid transporters (EAATs) generates beam-like responses in Crus II. These beam-like responses are suppressed by focal inhibition of MF-GC synaptic transmission. Using EAAT4 reporter transgenic mice, we show that peripherally evoked patch-like responses in Crus II are aligned between parasagittal bands of EAAT4. This is the first study to demonstrate beam-like responses in the cerebellar cortex to peripheral, MF, and GC stimulation in vivo. Furthermore, the spatial pattern of the responses depends on extracellular glutamate and its local regulation by EAATs. PMID:23843513

  18. Functional circuitry of a unique cerebellar specialization: the valvula cerebelli of a mormyrid fish.

    PubMed

    Zhang, Y; Shi, Z; Magnus, G; Meek, J; Han, V Z; Qiao, J T

    2011-05-19

    The valvula cerebelli of the mormyrid electric fish is a useful site for the study of cerebellar function. The valvula forms a part of the electrosensory-electromotor system of this fish, a system that offers many possibilities for the study of sensory-motor integration. The valvula also has a number of histological features not present in mammals which facilitate investigation of cerebellar circuitry and its plasticity. This initial study characterizes the basic physiology and pharmacology of cells in the valvula using an in vitro slice preparation. Intrinsic properties and synaptic responses of Purkinje cells and other cell types were examined. We found that Purkinje cells fire a small narrow Na(+) spike and a large broad Ca(2+) spike, generated in the axon initial segment and dendritic-soma region, respectively. Purkinje cells respond to parallel fiber inputs with graded excitatory postsynaptic potentials (EPSPs) and to climbing fiber inputs with all-or-none EPSPs. Efferent cells, Golgi cells, and deep stellate cells all fire a single type of large narrow spike and respond only to parallel fiber inputs. Both parallel fiber and climbing fiber responses in Purkinje cells appear to be entirely mediated by AMPA-type glutamate receptors, whereas parallel fiber responses in efferent cells and stellate cells include AMPA and NMDA components. In addition, a strong synaptic inhibition was uncovered in both Purkinje cells and efferent cells in response to the focal stimulation of parallel fibers. Dual cell recordings indicate that deep stellate cells contribute at least partially to this inhibition. We conclude that despite its unique histology, the local functional circuitry of the mormyrid valvula cerebelli is largely similar to that of the mammalian cerebellum. Thus, what is learned concerning the functioning of the mormyrid valvula cerebelli may be expected to be informative about cerebellar function in general. PMID:21414387

  19. Implications on cerebellar function from information coding.

    PubMed

    Huang, Chiming

    2008-01-01

    One function of the cerebellar cortex is to process information. There are at least two types of information. Temporal information is encoded in the timing pattern of action and synaptic potentials, whereas structural information is encoded in the spatial pattern of the cerebellar synaptic circuitry. Intuitively, analysis of highly complex information in the time domain would require a cerebellar cortex with structural complexity to match. Information theory offers a way to estimate quantitatively both types of information and thereby helps to test hypotheses or advance theories of cerebellar neurobiology. These estimates suggest: (i) That the mossy-fiber-granule-cell system carries far more (temporal) information than the climbing fiber system, (ii) that Purkinje cells extract only a fraction of the (temporal) information from their afferents, and (iii) that the cerebellar cortex has a large (spatial) information coding capacity. Concerning information, one can argue that the cerebellar cortex analyzes temporal information in its afferents as a search engine, in search of coincidental mossy fiber events based on timing cues provided by climbing fiber events. Results of successive searches are continuously being converted into structural information encoded in the spatial distribution pattern of granule-cell-Purkinje-cell synapses along granule cell axons, thereby providing an adaptive and indeed self-correcting dimension to the structural information code. The search engine operation involves cellular mechanisms acting on temporal events and is part of an associative learning process. The conversion and generation of structural information involves neuroplasticity mechanisms acting at the synaptic level, with electrophysiological as well as structural consequences, and may be part of the short- and long-term memory process. These and other attributes qualify the cerebellar cortex as a dynamic information processing center, contributing to memory and learning while

  20. Differing Presynaptic Contributions to LTP and Associative Learning in Behaving Mice

    PubMed Central

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

    2009-01-01

    The hippocampal CA3-CA1 synapse is an excellent experimental model for studying the interactions between short- and long-term plastic changes taking place following high-frequency stimulation (HFS) of Schaffer collaterals and during the acquisition and extinction of a classical eyeblink conditioning in behaving mice. Input/output curves and a full-range paired-pulse study enabled determining the optimal intensities and inter-stimulus intervals for evoking paired-pulse facilitation (PPF) or depression (PPD) at the CA3-CA1 synapse. Long-term potentiation (LTP) induced by HFS lasted ≈10 days. HFS-induced LTP evoked an initial depression of basal PPF. Recovery of PPF baseline values was a steady and progressive process lasting ≈20 days, i.e., longer than the total duration of the LTP. In a subsequent series of experiments, we checked whether PPF was affected similarly during activity-dependent synaptic changes. Animals were conditioned using a trace paradigm, with a tone as a conditioned stimulus (CS) and an electrical shock to the trigeminal nerve as an unconditioned stimulus (US). A pair of pulses (40 ms interval) was presented to the Schaffer collateral-commissural pathway to evoke field EPSPs (fEPSPs) during the CS-US interval. Basal PPF decreased steadily across conditioning sessions (i.e., in the opposite direction to that during LTP), reaching a minimum value during the 10th conditioning session. Thus, LTP and classical eyeblink conditioning share some presynaptic mechanisms, but with an opposite evolution. Furthermore, PPF and PPD might play a homeostatic role during long-term plastic changes at the CA3-CA1 synapse. PMID:19636387

  1. The LTP Experiment on LISA Pathfinder: Operational Definition of TT Gauge in Space

    NASA Astrophysics Data System (ADS)

    Armano, Michele

    2011-10-01

    The European Space Agency (ESA) and the National Aeronautics and Space Administration (NASA) are planning the Laser Interferometer Space Antenna (LISA) mission in order to detect GW. The need of accurate testing of free-fall and knowledge of noise in a space environment similar to LISA's is considered mandatory a pre-phase for the project. Therefore the LISA Pathfinder mission has been designed by ESA to fly the LISA Technology Package (LTP), aiming at testing free-fall by measuring the residual acceleration between two test-bodies in the dynamical scheme we address as "drag-free". The spectral map of the residual acceleration as function of frequency will convey information on the local noise level, thus producing a picture of the environmental working conditions for LISA itself. The thesis contains abundant material on the problem of compensating static gravity, the development of a theory of orthogonalization of reference and cross-talk for the LTP experiment. The construction of the laser detection procedure starting from GR and differential geometry arguments is carried on. Effort was put in pointing out the physical motivations for the choices made in several other papers by the author and colleagues. In this perspective the thesis is meant as a summary tool for the LTP collaboration. In the second part of the thesis we summarize our contributions for a measurement of G onboard LTP and review on possible tests of fundamental physics the mission might embody. A wide part of the thesis is now part of the LTP Operation Master Plan, describing the real science and operations onboard LISA Pathfinder. This thesis was defended on September 26th, 2006 at the University of Como, Italy.

  2. Coupled phosphatase and kinase switches produce the tristability required for LTP and LTD

    PubMed Central

    Pi, Hyun Jae

    2009-01-01

    Studies of long-term potentiation (LTP) and long-term depression (LTD) strongly suggest that individual synapses can be bidirectionally modified. A central question is the biochemical mechanisms that make LTP and LTD persistent. Previous theoretical models have proposed that the autophosphorylation properties of CaMKII could underlie a bistable molecular switch that maintains LTP and there is experimental support for this mechanism. In contrast, there has been comparatively little theoretical or experimental work regarding the mechanisms that maintain LTD. Several lines of evidence indicate that LTD is not simply a reversal of previous LTP, but rather involves separate biochemical reactions. These findings indicate that a minimal model of the synapse must involve a tristable system. Here we describe a phosphatase (PP2A) switch, which together with a kinase switch form a tristable system. PP2A can be activated by a Ca2+-dependent process, but can also be phosphorylated and inactivated by CaMKII. When dephosphorylated, PP2A can dephosphorylate itself. We show that these properties can lead to a persistent increase in PP2A during LTD (as reported experimentally), thus forming a phosphatase switch. We show that the coupled PP2A and CaMKII switches lead to a tristable system in which the kinase activity is high in the LTP state; the PP2A activity is high in the LTD state and neither activity is high in the basal state. Our results provide an explanation for the recent finding that inhibition of PP2A prevents LTD induction. PMID:19052204

  3. Acute intracerebral treatment with amyloid-beta (1–42) alters the profile of neuronal oscillations that accompany LTP induction and results in impaired LTP in freely behaving rats

    PubMed Central

    Kalweit, Alexander Nikolai; Yang, Honghong; Colitti-Klausnitzer, Jens; Fülöp, Livia; Bozsó, Zsolt; Penke, Botond; Manahan-Vaughan, Denise

    2015-01-01

    Accumulation of amyloid plaques comprises one of the major hallmarks of Alzheimer’s disease (AD). In rodents, acute treatment with amyloid-beta (Aβ; 1–42) elicits immediate debilitating effects on hippocampal long-term potentiation (LTP). Whereas LTP contributes to synaptic information storage, information is transferred across neurons by means of neuronal oscillations. Furthermore, changes in theta-gamma oscillations, that appear during high-frequency stimulation (HFS) to induce LTP, predict whether successful LTP will occur. Here, we explored if intra-cerebral treatment with Aβ(1–42), that prevents LTP, also results in alterations of hippocampal oscillations that occur during HFS of the perforant path-dentate gyrus synapse in 6-month-old behaving rats. HFS resulted in LTP that lasted for over 24 h. In Aβ-treated animals, LTP was significantly prevented. During HFS, spectral power for oscillations below 100 Hz (δ, θ, α, β and γ) was significantly higher in Aβ-treated animals compared to controls. In addition, the trough-to-peak amplitudes of theta and gamma cycles were higher during HFS in Aβ-treated animals. We also observed a lower amount of envelope-to-signal correlations during HFS in Aβ-treated animals. Overall, the characteristic profile of theta-gamma oscillations that accompany successful LTP induction was disrupted. These data indicate that alterations in network oscillations accompany Aβ-effects on hippocampal LTP. This may comprise an underlying mechanism through which disturbances in synaptic information storage and hippocampus-dependent memory occurs in AD. PMID:25999827

  4. Oculomotor studies of cerebellar function in autism.

    PubMed

    Nowinski, Caralynn V; Minshew, Nancy J; Luna, Beatriz; Takarae, Yukari; Sweeney, John A

    2005-11-15

    Histopathological, neuroimaging and genetic findings indicate cerebellar abnormalities in autism, but the extent of neurophysiological dysfunction associated with those findings has not been systematically examined. Suppression of intrusive saccades (square wave jerks) and the ability to sustain eccentric gaze, two phenomena requiring intact cerebellar function, were examined in 52 high-functioning individuals with autism and 52 age- and IQ-matched healthy subjects during visual fixation of static central and peripheral targets. Rates of intrusive saccades were not increased in autism during visual fixation, and foveopetal ocular drift was also not increased when subjects held an eccentric gaze. The absence of gross disturbances of visual fixation associated with cerebellar disease in individuals with autism, such as increased square wave jerk rates and foveopetal drift when holding eccentric gaze, indicates that the functional integrity of cerebellar--brainstem networks devoted to oculomotor control is preserved in autism despite reported anatomic variations. However, increased amplitude of intrusive saccades and reduced latency of target refixation after intrusive saccades were observed in individuals with autism, especially when subjects maintained fixation of remembered target locations without sensory guidance. The atypical metrics of intrusive saccades that were observed may be attributable to faulty functional connectivity in cortico-cerebellar networks. PMID:16214219

  5. Cerebellar modules operate at different frequencies

    PubMed Central

    Zhou, Haibo; Lin, Zhanmin; Voges, Kai; Ju, Chiheng; Gao, Zhenyu; Bosman, Laurens WJ; Ruigrok, Tom JH; Hoebeek, Freek E

    2014-01-01

    Due to the uniform cyto-architecture of the cerebellar cortex, its overall physiological characteristics have traditionally been considered to be homogeneous. In this study, we show in awake mice at rest that spiking activity of Purkinje cells, the sole output cells of the cerebellar cortex, differs between cerebellar modules and correlates with their expression of the glycolytic enzyme aldolase C or zebrin. Simple spike and complex spike frequencies were significantly higher in Purkinje cells located in zebrin-negative than zebrin-positive modules. The difference in simple spike frequency persisted when the synaptic input to, but not intrinsic activity of, Purkinje cells was manipulated. Blocking TRPC3, the effector channel of a cascade of proteins that have zebrin-like distribution patterns, attenuated the simple spike frequency difference. Our results indicate that zebrin-discriminated cerebellar modules operate at different frequencies, which depend on activation of TRPC3, and that this property is relevant for all cerebellar functions. DOI: http://dx.doi.org/10.7554/eLife.02536.001 PMID:24843004

  6. Metabolic anatomy of paraneoplastic cerebellar degeneration

    SciTech Connect

    Anderson, N.E.; Posner, J.B.; Sidtis, J.J.; Moeller, J.R.; Strother, S.C.; Dhawan, V.; Rottenberg, D.A.

