Center for Synaptic Plasticity

Bristol, United Kingdom

Center for Synaptic Plasticity

Bristol, United Kingdom
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Nicolas C.,University of Bristol | Peineau S.,University of Bristol | Peineau S.,French Institute of Health and Medical Research | Peineau S.,University Paris Diderot | And 26 more authors.
Neuron | Year: 2012

The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway is involved in many cellular processes, including cell growth and differentiation, immune functions and cancer. It is activated by various cytokines, growth factors, and protein tyrosine kinases (PTKs) and regulates the transcription of many genes. Of the four JAK isoforms and seven STAT isoforms known, JAK2 and STAT3 are highly expressed in the brain where they are present in the postsynaptic density (PSD). Here, we demonstrate a new neuronal function for the JAK/STAT pathway. Using a variety of complementary approaches, we show that the JAK/STAT pathway plays an essential role in the induction of NMDA-receptor dependent long-term depression (NMDAR-LTD) in the hippocampus. Therefore, in addition to established roles in cytokine signaling, the JAK/STAT pathway is involved in synaptic plasticity in the brain. The authors demonstrate a new neuronal function for the JAK/STAT pathway in the induction of NMDA-receptor-dependent long-term depression (NMDAR-LTD) in the hippocampus. © 2012 Elsevier Inc.

Liu M.-G.,Seoul National University | Liu M.-G.,King's College | Koga K.,King's College | Guo Y.-Y.,PLA Fourth Military Medical University | And 8 more authors.