    1988-06-01

    Eleven patients with acquired cerebellar degeneration (10 of whom had paraneoplastic cerebellar degeneration (PCD)) were evaluated using neuropsychological tests and /sup 18/F-fluorodeoxyglucose/positron emission tomography to (1) quantify motor, cognitive, and metabolic abnormalities; (2) determine if characteristic alterations in the regional cerebral metabolic rate for glucose (rCMRGlc) are associated with PCD; and (3) correlate behavioral and metabolic measures of disease severity. Eighteen volunteer subjects served as normal controls. Although some PCD neuropsychological test scores were abnormal, these results could not, in general, be dissociated from the effects of dysarthria and ataxia. rCMRGlc was reduced in patients with PCD (versus normal control subjects) in all regions except the brainstem. Analysis of patient and control rCMRGlc data using a mathematical model of regional metabolic interactions revealed two metabolic pattern descriptors, SSF1 and SSF2, which distinguished patients with PCD from normal control subjects; SSF2, which described a metabolic coupling between cerebellum, cuneus, and posterior temporal, lateral frontal, and paracentral cortex, correlated with quantitative indices of cerebellar dysfunction. Our inability to document substantial intellectual impairment in 7 of 10 patients with PCD contrasts with the 50% incidence of dementia in PCD reported by previous investigators. Widespread reductions in PCD rCMRGlc may result from the loss of cerebellar efferents to thalamus and forebrain structures, a reverse cerebellar diaschisis.

  7. Genetics Home Reference: autosomal recessive cerebellar ataxia type 1

    MedlinePlus

    ... Health Conditions ARCA1 autosomal recessive cerebellar ataxia type 1 Enable Javascript to view the expand/collapse boxes. ... Close All Description Autosomal recessive cerebellar ataxia type 1 ( ARCA1 ) is a condition characterized by progressive problems ...

  8. Neurodevelopmental malformations of the cerebellar vermis in genetically engineered rats

    EPA Science Inventory

    The cerebellar vermis is particularly vulnerable to neurodevelopmental malformations in humans and rodents. Sprague-Dawley, and Long-Evans rats exhibit spontaneous cerebellar malformations consisting of heterotopic neurons and glia in the molecular layer of the vermis. Malformati...

  9. Evolution of non-specific lipid transfer protein (nsLTP) genes in the Poaceae family: their duplication and diversity.

    PubMed

    Jang, Cheol Seong; Yim, Won Cheol; Moon, Jun-Cheol; Hung, Je Hyeong; Lee, Tong Geon; Lim, Sung Don; Cho, Seon Hae; Lee, Kwang Kook; Kim, Wook; Seo, Yong Weon; Lee, Byung-Moo

    2008-05-01

    Previously, the genes encoding non-specific lipid transfer proteins (nsLTPs) of the Poaceae family appear to evidence different genomic distribution and somewhat different shares of EST clones, which is suggestive of independent duplication(s) followed by functional diversity. To further evaluate the evolutionary fate of the Poaceae nsLTP genes, we have identified Ka/Ks values, conserved, mutated or lost cis-regulatory elements, responses to several elicitors, genome-wide expression profiles, and nsLTP gene-coexpression networks of both (or either) wheat and rice. The Ka/Ks values within each group and between groups appeared to be similar, but not identical, in both species. The conserved cis-regulatory elements, e.g. the RY repeat (CATGCA) element related to ABA regulation in group A, might be reflected in some degree of long-term conservation in transcriptional regulation post-dating speciation. In group A, wheat nsLTP genes, with the exception of TaLTP4, evidenced responses similar to those of plant elicitors; however, the rice nsLTP genes evidenced differences in expression profiles, even though the genes of both species have undergone purifying selection, thereby suggesting their independent functional diversity. The expression profiles of rice nsLTP genes with a microarray dataset of 155 gene expression omnibus sample (GSM) plates suggest that subfunctionalization is not the sole mechanism inherent to the evolutionary history of nsLTP genes but may, rather, function in concert with other mechanism(s). As inferred by the nsLTP gene-coexpression networks, the functional diversity of nsLTP genes appears not to be randomized, but rather to be specialized in the direction of specific biological processes over evolutionary time. PMID:18270740

  10. Landmark based shape analysis for cerebellar ataxia classification and cerebellar atrophy pattern visualization

    NASA Astrophysics Data System (ADS)

    Yang, Zhen; Abulnaga, S. Mazdak; Carass, Aaron; Kansal, Kalyani; Jedynak, Bruno M.; Onyike, Chiadi; Ying, Sarah H.; Prince, Jerry L.

    2016-03-01

    Cerebellar dysfunction can lead to a wide range of movement disorders. Studying the cerebellar atrophy pattern associated with different cerebellar disease types can potentially help in diagnosis, prognosis, and treatment planning. In this paper, we present a landmark based shape analysis pipeline to classify healthy control and different ataxia types and to visualize the characteristic cerebellar atrophy patterns associated with different types. A highly informative feature representation of the cerebellar structure is constructed by extracting dense homologous landmarks on the boundary surfaces of cerebellar sub-structures. A diagnosis group classifier based on this representation is built using partial least square dimension reduction and regularized linear discriminant analysis. The characteristic atrophy pattern for an ataxia type is visualized by sampling along the discriminant direction between healthy controls and the ataxia type. Experimental results show that the proposed method can successfully classify healthy controls and different ataxia types. The visualized cerebellar atrophy patterns were consistent with the regional volume decreases observed in previous studies, but the proposed method provides intuitive and detailed understanding about changes of overall size and shape of the cerebellum, as well as that of individual lobules.

  11. Landmark Based Shape Analysis for Cerebellar Ataxia Classification and Cerebellar Atrophy Pattern Visualization

    PubMed Central

    Yang, Zhen; Abulnaga, S. Mazdak; Carass, Aaron; Kansal, Kalyani; Jedynak, Bruno M.; Onyike, Chiadi; Ying, Sarah H.; Prince, Jerry L.

    2016-01-01

    Cerebellar dysfunction can lead to a wide range of movement disorders. Studying the cerebellar atrophy pattern associated with different cerebellar disease types can potentially help in diagnosis, prognosis, and treatment planning. In this paper, we present a landmark based shape analysis pipeline to classify healthy control and different ataxia types and to visualize the characteristic cerebellar atrophy patterns associated with different types. A highly informative feature representation of the cerebellar structure is constructed by extracting dense homologous landmarks on the boundary surfaces of cerebellar sub-structures. A diagnosis group classifier based on this representation is built using partial least square dimension reduction and regularized linear discriminant analysis. The characteristic atrophy pattern for an ataxia type is visualized by sampling along the discriminant direction between healthy controls and the ataxia type. Experimental results show that the proposed method can successfully classify healthy controls and different ataxia types. The visualized cerebellar atrophy patterns were consistent with the regional volume decreases observed in previous studies, but the proposed method provides intuitive and detailed understanding about changes of overall size and shape of the cerebellum, as well as that of individual lobules. PMID:27303111

  12. Cerebellar Glioblastoma Multiforme in an Adult

    PubMed Central

    Hur, Hyuk; Jung, Tae-Young; Kim, In-Young

    2008-01-01

    Primary cerebellar glioblastoma multiforme (GBM) is a rare tumor in adults that accounts for just 1% of all cases of GBM. Due to their rarity, cerebellar GBMs are not yet completely understood about the pathogenesis and the prognosis. Here, we present a case of GBM in a 69-year-old man. Neurologic examination revealed the presence of cerebellar signs. Magnetic resonance imaging (MRI) showed a 4.5 × 3.6 cm-sized, ill-defined, heterogeneously enhancing mass in the left cerebellum and two patchy hyperintense lesions in the right cerebellum with minimal enhancement. After operation, glioblastoma was histologically confirmed. Postoperative radiotherapy with concomitant and adjuvant temozolomide chemotherapy was subsequently followed. Here, a case of unusual GBM in the cerebellum is reported with review of literature regarding the pathogenesis, the differential diagnosis and prognosis. There was no evidence of recurrence during postoperative one year. This patient showed a good prognosis in spite of the multiple lesions. PMID:19096643

  13. Cerebellar contribution to feedforward control of locomotion

    PubMed Central

    Pisotta, Iolanda; Molinari, Marco

    2014-01-01

    The cerebellum is an important contributor to feedforward control mechanisms of the central nervous system, and sequencing—the process that allows spatial and temporal relationships between events to be recognized—has been implicated as the fundamental cerebellar mode of operation. By adopting such a mode and because cerebellar activity patterns are sensitive to a variety of sensorimotor-related tasks, the cerebellum is believed to support motor and cognitive functions that are encoded in the frontal and parietal lobes of the cerebral cortex. In this model, the cerebellum is hypothesized to make predictions about the consequences of a motor or cognitive command that originates from the cortex to prepare the entire system to cope with ongoing changes. In this framework, cerebellar predictive mechanisms for locomotion are addressed, focusing on sensorial and motoric sequencing. The hypothesis that sequence recognition is the mechanism by which the cerebellum functions in gait control is presented and discussed. PMID:25009490

  14. [Residual cerebellar ataxia following acute phenytoin intoxication].

    PubMed

    Awada, A; Amene, P; al Jumah, M; al Beladi, K

    1999-04-01

    A 30-year-old man was given high doses of phenytoin together with 4 antituberculous drugs for a seizure associated with a probable brain tuberculoma. He developed hepatic toxicity and his serum phenytoin reached the high level of 298 mumol/l (therapeutic range 40-79 mumol/l). All drugs were stopped and the biological parameters returned progressively to normal over the next 15 days. However, he remained with a cerebellar axial syndrome and was still severely ataxic 2 months later. Brain CT and MRI showed mild cerebellar atrophy. This case and the few other published ones, together with some recent experimental data, show that high doses of phenytoin can be toxic to the cerebellar cortical cells. The rarity of similar cases, while millions of epileptics are under phenytoin treatment, would however suggest that individual susceptibility may play a role in this toxicity. PMID:10367328

  15. Cerebellar contribution to feedforward control of locomotion.

    PubMed

    Pisotta, Iolanda; Molinari, Marco

    2014-01-01

    The cerebellum is an important contributor to feedforward control mechanisms of the central nervous system, and sequencing-the process that allows spatial and temporal relationships between events to be recognized-has been implicated as the fundamental cerebellar mode of operation. By adopting such a mode and because cerebellar activity patterns are sensitive to a variety of sensorimotor-related tasks, the cerebellum is believed to support motor and cognitive functions that are encoded in the frontal and parietal lobes of the cerebral cortex. In this model, the cerebellum is hypothesized to make predictions about the consequences of a motor or cognitive command that originates from the cortex to prepare the entire system to cope with ongoing changes. In this framework, cerebellar predictive mechanisms for locomotion are addressed, focusing on sensorial and motoric sequencing. The hypothesis that sequence recognition is the mechanism by which the cerebellum functions in gait control is presented and discussed. PMID:25009490

  16. 21 CFR 882.5820 - Implanted cerebellar stimulator.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Implanted cerebellar stimulator. 882.5820 Section... (CONTINUED) MEDICAL DEVICES NEUROLOGICAL DEVICES Neurological Therapeutic Devices § 882.5820 Implanted cerebellar stimulator. (a) Identification. An implanted cerebellar stimulator is a device used to...

  17. 21 CFR 882.5820 - Implanted cerebellar stimulator.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Implanted cerebellar stimulator. 882.5820 Section... (CONTINUED) MEDICAL DEVICES NEUROLOGICAL DEVICES Neurological Therapeutic Devices § 882.5820 Implanted cerebellar stimulator. (a) Identification. An implanted cerebellar stimulator is a device used to...

  18. 21 CFR 882.5820 - Implanted cerebellar stimulator.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Implanted cerebellar stimulator. 882.5820 Section... (CONTINUED) MEDICAL DEVICES NEUROLOGICAL DEVICES Neurological Therapeutic Devices § 882.5820 Implanted cerebellar stimulator. (a) Identification. An implanted cerebellar stimulator is a device used to...

  19. High-affinity uptake of noradrenaline in postsynaptic neurones.

    PubMed Central

    al-Damluji, S.; Krsmanovic, L. Z.; Catt, K. J.

    1993-01-01

    1. Neurotransmitters released from nerve endings are inactivated by re-uptake into the presynaptic nerve terminals and possibly into neighbouring glial cells. While analysing the functional properties of alpha 1-adrenoceptors in the hypothalamus, we observed a high-affinity uptake process for noradrenaline in postsynaptic peptidergic neurones. 2. In primary hypothalamic cell cultures and in a hypothalamic neuronal cell line, [3H]-prazosin bound with high affinity and was displaced by unlabelled prazosin in concentrations of 10(-10) to 10(-7) M. However, at concentrations of unlabelled prazosin above 10(-7) M, there was a paradoxical increase in apparent [3H]-prazosin binding. 3. Methoxamine, an alpha 1-adrenoceptor ligand that is not subject to significant neuronal uptake, displaced [3H]-prazosin but did not cause the paradoxical increase in the apparent binding of [3H]-prazosin. Cooling the cells to 4 degrees C reduced the total amount of prazosin associated with the cells; under these conditions, methoxamine almost completely inhibited [3H]-prazosin binding to the cells. 4. In the presence of desipramine (DMI), unlabelled prazosin displaced [3H]-prazosin as before, but no paradoxical increase in apparent binding was seen above 10(-7) M. 5. The paradoxical increase of [3H]-prazosin binding was not observed in membrane preparations of hypothalamic neurones. These findings indicated that the paradoxical increase in apparent [3H]-prazosin binding was due to a cellular uptake process that becomes evident at high concentrations of the ligand. 6. DMI (10(-5) M) had no effect on the specific binding of [3H]-prazosin.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8358534

  20. The Cerebellar Mutism Syndrome and Its Relation to Cerebellar Cognitive Function and the Cerebellar Cognitive Affective Disorder

    ERIC Educational Resources Information Center

    Wells, Elizabeth M.; Walsh, Karin S.; Khademian, Zarir P.; Keating, Robert F.; Packer, Roger J.

    2008-01-01

    The postoperative cerebellar mutism syndrome (CMS), consisting of diminished speech output, hypotonia, ataxia, and emotional lability, occurs after surgery in up to 25% of patients with medulloblastoma and occasionally after removal of other posterior fossa tumors. Although the mutism is transient, speech rarely normalizes and the syndrome is…

  1. A requirement for the immediate early gene Zif268 in the expression of late LTP and long-term memories.

    PubMed

    Jones, M W; Errington, M L; French, P J; Fine, A; Bliss, T V; Garel, S; Charnay, P; Bozon, B; Laroche, S; Davis, S

    2001-03-01

    The induction of long-term potentiation (LTP) in the dentate gyrus of the hippocampus is associated with a rapid and robust transcription of the immediate early gene Zif268. We used a mutant mouse with a targeted disruption of Zif268 to ask whether this gene, which encodes a zinc finger transcription factor, is required for the maintenance of late LTP and for the expression of long-term memory. We show that whereas mutant mice exhibit early LTP in the dentate gyrus, late LTP is absent when measured 24 and 48 hours after tetanus in the freely moving animal. In both spatial and non-spatial learning tasks, short-term memory remained intact, whereas performance was impaired in tests requiring long-term memory. Thus, Zif268 is essential for the transition from short- to long-term synaptic plasticity and for the expression of long-term memories. PMID:11224546

  2. Synaptic excitation is regulated by the postsynaptic dSK channel at the Drosophila larval NMJ

    PubMed Central

    Gertner, Daniel M.; Desai, Sunil

    2014-01-01

    In the mammalian central nervous system, the postsynaptic small-conductance Ca2+-dependent K+ (SK) channel has been shown to reduce postsynaptic depolarization and limit Ca2+ influx through N-methyl-d-aspartate receptors. To examine further the role of the postsynaptic SK channel in synaptic transmission, we studied its action at the Drosophila larval neuromuscular junction (NMJ). Repetitive synaptic stimulation produced an increase in postsynaptic membrane conductance leading to depression of excitatory postsynaptic potential amplitude and hyperpolarization of the resting membrane potential (RMP). This reduction in synaptic excitation was due to the postsynaptic Drosophila SK (dSK) channel; synaptic depression, increased membrane conductance and RMP hyperpolarization were reduced in dSK mutants or after expressing a Ca2+ buffer in the muscle. Ca2+ entering at the postsynaptic membrane was sufficient to activate dSK channels based upon studies in which the muscle membrane was voltage clamped to prevent opening voltage-dependent Ca2+ channels. Increasing external Ca2+ produced an increase in resting membrane conductance and RMP that was not seen in dSK mutants or after adding the glutamate-receptor blocker philanthotoxin. Thus it appeared that dSK channels were also activated by spontaneous transmitter release and played a role in setting membrane conductance and RMP. In mammals, dephosphorylation by protein phosphatase 2A (PP2A) increased the Ca2+ sensitivity of the SK channel; PP2A appeared to increase the sensitivity of the dSK channel since PP2A inhibitors reduced activation of the dSK channel by evoked synaptic activity or increased external Ca2+. It is proposed that spontaneous and evoked transmitter release activate the postsynaptic dSK channel to limit synaptic excitation and stabilize synapses. PMID:24671529

  3. The Human Postsynaptic Density Shares Conserved Elements with Proteomes of Unicellular Eukaryotes and Prokaryotes

    PubMed Central

    Emes, Richard David; Grant, Seth G. N.

    2011-01-01

    The animal nervous system processes information from the environment and mediates learning and memory using molecular signaling pathways in the postsynaptic terminal of synapses. Postsynaptic neurotransmitter receptors assemble to form multiprotein complexes that drive signal transduction pathways to downstream cell biological processes. Studies of mouse and Drosophila postsynaptic proteins have identified key roles in synaptic physiology and behavior for a wide range of proteins including receptors, scaffolds, enzymes, structural, translational, and transcriptional regulators. Comparative proteomic and genomic studies identified components of the postsynaptic proteome conserved in eukaryotes and early metazoans. We extend these studies, and examine the conservation of genes and domains found in the human postsynaptic density with those across the three superkingdoms, archaeal, bacteria, and eukaryota. A conserved set of proteins essential for basic cellular functions were conserved across the three superkingdoms, whereas synaptic structural and many signaling molecules were specific to the eukaryote lineage. Genes involved with metabolism and environmental signaling in Escherichia coli including the chemotactic and ArcAB Two-Component signal transduction systems shared homologous genes in the mammalian postsynaptic proteome. These data suggest conservation between prokaryotes and mammalian synapses of signaling mechanisms from receptors to transcriptional responses, a process essential to learning and memory in vertebrates. A number of human postsynaptic proteins with homologs in prokaryotes are mutated in human genetic diseases with nervous system pathology. These data also indicate that structural and signaling proteins characteristic of postsynaptic complexes arose in the eukaryotic lineage and rapidly expanded following the emergence of the metazoa, and provide an insight into the early evolution of synaptic mechanisms and conserved mechanisms of learning and

  4. Distributed cerebellar plasticity implements adaptable gain control in a manipulation task: a closed-loop robotic simulation

    PubMed Central

    Garrido, Jesús A.; Luque, Niceto R.; D'Angelo, Egidio; Ros, Eduardo

    2013-01-01

    Adaptable gain regulation is at the core of the forward controller operation performed by the cerebro-cerebellar loops and it allows the intensity of motor acts to be finely tuned in a predictive manner. In order to learn and store information about body-object dynamics and to generate an internal model of movement, the cerebellum is thought to employ long-term synaptic plasticity. LTD at the PF-PC synapse has classically been assumed to subserve this function (Marr, 1969). However, this plasticity alone cannot account for the broad dynamic ranges and time scales of cerebellar adaptation. We therefore tested the role of plasticity distributed over multiple synaptic sites (Hansel et al., 2001; Gao et al., 2012) by generating an analog cerebellar model embedded into a control loop connected to a robotic simulator. The robot used a three-joint arm and performed repetitive fast manipulations with different masses along an 8-shape trajectory. In accordance with biological evidence, the cerebellum model was endowed with both LTD and LTP at the PF-PC, MF-DCN and PC-DCN synapses. This resulted in a network scheme whose effectiveness was extended considerably compared to one including just PF-PC synaptic plasticity. Indeed, the system including distributed plasticity reliably self-adapted to manipulate different masses and to learn the arm-object dynamics over a time course that included fast learning and consolidation, along the lines of what has been observed in behavioral tests. In particular, PF-PC plasticity operated as a time correlator between the actual input state and the system error, while MF-DCN and PC-DCN plasticity played a key role in generating the gain controller. This model suggests that distributed synaptic plasticity allows generation of the complex learning properties of the cerebellum. The incorporation of further plasticity mechanisms and of spiking signal processing will allow this concept to be extended in a more realistic computational scenario

  5. Distributed cerebellar plasticity implements adaptable gain control in a manipulation task: a closed-loop robotic simulation.

    PubMed

    Garrido, Jesús A; Luque, Niceto R; D'Angelo, Egidio; Ros, Eduardo

    2013-01-01

    Adaptable gain regulation is at the core of the forward controller operation performed by the cerebro-cerebellar loops and it allows the intensity of motor acts to be finely tuned in a predictive manner. In order to learn and store information about body-object dynamics and to generate an internal model of movement, the cerebellum is thought to employ long-term synaptic plasticity. LTD at the PF-PC synapse has classically been assumed to subserve this function (Marr, 1969). However, this plasticity alone cannot account for the broad dynamic ranges and time scales of cerebellar adaptation. We therefore tested the role of plasticity distributed over multiple synaptic sites (Hansel et al., 2001; Gao et al., 2012) by generating an analog cerebellar model embedded into a control loop connected to a robotic simulator. The robot used a three-joint arm and performed repetitive fast manipulations with different masses along an 8-shape trajectory. In accordance with biological evidence, the cerebellum model was endowed with both LTD and LTP at the PF-PC, MF-DCN and PC-DCN synapses. This resulted in a network scheme whose effectiveness was extended considerably compared to one including just PF-PC synaptic plasticity. Indeed, the system including distributed plasticity reliably self-adapted to manipulate different masses and to learn the arm-object dynamics over a time course that included fast learning and consolidation, along the lines of what has been observed in behavioral tests. In particular, PF-PC plasticity operated as a time correlator between the actual input state and the system error, while MF-DCN and PC-DCN plasticity played a key role in generating the gain controller. This model suggests that distributed synaptic plasticity allows generation of the complex learning properties of the cerebellum. The incorporation of further plasticity mechanisms and of spiking signal processing will allow this concept to be extended in a more realistic computational scenario

  6. Norepinephrine triggers metaplasticity of LTP by increasing translation of specific mRNAs.

    PubMed

    Maity, Sabyasachi; Rah, Sean; Sonenberg, Nahum; Gkogkas, Christos G; Nguyen, Peter V

    2015-10-01

    Norepinephrine (NE) is a key modulator of synaptic plasticity in the hippocampus, a brain structure crucially involved in memory formation. NE boosts synaptic plasticity mostly through initiation of signaling cascades downstream from beta (β)-adrenergic receptors (β-ARs). Previous studies demonstrated that a β-adrenergic receptor agonist, isoproterenol, can modify the threshold for long-term potentiation (LTP), a putative cellular mechanism for learning and memory, in a process known as "metaplasticity." Metaplasticity is the ability of synaptic plasticity to be modified by prior experience. We asked whether NE itself could engage metaplastic mechanisms in area CA1 of mouse hippocampal slices. Using extracellular field potential recording and stimulation, we show that application of NE (10 µM), which did not alter basal synaptic strength, enhances the future maintenance of LTP elicited by subthreshold, high-frequency stimulation (HFS: 1 × 100 Hz, 1 sec). HFS applied 30 min after NE washout induced long-lasting (>4 h) LTP, which was significantly extended in duration relative to HFS alone. This NE-induced metaplasticity required β1-AR activation, as coapplication of the β1-receptor antagonist CGP-20712A (1 µM) attenuated maintenance of LTP. We also found that NE-mediated metaplasticity was translation- and transcription-dependent. Polysomal profiles of CA1 revealed increased translation rates for specific mRNAs during NE-induced metaplasticity. Thus, activation of β-ARs by NE primes synapses for future long-lasting plasticity on time scales extending beyond fast synaptic transmission; this may facilitate neural information processing and the subsequent formation of lasting memories. PMID:26373828

  7. Metaplastic Effect of Apamin on LTP and Paired-Pulse Facilitation

    ERIC Educational Resources Information Center

    Ris, Laurence; Capron, Brigitte; Sclavons, Coralie; Liegeois, Jean-Francois; Seutin, Vincent; Godaux, Emile

    2007-01-01

    In area CA1 of hippocampal slices, a single 1-sec train of 100-Hz stimulation generally triggers a short-lasting long-term potentiation (S-LTP) of 1-2 h. Here, we found that when such a train was applied 45 min after application of the small conductance Ca[superscript 2+]-activated K[superscript +] (SK) channel blocker apamin, it induced a…

  8. Nicotine primes the effect of cocaine on the induction of LTP in the amygdala.

    PubMed

    Huang, Yan-You; Kandel, Denise B; Kandel, Eric R; Levine, Amir

    2013-11-01

    In human populations, there is a well-defined sequence of involvement in drugs of abuse, in which the use of nicotine or alcohol precedes the use of marijuana, which in turn, precedes the use of cocaine. The term "Gateway Hypothesis" describes this developmental sequence of drug involvement. In prior work, we have developed a mouse model to study the underlying metaplastic behavioral, cellular and molecular mechanisms by which exposure to one drug, namely nicotine, affects the response to another drug, namely cocaine. We found that nicotine enhances significantly the changes in synaptic plasticity in the striatum induced by cocaine (Levine et al., 2011). Here we ask: does the metaplastic effect of nicotine on cocaine also apply in the amygdala, a brain region that is involved in the orchestration of emotions and in drug addiction? We find that pretreatment with nicotine enhances long-term synaptic potentiation (LTP) in response to cocaine in the amygdala. Both short-term (1 day) and long-term (7 days) pre-exposure to nicotine facilitate the induction of LTP by cocaine. The effect of nicotine on LTP is unidirectional; exposure to nicotine following treatment with cocaine is ineffective. This metaplastic effect of nicotine on cocaine is long lasting but reversible. The facilitation of LTP can be obtained for 24 but not 40 days after cessation of nicotine. As is the case in the striatum, pretreatment with Suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, simulates the priming effect of nicotine. These results provide further evidence that the priming effect of nicotine may be achieved, at least partially, by the inhibition of histone acetylation and indicate that the amygdala appears to be an important brain structure for the processing of the metaplastic effect of nicotine on cocaine. This article is part of the Special Issue entitled 'Glutamate Receptor-Dependent Synaptic Plasticity'. PMID:23597510

  9. Extrasynaptic and Postsynaptic Receptors in Glycinergic and GABAergic Neurotransmission: A Division of Labor?

    PubMed Central

    Muller, Emilie; Le-Corronc, Hervé; Legendre, Pascal

    2008-01-01

    Glycine and GABA mediate inhibitory neurotransmission in the spinal cord and central nervous system. The general concept of neurotransmission is now challenged by the contribution of both phasic activation of postsynaptic glycine and GABAA receptors (GlyRs and GABAARs, respectively) and tonic activity of these receptors located at extrasynaptic sites. GlyR and GABAAR kinetics depend on several parameters, including subunit composition, subsynaptic localization and activation mode. Postsynaptic and extrasynaptic receptors display different subunit compositions and are activated by fast presynaptic and slow paracrine release of neurotransmitters, respectively. GlyR and GABAAR functional properties also rely on their aggregation level, which is higher at postsynaptic densities than at extrasynaptic loci. Finally, these receptors can co-aggregate at mixed inhibitory postsynaptic densities where they cross-modulate their activity, providing another parameter of functional complexity. GlyR and GABAAR density at postsynaptic sites results from the balance between their internalization and insertion in the plasma membrane, but also on their lateral diffusion from and to the postsynaptic loci. The dynamic exchange of receptors between synaptic and extrasynaptic sites and their functional adaptation in terms of kinetics point out a new adaptive process of inhibitory neurotransmission. PMID:18946536

  10. The Cdc42-selective GAP Rich regulates postsynaptic development and retrograde BMP transsynaptic signaling

    PubMed Central

    Nahm, Minyeop; Long, A. Ashleigh; Paik, Sang Kyoo; Kim, Sungdae; Bae, Yong Chul

    2010-01-01

    Retrograde bone morphogenetic protein signaling mediated by the Glass bottom boat (Gbb) ligand modulates structural and functional synaptogenesis at the Drosophila melanogaster neuromuscular junction. However, the molecular mechanisms regulating postsynaptic Gbb release are poorly understood. In this study, we show that Drosophila Rich (dRich), a conserved Cdc42-selective guanosine triphosphatase–activating protein (GAP), inhibits the Cdc42–Wsp pathway to stimulate postsynaptic Gbb release. Loss of dRich causes synaptic undergrowth and strongly impairs neurotransmitter release. These presynaptic defects are rescued by targeted postsynaptic expression of wild-type dRich but not a GAP-deficient mutant. dRich inhibits the postsynaptic localization of the Cdc42 effector Wsp (Drosophila orthologue of mammalian Wiskott-Aldrich syndrome protein, WASp), and manifestation of synaptogenesis defects in drich mutants requires Wsp signaling. In addition, dRich regulates postsynaptic organization independently of Cdc42. Importantly, dRich increases Gbb release and elevates presynaptic phosphorylated Mad levels. We propose that dRich coordinates the Gbb-dependent modulation of synaptic growth and function with postsynaptic development. PMID:21041451

  11. Inverse Stochastic Resonance in Cerebellar Purkinje Cells.

    PubMed

    Buchin, Anatoly; Rieubland, Sarah; Häusser, Michael; Gutkin, Boris S; Roth, Arnd

    2016-08-01

    Purkinje neurons play an important role in cerebellar computation since their axons are the only projection from the cerebellar cortex to deeper cerebellar structures. They have complex internal dynamics, which allow them to fire spontaneously, display bistability, and also to be involved in network phenomena such as high frequency oscillations and travelling waves. Purkinje cells exhibit type II excitability, which can be revealed by a discontinuity in their f-I curves. We show that this excitability mechanism allows Purkinje cells to be efficiently inhibited by noise of a particular variance, a phenomenon known as inverse stochastic resonance (ISR). While ISR has been described in theoretical models of single neurons, here we provide the first experimental evidence for this effect. We find that an adaptive exponential integrate-and-fire model fitted to the basic Purkinje cell characteristics using a modified dynamic IV method displays ISR and bistability between the resting state and a repetitive activity limit cycle. ISR allows the Purkinje cell to operate in different functional regimes: the all-or-none toggle or the linear filter mode, depending on the variance of the synaptic input. We propose that synaptic noise allows Purkinje cells to quickly switch between these functional regimes. Using mutual information analysis, we demonstrate that ISR can lead to a locally optimal information transfer between the input and output spike train of the Purkinje cell. These results provide the first experimental evidence for ISR and suggest a functional role for ISR in cerebellar information processing. PMID:27541958

  12. Cerebellar Disease in an Adult Cow

    PubMed Central

    Oz, H. H.; Nicholson, S. S.; Al-Bagdadi, F. K.; Zeman, D. H.

    1986-01-01

    This is the report of clinical signs and lesions of a cerebellar disorder in an adult four year old Limousin cow grazing perennial ryegrass (Lolium perenne). The most striking histopathological lesion was a marked paucity of Purkinje cells throughout the cerebellum. ImagesFigure 1.Figure 2. PMID:17422607

  13. Vergence Deficits in Patients with Cerebellar Lesions

    ERIC Educational Resources Information Center

    Sander, T.; Sprenger, A.; Neumann, G.; Machner, B.; Gottschalk, S.; Rambold, H.; Helmchen, C.

    2009-01-01

    The cerebellum is part of the cortico-ponto-cerebellar circuit for conjugate eye movements. Recent animal data suggest an additional role of the cerebellum for the control of binocular alignment and disconjugate, i.e. vergence eye movements. The latter is separated into two different components: fast vergence (to step targets) and slow vergence…

  14. Inverse Stochastic Resonance in Cerebellar Purkinje Cells

    PubMed Central

    Häusser, Michael; Gutkin, Boris S.; Roth, Arnd

    2016-01-01

    Purkinje neurons play an important role in cerebellar computation since their axons are the only projection from the cerebellar cortex to deeper cerebellar structures. They have complex internal dynamics, which allow them to fire spontaneously, display bistability, and also to be involved in network phenomena such as high frequency oscillations and travelling waves. Purkinje cells exhibit type II excitability, which can be revealed by a discontinuity in their f-I curves. We show that this excitability mechanism allows Purkinje cells to be efficiently inhibited by noise of a particular variance, a phenomenon known as inverse stochastic resonance (ISR). While ISR has been described in theoretical models of single neurons, here we provide the first experimental evidence for this effect. We find that an adaptive exponential integrate-and-fire model fitted to the basic Purkinje cell characteristics using a modified dynamic IV method displays ISR and bistability between the resting state and a repetitive activity limit cycle. ISR allows the Purkinje cell to operate in different functional regimes: the all-or-none toggle or the linear filter mode, depending on the variance of the synaptic input. We propose that synaptic noise allows Purkinje cells to quickly switch between these functional regimes. Using mutual information analysis, we demonstrate that ISR can lead to a locally optimal information transfer between the input and output spike train of the Purkinje cell. These results provide the first experimental evidence for ISR and suggest a functional role for ISR in cerebellar information processing. PMID:27541958

  15. Radiation-induced cerebellar chondrosarcoma. Case report

    SciTech Connect

    Bernstein, M.; Perrin, R.G.; Platts, M.E.; Simpson, W.J.

    1984-07-01

    The authors report a case of chondrosarcoma arising in the cerebellum 16 years after treatment of a cerebellar malignant astrocytoma by subtotal resection and irradiation. It is thought that the chondrosarcoma arising within the intracranial cavity was a probable consequence of previous ionizing radiation.

  16. Improving cerebellar segmentation with statistical fusion

    NASA Astrophysics Data System (ADS)

    Plassard, Andrew J.; Yang, Zhen; Prince, Jerry L.; Claassen, Daniel O.; Landman, Bennett A.

    2016-03-01

    The cerebellum is a somatotopically organized central component of the central nervous system well known to be involved with motor coordination and increasingly recognized roles in cognition and planning. Recent work in multiatlas labeling has created methods that offer the potential for fully automated 3-D parcellation of the cerebellar lobules and vermis (which are organizationally equivalent to cortical gray matter areas). This work explores the trade offs of using different statistical fusion techniques and post hoc optimizations in two datasets with distinct imaging protocols. We offer a novel fusion technique by extending the ideas of the Selective and Iterative Method for Performance Level Estimation (SIMPLE) to a patch-based performance model. We demonstrate the effectiveness of our algorithm, Non- Local SIMPLE, for segmentation of a mixed population of healthy subjects and patients with severe cerebellar anatomy. Under the first imaging protocol, we show that Non-Local SIMPLE outperforms previous gold-standard segmentation techniques. In the second imaging protocol, we show that Non-Local SIMPLE outperforms previous gold standard techniques but is outperformed by a non-locally weighted vote with the deeper population of atlases available. This work advances the state of the art in open source cerebellar segmentation algorithms and offers the opportunity for routinely including cerebellar segmentation in magnetic resonance imaging studies that acquire whole brain T1-weighted volumes with approximately 1 mm isotropic resolution.

  17. Improving Cerebellar Segmentation with Statistical Fusion

    PubMed Central

    Plassard, Andrew J.; Yang, Zhen; Prince, Jerry L.; Claassen, Daniel O.; Landman, Bennett A.

    2016-01-01

    The cerebellum is a somatotopically organized central component of the central nervous system well known to be involved with motor coordination and increasingly recognized roles in cognition and planning. Recent work in multi-atlas labeling has created methods that offer the potential for fully automated 3-D parcellation of the cerebellar lobules and vermis (which are organizationally equivalent to cortical gray matter areas). This work explores the trade offs of using different statistical fusion techniques and post hoc optimizations in two datasets with distinct imaging protocols. We offer a novel fusion technique by extending the ideas of the Selective and Iterative Method for Performance Level Estimation (SIMPLE) to a patch-based performance model. We demonstrate the effectiveness of our algorithm, Non-Local SIMPLE, for segmentation of a mixed population of healthy subjects and patients with severe cerebellar anatomy. Under the first imaging protocol, we show that Non-Local SIMPLE outperforms previous gold-standard segmentation techniques. In the second imaging protocol, we show that Non-Local SIMPLE outperforms previous gold standard techniques but is outperformed by a non-locally weighted vote with the deeper population of atlases available. This work advances the state of the art in open source cerebellar segmentation algorithms and offers the opportunity for routinely including cerebellar segmentation in magnetic resonance imaging studies that acquire whole brain T1-weighted volumes with approximately 1 mm isotropic resolution. PMID:27127334

  18. Isolation and full characterisation of a potentially allergenic lipid transfer protein (LTP) in almond.

    PubMed

    Buhler, Sofie; Tedeschi, Tullia; Faccini, Andrea; Garino, Cristiano; Arlorio, Marco; Dossena, Arnaldo; Sforza, Stefano

    2015-01-01

    Non-specific lipid transfer proteins (nsLTP) were shown to be among the most significant allergens, in particular in several fruits belonging to the Rosaceae family. The molecular features of LTPs, such as the presence of eight cysteine residues forming four disulfide bridges, confer a compact structure, decreasing the probability of degradation due to cooking or digestion, thereby increasing the chance of systemic absorption and severe allergic reactions. Few studies on LTP-induced allergies regarding almond (Prunus dulcis L) are available in the literature. In the present work, we describe for the first time the extraction and purification of an almond LTP, achieving its full characterisation by using liquid chromatography and exact mass spectrometry; the full sequence was identified by means of LC-ESI-Orbitrap-MS applying a bottom-up approach. The characterised protein consists of 92 amino acids and has a calculated exact MW of 9579.0. The presence of four disulfide bridges was confirmed after reduction, as shown by a mass increment of 8 Da. Finally, its potential allergenicity was confirmed via an in silico approach. The results presented here demonstrate the enormous potential of advanced MS techniques for obtaining high-quality structural and functional data of allergenic proteins in a short time. PMID:25658292

  19. A PARP1-ERK2 synergism is required for the induction of LTP

    PubMed Central

    Visochek, L.; Grigoryan, G.; Kalal, A.; Milshtein-Parush, H.; Gazit, N.; Slutsky, I.; Yeheskel, A.; Shainberg, A.; Castiel, A.; Seger, R.; Langelier, M. F.; Dantzer, F.; Pascal, J. M.; Segal, M.; Cohen-Armon, M.

    2016-01-01

    Unexpectedly, a post-translational modification of DNA-binding proteins, initiating the cell response to single-strand DNA damage, was also required for long-term memory acquisition in a variety of learning paradigms. Our findings disclose a molecular mechanism based on PARP1-Erk synergism, which may underlie this phenomenon. A stimulation induced PARP1 binding to phosphorylated Erk2 in the chromatin of cerebral neurons caused Erk-induced PARP1 activation, rendering transcription factors and promoters of immediate early genes (IEG) accessible to PARP1-bound phosphorylated Erk2. Thus, Erk-induced PARP1 activation mediated IEG expression implicated in long-term memory. PARP1 inhibition, silencing, or genetic deletion abrogated stimulation-induced Erk-recruitment to IEG promoters, gene expression and LTP generation in hippocampal CA3-CA1-connections. Moreover, a predominant binding of PARP1 to single-strand DNA breaks, occluding its Erk binding sites, suppressed IEG expression and prevented the generation of LTP. These findings outline a PARP1-dependent mechanism required for LTP generation, which may be implicated in long-term memory acquisition and in its deterioration in senescence. PMID:27121568

  20. Involvement of cellular metabolism in age-related LTP modifications in rat hippocampal slices

    PubMed Central

    Drulis-Fajdasz, Dominika; Wójtowicz, Tomasz; Wawrzyniak, Marcin; Wlodarczyk, Jakub; Mozrzymas, Jerzy W.; Rakus, Dariusz

    2015-01-01

    Recent studies emphasized crucial role of astrocytic glycogen metabolism in regulation of synaptic transmission and plasticity in young animals. However, the interplay between age-related synaptic plasticity impairments and changes in energetic metabolism remains obscure. To address this issue, we investigated, in hippocampal slices of young (one month) and aged rats (20-22-months), the impact of glycogen degradation inhibition on LTP, mRNA expression for glycogen metabolism enzymes and morphology of dendritic spines. We show that, whereas in young hippocampi, inhibition of glycogen phosphorolysis disrupts the late phase of LTP in the Schaffer collateral-CA1 pathway, in aged rats, blockade of glycogen phosphorylase tends to enhance it. Gene expression for key energy metabolism enzymes, such as glycogen synthase and phosphorylase and glutamine synthetase showed marked differences between young and aged groups and changes in expression of these enzymes preceded plasticity phenomena. Interestingly, in the aged group, a prominent expression of these enzymes was found also in neurons. Concluding, we show that LTP in the considered pathway is differentially modulated by metabolic processes in young and aging animals, indicating a novel venue of studies aiming at preventing cognitive decline during aging. PMID:26101857

  1. A PARP1-ERK2 synergism is required for the induction of LTP.

    PubMed

    Visochek, L; Grigoryan, G; Kalal, A; Milshtein-Parush, H; Gazit, N; Slutsky, I; Yeheskel, A; Shainberg, A; Castiel, A; Seger, R; Langelier, M F; Dantzer, F; Pascal, J M; Segal, M; Cohen-Armon, M

    2016-01-01

    Unexpectedly, a post-translational modification of DNA-binding proteins, initiating the cell response to single-strand DNA damage, was also required for long-term memory acquisition in a variety of learning paradigms. Our findings disclose a molecular mechanism based on PARP1-Erk synergism, which may underlie this phenomenon. A stimulation induced PARP1 binding to phosphorylated Erk2 in the chromatin of cerebral neurons caused Erk-induced PARP1 activation, rendering transcription factors and promoters of immediate early genes (IEG) accessible to PARP1-bound phosphorylated Erk2. Thus, Erk-induced PARP1 activation mediated IEG expression implicated in long-term memory. PARP1 inhibition, silencing, or genetic deletion abrogated stimulation-induced Erk-recruitment to IEG promoters, gene expression and LTP generation in hippocampal CA3-CA1-connections. Moreover, a predominant binding of PARP1 to single-strand DNA breaks, occluding its Erk binding sites, suppressed IEG expression and prevented the generation of LTP. These findings outline a PARP1-dependent mechanism required for LTP generation, which may be implicated in long-term memory acquisition and in its deterioration in senescence. PMID:27121568

  2. Subchronic phencyclidine treatment in adult mice increases GABAergic transmission and LTP threshold in the hippocampus.

    PubMed

    Nomura, Toshihiro; Oyamada, Yoshihiro; Fernandes, Herman B; Remmers, Christine L; Xu, Jian; Meltzer, Herbert Y; Contractor, Anis

    2016-01-01

    Repeated administration of non-competitive N-methyl-d-aspartate (NMDA) receptor antagonists such as phencyclidine (PCP) to rodents causes long-lasting deficits in cognition and memory, and has effects on behaviors that have been suggested to be models of the cognitive impairment associated with schizophrenia (CIAS). Despite this being a widely studied animal model, little is known about the long lasting changes in synapses and circuits that underlie the altered behaviors. Here we examined synaptic transmission ex-vivo in the hippocampus of mice after a subchronic PCP (scPCP) administration regime. We found that after at least one week of drug free washout period when mice have impaired cognitive function, the threshold for long-term potentiation (LTP) of CA1 excitatory synapses was elevated. This elevated LTP threshold was directly related to increased inhibitory input to CA1 pyramidal cells through increased activity of GABAergic neurons. These results suggest repeated PCP administration causes a long-lasting metaplastic change in the inhibitory circuits in the hippocampus that results in impaired LTP, and could contribute to the deficits in hippocampal-dependent memory in PCP-treated mice. Changes in GABA signaling have been described in patients with schizophrenia, therefore our results support using scPCP as a model of CIAS. This article is part of the Special Issue entitled 'Synaptopathy--from Biology to Therapy'. PMID:25937215

  3. Lunar transient phenomena /LTP/ - Manifestations, site distribution, correlations and possible causes

    NASA Technical Reports Server (NTRS)

    Cameron, W. S.

    1977-01-01

    More than 1400 observations of lunar transient phenomena (LTP), encompassing brightenings, darkenings, and gaseous, reddish, and bluish events, are analyzed in an attempt to determine the possible causes of LTP. Hypotheses considered include effects of earth tides on the moon, low-angle illumination, thermal luminescence, UV heating, solar-particle acceleration by the magnetopause of earth's magnetotail, terrestrial magnetotail bow-shock-front turbulence, cathode luminescence due to magnetotail effects, and solar-flare particle bombardment. Analysis are performed in terms of histograms of the number of observations vs. phase of anomalistic period and of number vs. moon's age, percentage of numbers of observed phenomena and percentage of expected numbers as well as their ratios, and albedo behavior over a lunation period of chosen permanent points in ten specific features. The results indicate that different phenomena may have different causes, strong tidal effects are dubious, correlations with sunrise are most frequent, and the distribution of all LTP sites is distinct from that of deep- and shallow-focus moonquake epicenters.

  4. Dopamine agonists rescue Aβ-induced LTP impairment by Src-family tyrosine kinases.

    PubMed

    Yuan Xiang, PingAn; Janc, Oliwia; Grochowska, Katarzyna M; Kreutz, Michael R; Reymann, Klaus G

    2016-04-01

    Soluble forms of oligomeric amyloid beta (AβO) are involved in the loss of synaptic plasticity and memory, especially in early phases of Alzheimer's disease. Stimulation of dopamine D1/D5 receptors (D1R/D5R) is known to increase surface expression of synaptic α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate subtype glutamate and N-methyl-D-aspartate subtype glutamate receptors and facilitates the induction of the late phase of long-term potentiation (LTP), probably via a related mechanism. In this study, we show that the D1/D5R agonist SKF38393 protects LTP of hippocampal CA1 synapses from the deleterious action of oligomeric amyloid beta. Unexpectedly, the D1R/D5R-mediated recovery of LTP is independent of protein kinase A or phospholipase C pathways. Instead, we found that the inhibition of Src-family tyrosine kinases completely abolished the protective effects of D1R/D5R stimulation in a cellular model of learning and memory. PMID:26973108

  5. Improved segmentation of cerebellar structures in children

    PubMed Central

    Narayanan, Priya Lakshmi; Boonazier, Natalie; Warton, Christopher; Molteno, Christopher D; Joseph, Jesuchristopher; Jacobson, Joseph L; Jacobson, Sandra W; Zöllei, Lilla; Meintjes, Ernesta M

    2016-01-01

    Background Consistent localization of cerebellar cortex in a standard coordinate system is important for functional studies and detection of anatomical alterations in studies of morphometry. To date, no pediatric cerebellar atlas is available. New method The probabilistic Cape Town Pediatric Cerebellar Atlas (CAPCA18) was constructed in the age-appropriate National Institute of Health Pediatric Database asymmetric template space using manual tracings of 16 cerebellar compartments in 18 healthy children (9–13 years) from Cape Town, South Africa. The individual atlases of the training subjects were also used to implement multi atlas label fusion using multi atlas majority voting (MAMV) and multi atlas generative model (MAGM) approaches. Segmentation accuracy in 14 test subjects was compared for each method to ‘gold standard’ manual tracings. Results Spatial overlap between manual tracings and CAPCA18 automated segmentation was 73% or higher for all lobules in both hemispheres, except VIIb and X. Automated segmentation using MAGM yielded the best segmentation accuracy over all lobules (mean Dice Similarity Coefficient 0.76; range 0.55–0.91). Comparison with existing methods In all lobules, spatial overlap of CAPCA18 segmentations with manual tracings was similar or higher than those obtained with SUIT (spatially unbiased infra-tentorial template), providing additional evidence of the benefits of an age appropriate atlas. MAGM segmentation accuracy was comparable to values reported recently by Park et al. (2014) in adults (across all lobules mean DSC = 0.73, range 0.40–0.89). Conclusions CAPCA18 and the associated multi atlases of the training subjects yield improved segmentation of cerebellar structures in children. PMID:26743973

  6. Orthostatic hypotension in acute cerebellar infarction.

    PubMed

    Kim, Hyun-Ah; Lee, Hyung

    2016-01-01

    To investigate the frequency and pattern of orthostatic hypotension (OH) associated with acute isolated cerebellar infarction, and to identify the cerebellar structure(s) potentially responsible for OH, 29 patients (mean age 60.0) with acute isolated cerebellar infarction performed a standard battery of autonomic function tests including the head up tilt test using Finapres for recording of the beat-to-beat BP response during the acute period. Cerebellar infarction related OH was defined as fall in BP (>20 mmHg systolic BP) on tilting in patients without any disease(s) that could potentially cause autonomic dysfunction, or in patients who had a potential cause of autonomic dysfunction, but showed the absence of OH during a follow-up test. The severity and distribution of autonomic dysfunction were measured by the composite autonomic severity score (CASS). Nine patients (31 %) had OH (range 24-53 mmHg) on tilting during the acute period. Most patients (7/9) had a remarkable decrement in systolic BP immediately upon tilting, but OH rapidly normalized. Mean of maximal decrease in systolic BP during head up tilt test was 37.0 mmHg. The OH group showed mild autonomic dysfunctions (CASS, 3.7) with adrenergic sympathetic dysfunction appearing as the most common abnormality. Lesion subtraction analyses revealed that damage to the medial part of the superior semilunar lobule (Crus I) and tonsil was more frequent in OH group compared to non-OH group. Cerebellar infarction may cause a brief episode of OH. The medial part of the superior semilunar lobule and tonsil may participate in regulating the early BP response during orthostasis. PMID:26530504

  7. IKK regulates the deubiquitinase CYLD at the postsynaptic density

    SciTech Connect

    Thein, Soe; Pham, Anna; Bayer, K. Ulrich; Tao-Cheng, Jung-Hwa; Dosemeci, Ayse

    2014-07-18

    Highlights: • CYLD is phosphorylated by IKK in isolated PSDs in the absence of Ca{sup 2+}. • CYLD is phosphorylated by IKK at the PSDs of intact neurons in basal conditions. • Phosphorylation of CYLD by IKK increases its deubiquitinase activity. • The process is likely to influence protein trafficking at the PSD in basal conditions. - Abstract: K63-linked polyubiquitination of proteins regulates their trafficking into specific cellular pathways such as endocytosis and autophagy. CYLD, a deubiquitinase specific for K63-linked polyubiquitins, is present in high quantities at the postsynaptic density (PSD). It was previously shown that, under excitatory conditions, CaMKII activates CYLD in a Ca{sup 2+}-dependent manner. The observation that CYLD can also be phosphorylated in the absence of Ca{sup 2+} in isolated PSDs led us to further explore the regulation of CYLD under basal conditions. A possible involvement of the autonomous form of CaMKII and IKK, both kinases known to be localized at the PSD, was examined. A CaMKII inhibitor CN21 had no effect on CYLD phosphorylation in the absence of Ca{sup 2+}, but two different IKK inhibitors, IKK16 and tatNEMO, inhibited its phosphorylation. Immuno-electron microscopy on hippocampal cultures, using an antibody for CYLD phosphorylated at S-418, revealed that the phosphorylated form of CYLD is present at the PSD under basal conditions. Phosphorylation of CYLD under basal conditions was inhibited by IKK16. NMDA treatment further promoted phosphorylation of CYLD at the PSD, but IKK16 failed to block the NMDA-induced effect. In vitro experiments using purified proteins demonstrated direct phosphorylation and activation of CYLD by the beta catalytic subunit of IKK. Activation of IKK in isolated PSDs also promoted phosphorylation of CYLD and an increase in endogenous deubiquitinase activity for K63-linked polyubiquitins. Altogether, the results suggest that in the absence of excitatory conditions, constitutive IKK activity

  8. Anatomy and approaches along the cerebellar-brainstem fissures.

    PubMed

    Matsushima, Ken; Yagmurlu, Kaan; Kohno, Michihiro; Rhoton, Albert L

    2016-01-01

    OBJECT Fissure dissection is routinely used in the supratentorial region to access deeply situated pathology while minimizing division of neural tissue. Use of fissure dissection is also practical in the posterior fossa. In this study, the microsurgical anatomy of the 3 cerebellar-brainstem fissures (cerebellomesencephalic, cerebellopontine, and cerebellomedullary) and the various procedures exposing these fissures in brainstem surgery were examined. METHODS Seven cadaveric heads were examined with a microsurgical technique and 3 with fiber dissection to clarify the anatomy of the cerebellar-brainstem and adjacent cerebellar fissures, in which the major vessels and neural structures are located. Several approaches directed along the cerebellar surfaces and fissures, including the supracerebellar infratentorial, occipital transtentorial, retrosigmoid, and midline suboccipital approaches, were examined. The 3 heads examined using fiber dissection defined the anatomy of the cerebellar peduncles coursing in the depths of these fissures. RESULTS Dissections directed along the cerebellar-brainstem and cerebellar fissures provided access to the posterior and posterolateral midbrain and upper pons, lateral pons, floor and lateral wall of the fourth ventricle, and dorsal and lateral medulla. CONCLUSIONS Opening the cerebellar-brainstem and adjacent cerebellar fissures provided access to the brainstem surface hidden by the cerebellum, while minimizing division of neural tissue. Most of the major cerebellar arteries, veins, and vital neural structures are located in or near these fissures and can be accessed through them. PMID:26274986

  9. Temporal coupling between neuronal activity and blood flow in rat cerebellar cortex as indicated by field potential analysis

    PubMed Central

    Mathiesen, Claus; Caesar, Kirsten; Lauritzen, Martin

    2000-01-01

    Laser-Doppler flowmetry and extracellular recordings of field potentials were used to examine the temporal coupling between neuronal activity and increases in cerebellar blood flow (CeBF). Climbing fibre-evoked increases in CeBF were dependent on stimulus duration, indicating that increases in CeBF reflected a time integral in neuronal activity. The simplest way to represent neuronal activity over time was to obtain a running summation of evoked field potential amplitudes (runΣFP). RunΣFP was calculated for each stimulus protocol and compared with the time course of the CeBF responses to demonstrate coupling between nerve cell activity and CeBF. In the climbing fibre system, the amplitude and time course of CeBF were in agreement with the calculated postsynaptic runΣFP (2–20 Hz for 60 s). This suggested coupling between CeBF and neuronal activity in this excitatory, monosynaptic, afferent-input system under these conditions. There was no correlation between runΣFP and CeBF during prolonged stimulation. Parallel fibre-evoked increases in CeBF correlated with runΣFP of pre- and postsynaptic potentials (2–15 Hz for 60 s). At higher stimulation frequencies and during longer-lasting stimulation the time course and amplitudes of CeBF responses correlated with runΣFP of presynaptic, but not postsynaptic potentials. This suggested a more complex relationship in this mixed inhibitory-excitatory, disynaptic, afferent-input system. This study has demonstrated temporal coupling between neuronal activity and CeBF in the monosynaptic, excitatory climbing-fibre system. In the mixed mono- and disynaptic parallel fibre system, temporal coupling was most clearly observed at low stimulation frequencies. We propose that appropriate modelling of electrophysiological data is needed to document functional coupling of neuronal activity and blood flow. PMID:10673558

  10. Potentiation of tonic GABAergic inhibition by activation of postsynaptic kainate receptors.

    PubMed

    Jiang, L; Kang, D; Kang, J

    2015-07-01

    Presynaptic kainate-type glutamate ionotropic receptors (KARs) that mediate either the depression or the facilitation of GABA release have been intensively studied. Little attention has been given to the modulation of GABAA receptors (GABAARs) by postsynaptic KARs. Recent studies suggest that two GABAAR populations, synaptic (sGABAAR) and extrasynaptic (eGABAAR) GABAARs, mediate phasic and tonic forms of inhibition, respectively. Tonic inhibition plays an important role in the excitability of neuronal circuits and the occurrence of epileptic seizures. For this study, we are the first to report that the activation of postsynaptic KARs by the KAR agonist, Kainic acid (KA, 5 μM), enhanced tonic inhibition by potentiating eGABAARs. KA enhanced THIP-induced eGABAAR currents and prolonged the rise and decay time of muscimol-induced sGABAAR/eGABAAR currents, but also depressed the amplitude of evoked inhibitory postsynaptic currents (IPSCs), unitary IPSCs (uIPSCs), and muscimol-induced sGABAAR/eGABAAR currents. The PKC inhibitor, staurosporine (1 μM), in the patch pipette solution fully blocked the KA-induced potentiation of tonic inhibition, suggesting the involvement of an intracellular PKC pathway. Our study suggests that the activation of postsynaptic KARs potentiates eGABAARs but depresses sGABAARs. By activating postsynaptic KARs, synaptically released glutamate depresses phasic inhibition to facilitate neuronal plasticity, but potentiates tonic inhibition to protect neurons from over-excitation. PMID:25934031

  11. The Knockdown of αkap Alters the Postsynaptic Apparatus of Neuromuscular Junctions in Living Mice

    PubMed Central

    Martinez-Pena y Valenzuela, Isabel; Aittaleb, Mohamed; Chen, Po-Ju

    2015-01-01

    A muscle-specific nonkinase anchoring protein (αkap), encoded within the calcium/calmodulin kinase II (camk2) α gene, was recently found to control the stability of acetylcholine receptor (AChR) clusters on the surface of cultured myotubes. However, it remains unknown whether this protein has any effect on receptor stability and the maintenance of the structural integrity of neuromuscular synapses in vivo. By knocking down the endogenous expression of αkap in mouse sternomastoid muscles with shRNA, we found that the postsynaptic receptor density was dramatically reduced, the turnover rate of receptors at synaptic sites was significantly increased, and the insertion rates of both newly synthesized and recycled receptors into the postsynaptic membrane were depressed. Moreover, we found that αkap shRNA knockdown impaired synaptic structure as postsynaptic AChR clusters and their associated postsynaptic scaffold proteins within the neuromuscular junction were completely eliminated. These results provide new mechanistic insight into the role of αkap in regulating the stability of the postsynaptic apparatus of neuromuscular synapses. PMID:25834039

  12. Studying Cerebellar Circuits by Remote Control of Selected Neuronal Types with GABAA Receptors

    PubMed Central

    Wisden, William; Murray, Andrew J.; McClure, Christina; Wulff, Peer

    2009-01-01

    Although GABAA receptor-mediated inhibition of cerebellar Purkinje cells by molecular layer interneurons (MLIs) has been studied intensely at the cellular level, it has remained unclear how this inhibition regulates cerebellum-dependent behaviour. We have implemented two complementary approaches to investigate the function of the MLI-Purkinje cell synapse on the behavioural level. In the first approach we permanently disrupted inhibitory fast synaptic transmission at the synapse by genetically removing the postsynaptic GABAA receptors from Purkinje cells (PC-Δγ2 mice). We found that chronic disruption of the MLI-Purkinje cell synapse strongly impaired cerebellar learning of the vestibular occular reflex (VOR), presumably by disrupting the temporal patterns of Purkinje cell activity. However, in PC-Δγ2 mice the baseline VOR reflex was only mildly affected; indeed PC-Δγ2 mice show no ataxia or gait abnormalities, suggesting that MLI control of Purkinje cell activity is either not involved in ongoing motor tasks or that the system compensates for its loss. To investigate the latter possibility we developed an alternative genetic technique; we made the MLI-Purkinje cell synapse selectively sensitive to rapid manipulation with the GABAA receptor modulator zolpidem (PC-γ2-swap mice). Minutes after intraperitoneal zolpidem injection, these PC-γ2-swap mice developed severe motor abnormalities, revealing a substantial contribution of the MLI-Purkinje cell synapses to real time motor control. The cell-type selective permanent knockout of synaptic GABAergic input and the fast reversible modulation of GABAergic input at the same synapse illustrate how pursuing both strategies gives a fuller view. PMID:20076763

  13. Effects of Transforming Growth Factor Beta 1 in Cerebellar Development: Role in Synapse Formation

    PubMed Central

    Araujo, Ana P. B.; Diniz, Luan P.; Eller, Cristiane M.; de Matos, Beatriz G.; Martinez, Rodrigo; Gomes, Flávia C. A.

    2016-01-01

    Granule cells (GC) are the most numerous glutamatergic neurons in the cerebellar cortex and represent almost half of the neurons of the central nervous system. Despite recent advances, the mechanisms of how the glutamatergic synapses are formed in the cerebellum remain unclear. Among the TGF-β family, TGF-beta 1 (TGF-β1) has been described as a synaptogenic molecule in invertebrates and in the vertebrate peripheral nervous system. A recent paper from our group demonstrated that TGF-β1 increases the excitatory synapse formation in cortical neurons. Here, we investigated the role of TGF-β1 in glutamatergic cerebellar neurons. We showed that the expression profile of TGF-β1 and its receptor, TβRII, in the cerebellum is consistent with a role in synapse formation in vitro and in vivo. It is low in the early postnatal days (P1–P9), increases after postnatal day 12 (P12), and remains high until adulthood (P30). We also found that granule neurons express the TGF-β receptor mRNA and protein, suggesting that they may be responsive to the synaptogenic effect of TGF-β1. Treatment of granular cell cultures with TGF-β1 increased the number of glutamatergic excitatory synapses by 100%, as shown by immunocytochemistry assays for presynaptic (synaptophysin) and post-synaptic (PSD-95) proteins. This effect was dependent on TβRI activation because addition of a pharmacological inhibitor of TGF-β, SB-431542, impaired the formation of synapses between granular neurons. Together, these findings suggest that TGF-β1 has a specific key function in the cerebellum through regulation of excitatory synapse formation between granule neurons. PMID:27199658

  14. Nitric Oxide Regulates Input Specificity of Long-Term Depression and Context Dependence of Cerebellar Learning

    PubMed Central

    Ogasawara, Hideaki; Doi, Tomokazu; Doya, Kenji; Kawato, Mitsuo

    2007-01-01

    Recent studies have shown that multiple internal models are acquired in the cerebellum and that these can be switched under a given context of behavior. It has been proposed that long-term depression (LTD) of parallel fiber (PF)–Purkinje cell (PC) synapses forms the cellular basis of cerebellar learning, and that the presynaptically synthesized messenger nitric oxide (NO) is a crucial “gatekeeper” for LTD. Because NO diffuses freely to neighboring synapses, this volume learning is not input-specific and brings into question the biological significance of LTD as the basic mechanism for efficient supervised learning. To better characterize the role of NO in cerebellar learning, we simulated the sequence of electrophysiological and biochemical events in PF–PC LTD by combining established simulation models of the electrophysiology, calcium dynamics, and signaling pathways of the PC. The results demonstrate that the local NO concentration is critical for induction of LTD and for its input specificity. Pre- and postsynaptic coincident firing is not sufficient for a PF–PC synapse to undergo LTD, and LTD is induced only when a sufficient amount of NO is provided by activation of the surrounding PFs. On the other hand, above-adequate levels of activity in nearby PFs cause accumulation of NO, which also allows LTD in neighboring synapses that were not directly stimulated, ruining input specificity. These findings lead us to propose the hypothesis that NO represents the relevance of a given context and enables context-dependent selection of internal models to be updated. We also predict sparse PF activity in vivo because, otherwise, input specificity would be lost. PMID:17222054

  15. Cerebellar ataxia as presenting feature of hypothyroidism.

    PubMed

    Kotwal, Suman Kumar; Kotwal, Shalija; Gupta, Rohan; Singh, Jang Bhadur; Mahajan, Annil

    2016-04-01

    Symptoms and signs of the hypothyroidism vary in relation to the magnitude and acuteness of the thyroid hormone deficiency. The usual clinical features are constipation, fatigue, cold intolerance and weight gain. Rarely it can present with neurologic problems like reversible cerebellar ataxia, dementia, peripheral neuropathy, psychosis and coma. Hypothyroidism should be suspected in all cases of ataxia, as it is easily treatable. A 40 year-old male presented with the history facial puffiness, hoarseness of voice and gait-ataxia. Investigations revealed frank primary hypothyroidism. Anti-TPO antibody was positive. Thyroxine was started and patient improved completely within eight weeks. Hypothyroidism can present with ataxia as presenting feature. Hypothyroidism should be considered in all cases of cerebellar ataxia as it is a reversible cause of ataxia. PMID:26886095

  16. An update on Spino-cerebellar ataxias

    PubMed Central

    Mondal, Banashree; Paul, Pritikanta; Paul, Madhuparna; Kumar, Hrishikesh

    2013-01-01

    The dominantly inherited ataxias, also known as Spino-cerebellar ataxias (SCAs), are rapidly expanding entities. New mutations are being identified at remarkable regularity. Recent awareness of molecular abnormalities in SCAs has addressed some of the long sought questions, but gaps in knowledge still exist. Three major categories of SCAs, according to molecular mechanisms, have evolved over recent few years: Polyglutamate expansion ataxia, non-coding zone repeat ataxia, and ataxia due to conventional mutation. Using the fulcrum of these mechanisms, the article provides an update of SCAs. Shared and specific clinical features, genetic abnormalities, and possible links between molecular abnormalities and cerebellar degeneration have been discussed. Emphasis has been placed on the mechanisms of polyglutamate toxicity. PMID:24101804

  17. Learning of Sensory Sequences in Cerebellar Patients

    PubMed Central

    Frings, Markus; Boenisch, Raoul; Gerwig, Marcus; Diener, Hans-Christoph; Timmann, Dagmar

    2004-01-01

    A possible role of the cerebellum in detecting and recognizing event sequences has been proposed. The present study sought to determine whether patients with cerebellar lesions are impaired in the acquisition and discrimination of sequences of sensory stimuli of different modalities. A group of 26 cerebellar patients and 26 controls matched for age, sex, handedness, musicality, and level of education were tested. Auditory and visual sensory sequences were presented out of different sensory pattern categories (tones with different acoustic frequencies and durations, visual stimuli with different spatial locations and colors, sequential vision of irregular shapes) and different ranges of inter-cue time intervals (fast and slow). Motor requirements were small, with vocal responses and no time restrictions. Perception of visual and acoustic stimuli was generally preserved in patients and controls. The number of errors was significantly higher in the faster tempo of sequence presentation in learning of sequences of tones of different frequencies and in learning of sequences of visual stimuli of different spatial locations and different colors. No difference in tempo between the groups was shown. The total number of errors between the two groups was identical in the sequence conditions. No major disturbances in acquisition or discrimination of various sensory sequences were observed in the group of cerebellar patients. Sequence learning may be impaired only in tasks with significant motor demands. PMID:15169865

  18. [Diagnostic and treatment of hypertensive cerebellar hematomas].

    PubMed

    Krylov, V V; Dash'ian, V G; Murashko, A A; Burov, S A

    2009-01-01

    Authors analyzed the results of treatment of 56 patients with hypertensive cerebellar hemorrhages (volume 0,5-41 cm3). Brain stem symptoms were found in 45 (80%) of patients. The dislocation of brain stem was observed in 38 (68%) cases, occlusive hydrocephaly - in 22 (39%), intraventricular hemorrhage - in 26 (46%). Severity of state depended on character of disease course, presence of stem symptoms, awakening level, volume and localization of cerebellar hematoma, development of intraventricular hemorrhage, occlusive hydrocephaly and dislocation of brain stem. Thirty-six patients were operated. After the neurosurgical intervention, 22 (61%) patients were discharged without or with the minimal neurological deficit, 1 (3%) with marked disability and 13 (36%) patients died. In conclusion, the removal of hematoma is recommended in dislocation of brain stem and disturbance of consiousnes: the ventricular drainage - in occlusive hydrocephaly developed as a consequence of hemotamponade of IV ventricular. The surgical treatment is not recommended to patients with cerebellar hematomas with the volume less than 7 cm3. PMID:19491806

  19. From cerebellar texture to movement optimization.

    PubMed

    Sultan, Fahad

    2014-10-01

    The cerebellum is a major site for supervised procedural learning and appears to be crucial for optimizing sensorimotor performance. However, the site and origin of the supervising signal are still elusive. Furthermore, its relationship with the prominent neuronal circuitry remains puzzling. In this paper, I will review the relevant information and seek to synthesize a working hypothesis that explains the unique cerebellar structure. The aim of this review was to link the distinctive functions of the cerebellum, as derived from cerebellar lesion studies, with potential elementary computations, as observed by a bottom-up approach from the cerebellar microcircuitry. The parallel fiber geometry is ideal for performing millisecond computations that extract instructive signals. In this scenario, the higher time derivatives of kinematics such as acceleration and/or jerk that occur during motor performance are detected via a tidal wave mechanism and are used (with appropriate gating) as the instructive signal to guide motor smoothing. The advantage of such a mechanism is that movements are optimized by reducing "jerkiness" which, in turn, lowers their energy requirements. PMID:25037239

  20. Cerebro-cerebellar circuits in autism spectrum disorder

    PubMed Central

    D'Mello, Anila M.; Stoodley, Catherine J.

    2015-01-01

    The cerebellum is one of the most consistent sites of abnormality in autism spectrum disorder (ASD) and cerebellar damage is associated with an increased risk of ASD symptoms, suggesting that cerebellar dysfunction may play a crucial role in the etiology of ASD. The cerebellum forms multiple closed-loop circuits with cerebral cortical regions that underpin movement, language, and social processing. Through these circuits, cerebellar dysfunction could impact the core ASD symptoms of social and communication deficits and repetitive and stereotyped behaviors. The emerging topography of sensorimotor, cognitive, and affective subregions in the cerebellum provides a new framework for interpreting the significance of regional cerebellar findings in ASD and their relationship to broader cerebro-cerebellar circuits. Further, recent research supports the idea that the integrity of cerebro-cerebellar loops might be important for early cortical development; disruptions in specific cerebro-cerebellar loops in ASD might impede the specialization of cortical regions involved in motor control, language, and social interaction, leading to impairments in these domains. Consistent with this concept, structural, and functional differences in sensorimotor regions of the cerebellum and sensorimotor cerebro-cerebellar circuits are associated with deficits in motor control and increased repetitive and stereotyped behaviors in ASD. Further, communication and social impairments are associated with atypical activation and structure in cerebro-cerebellar loops underpinning language and social cognition. Finally, there is converging evidence from structural, functional, and connectivity neuroimaging studies that cerebellar right Crus I/II abnormalities are related to more severe ASD impairments in all domains. We propose that cerebellar abnormalities may disrupt optimization of both structure and function in specific cerebro-cerebellar circuits in ASD. PMID:26594140

  1. Cavernous angioma with olivary hypertrophy and contralateral cerebellar diaschisis.

    PubMed

    Komaba, Y; Nomoto, T; Kitamura, S; Terashi, A

    1997-07-01

    We describe a 66-year-old man with a 20-year history of ataxic gait who suddenly developed diplopia on rightward gaze. Neurologic examination revealed right hemi-ataxia and hemi-hypesthesia, and left internuclear ophthalmoplegia. MRI showed a cavernous angioma in the left tectum, mild right cerebellar atrophy, and left interior olivary hypertrophy. Single photon emission computed tomography (SPECT) imaging demonstrated contralateral cerebellar diaschisis. We discuss the findings and review the literature concerning contralateral cerebellar diaschisis. PMID:9240502

  2. The planar cell polarity protein Vangl2 is involved in postsynaptic compartmentalization.

    PubMed

    Nagaoka, Tadahiro; Kishi, Masashi

    2016-01-26

    The excitatory postsynaptic region of the vertebrate hippocampus is usually compartmentalized into the postsynaptic density (PSD) and N-cadherin-rich domain, which is important for synaptic adhesion. However, the molecular mechanisms underlying the compartment formation are unknown. In the present report, we show that the planar cell polarity (PCP) protein Van Gogh-like 2 (Vangl2) plays a role in this regionalization. In cultured rat hippocampal neurons that were subjected to Vangl2 expression silencing, the formed clusters of PSD-95, one of the major scaffolding proteins in PSD, tended to overlap with those of N-cadherin. Further, in the dendrites of these neurons, the immunofluorescence of PSD-95 was to some extent diffused, without a significant change in the total signal. Because Vangl2 physically interacts with both PSD-95 and N-cadherin in vivo, these results suggest that a PCP-related direct molecular mechanism underlies the horizontal polarization of the postsynaptic regions. PMID:26683906

  3. Cerebellar liponeurocytoma in two siblings suggests a possible familial predisposition.

    PubMed

    Pikis, Stylianos; Fellig, Yakov; Margolin, Emil

    2016-10-01

    There is limited data on the genetic origin and natural history of cerebellar liponeurocytoma. To the best of our knowledge there has been only one report of a familial presentation of this rare entity. We report a 72-year-old female with a posterior fossa tumor presenting with progressive cerebellar signs and symptoms. The patient underwent total tumor resection via an uncomplicated sub-occipital craniotomy. Histopathologic examination was diagnostic for cerebellar liponeurocytoma. Her sister was previously treated for a similar tumor. Our report provides further evidence for the possible existence of a hereditary abnormality predisposing afflicted families to cerebellar liponeurocytoma development. PMID:27349466

  4. Modulatory effects of serotonin on glutamatergic synaptic transmission and long-term depression in the deep cerebellar nuclei.

    PubMed

    Murano, M; Saitow, F; Suzuki, H

    2011-01-13

    The deep cerebellar nuclei (DCN) are the terminal components of the cerebellar circuitry and constitute its primary output structure. Their activity is important for certain forms of motor learning as well as generation and control of movement. DCN neurons receive glutamatergic excitatory inputs from the pontine nuclei via mossy fibres (MFs) and concomitantly receive inputs from 5-HT-containing neurons of the raphe nuclei. We aimed to explore the roles of 5-HT at MF-DCN synapses by using cerebellar slices from 11 to 15-day-old rats. Bath application of 5-HT reversibly decreased the amplitude of stimulation-evoked excitatory postsynaptic currents (eEPSCs) via the activation of 5-HT1B receptors at the presynaptic terminals of the MFs. Burst stimulation of the MFs elicited long-term depression (LTD) at the MF-DCN synapses that require activation of the group I metabotropic glutamate receptor (mGluR). In the presence of 5-HT, the extent of burst-induced LTD of MF EPSCs was significantly reduced. Application of 5-HT also decreased the amplitude of mGluR-dependent slow EPSCs evoked by similar burst stimulation. Furthermore, (S)-3,5-dihydroxyphenylglycine (DHPG), a group I mGluR agonist, induced chemical LTD of MF EPSCs, and 5-HT had no significant effect on this LTD. Taken together, the results suggest that 5-HT not only has transitory inhibitory effects on MF EPSCs but also plays a role in regulating the long-term synaptic efficacy. PMID:20969929

  5. Importance of Nitric Oxide for Local Increases of Blood Flow in Rat Cerebellar Cortex During Electrical Stimulation

    NASA Astrophysics Data System (ADS)

    Akgoren, Nuran; Fabricius, Martin; Lauritzen, Martin

    1994-06-01

    The endothelium-derived relaxing factor, probably nitric oxide (NO), is a potent vasodilator that regulates the vascular tone in several vascular beds, including the brain. We explored the possibility that NO might be of importance for the increase of cerebral blood flow (CBF) associated with activity of the well-defined neuronal circuits of the rat cerebellar cortex. Laser-Doppler flowmetry was used to measure increases of cerebellar blood flow evoked by trains of electrical stimulations of the dorsal surface. The evoked increases of CBF were frequency-dependent, being larger on than off the parallel fiber tracts, suggesting that conduction along parallel fibers and synaptic activation of target cells were important for the increase of CBF. This was verified experimentally since the evoked CBF increases were abolished by tetrodotoxin and reduced by 10 mM Mg2+ and selective antagonists for non-N-methyl-D-aspartate receptors. The cerebellar cortex contains high levels of NO synthase. This raised the possibility that NO was involved in the increase of CBF associated with neuronal activation. NO synthase inhibition by topical application of N^G-nitro-L-arginine attenuated the evoked CBF increase by about 50%. This effect was partially reversed by pretreatment with L-arginine, the natural substrate for the enzyme, while N^G-nitro-D-arginine, the inactive enantiomer, had no effect on the evoked CBF increases. Simultaneous blockade of non-N-methyl-D-aspartate receptors and NO synthase had no further suppressing effect on the blood flow increase than either substance alone, suggesting that the NO-dependent flow rise was dependent on postsynaptic mechanisms. These findings are consistent with the idea that local synthesis of NO is involved in the transduction mechanism between neuronal activity and increased CBF.

  6. On the role of a Lipid-Transfer Protein. Arabidopsis ltp3 mutant is compromised in germination and seedling growth.

    PubMed Central

    Pagnussat, Luciana A; Oyarburo, Natalia; Cimmino, Carlos; Pinedo, Marcela L; de la Canal, Laura

    2015-01-01

    Plant Lipid-Transfer Proteins (LTPs) exhibit the ability to reversibly bind/transport lipids in vitro. LTPs have been involved in diverse physiological processes but conclusive evidence on their role has only been presented for a few members, none of them related to seed physiology. Arabidopsis seeds rely on storage oil breakdown to supply carbon skeletons and energy for seedling growth. Here, Arabidopsis ltp3 mutant was analyzed for its ability to germinate and for seedling establishment. Ltp3 showed delayed germination and reduced germination frequency. Seedling growth appeared reduced in the mutant but this growth restriction was rescued by the addition of an exogenous carbon supply, suggesting a defective oil mobilization. Lipid breakdown analysis during seedling growth revealed a differential profile in the mutant compared to the wild type. The involvement of LTP3 in germination and seedling growth and its relationship with the lipid transfer ability of this protein is discussed. PMID:26479260

  7. Extracellular Tau Oligomers Produce An Immediate Impairment of LTP and Memory.

    PubMed

    Fá, M; Puzzo, D; Piacentini, R; Staniszewski, A; Zhang, H; Baltrons, M A; Li Puma, D D; Chatterjee, I; Li, J; Saeed, F; Berman, H L; Ripoli, C; Gulisano, W; Gonzalez, J; Tian, H; Costa, J A; Lopez, P; Davidowitz, E; Yu, W H; Haroutunian, V; Brown, L M; Palmeri, A; Sigurdsson, E M; Duff, K E; Teich, A F; Honig, L S; Sierks, M; Moe, J G; D'Adamio, L; Grassi, C; Kanaan, N M; Fraser, P E; Arancio, O

    2016-01-01

    Non-fibrillar soluble oligomeric forms of amyloid-β peptide (oAβ) and tau proteins are likely to play a major role in Alzheimer's disease (AD). The prevailing hypothesis on the disease etiopathogenesis is that oAβ initiates tau pathology that slowly spreads throughout the medial temporal cortex and neocortices independently of Aβ, eventually leading to memory loss. Here we show that a brief exposure to extracellular recombinant human tau oligomers (oTau), but not monomers, produces an impairment of long-term potentiation (LTP) and memory, independent of the presence of high oAβ levels. The impairment is immediate as it raises as soon as 20 min after exposure to the oligomers. These effects are reproduced either by oTau extracted from AD human specimens, or naturally produced in mice overexpressing human tau. Finally, we found that oTau could also act in combination with oAβ to produce these effects, as sub-toxic doses of the two peptides combined lead to LTP and memory impairment. These findings provide a novel view of the effects of tau and Aβ on memory loss, offering new therapeutic opportunities in the therapy of AD and other neurodegenerative diseases associated with Aβ and tau pathology. PMID:26786552

  8. Extracellular Tau Oligomers Produce An Immediate Impairment of LTP and Memory

    PubMed Central

    Fá, M.; Puzzo, D.; Piacentini, R.; Staniszewski, A.; Zhang, H.; Baltrons, M. A.; Li Puma, D. D.; Chatterjee, I.; Li, J.; Saeed, F.; Berman, H. L.; Ripoli, C.; Gulisano, W.; Gonzalez, J.; Tian, H.; Costa, J. A.; Lopez, P.; Davidowitz, E.; Yu, W. H.; Haroutunian, V.; Brown, L. M.; Palmeri, A.; Sigurdsson, E. M.; Duff, K. E.; Teich, A. F.; Honig, L. S.; Sierks, M.; Moe, J. G.; D’Adamio, L.; Grassi, C.; Kanaan, N. M.; Fraser, P. E.; Arancio, O.

    2016-01-01

    Non-fibrillar soluble oligomeric forms of amyloid-β peptide (oAβ) and tau proteins are likely to play a major role in Alzheimer’s disease (AD). The prevailing hypothesis on the disease etiopathogenesis is that oAβ initiates tau pathology that slowly spreads throughout the medial temporal cortex and neocortices independently of Aβ, eventually leading to memory loss. Here we show that a brief exposure to extracellular recombinant human tau oligomers (oTau), but not monomers, produces an impairment of long-term potentiation (LTP) and memory, independent of the presence of high oAβ levels. The impairment is immediate as it raises as soon as 20 min after exposure to the oligomers. These effects are reproduced either by oTau extracted from AD human specimens, or naturally produced in mice overexpressing human tau. Finally, we found that oTau could also act in combination with oAβ to produce these effects, as sub-toxic doses of the two peptides combined lead to LTP and memory impairment. These findings provide a novel view of the effects of tau and Aβ on memory loss, offering new therapeutic opportunities in the therapy of AD and other neurodegenerative diseases associated with Aβ and tau pathology. PMID:26786552

  9. Licklider Transmission Protocol (LTP)-base DTN for cislunar communications in presence of long link disruption

    NASA Astrophysics Data System (ADS)

    Gullapalli, Vasdev

    The National Aeronautics and Space Administration (NASA) are consigned to the safe, sustained, affordable human and robotic exploration of the Moon, Mars, and beyond. The goal is to create sustainable human settlements on the Moon and Mars with the motivation to preserve the human race. So, NASA has been trying different protocols to advance cis-lunar communication such as Delay Tolerant Networking (DTN), and the latest one: Interplanetary Overlay Network (ION). ION is an implementation of DTN. ION was designed mainly to reduce the cost and risk in space communication. ION implements the TCPCL, LTPCL, and UDPCL to work with high channel Bit Error Rate (BER), long link breaks, and long link delays. In this thesis, we present a performance evaluation of Licklider Transmission Protocol (LTP)-based DTN for cis-lunar communications in presence of long link disruption. Based on experimental evaluation and statistical analysis, we conclude that good-put performance variation is very less for different bit error rates at the particular link break, and also LTP is capable for reliable communication even in the link break for 16 hours to the maximum. Finally, the protocol is the best for higher BER's and long link break.

  10. Acid-sensing ion channel 1a contributes to hippocampal LTP inducibility through multiple mechanisms.

    PubMed

    Liu, Ming-Gang; Li, Hu-Song; Li, Wei-Guang; Wu, Yan-Jiao; Deng, Shi-Ning; Huang, Chen; Maximyuk, Oleksandr; Sukach, Volodymyr; Krishtal, Oleg; Zhu, Michael X; Xu, Tian-Le

    2016-01-01

    The exact roles of acid-sensing ion channels (ASICs) in synaptic plasticity remain elusive. Here, we address the contribution of ASIC1a to five forms of synaptic plasticity in the mouse hippocampus using an in vitro multi-electrode array recording system. We found that genetic deletion or pharmacological blockade of ASIC1a greatly reduced, but did not fully abolish, the probability of long-term potentiation (LTP) induction by either single or repeated high frequency stimulation or theta burst stimulation in the CA1 region. However, these treatments did not affect hippocampal long-term depression induced by low frequency electrical stimulation or (RS)-3,5-dihydroxyphenylglycine. We also show that ASIC1a exerts its action in hippocampal LTP through multiple mechanisms that include but are not limited to augmentation of NMDA receptor function. Taken together, these results reveal new insights into the role of ASIC1a in hippocampal synaptic plasticity and the underlying mechanisms. This unbiased study also demonstrates a novel and objective way to assay synaptic plasticity mechanisms in the brain. PMID:26996240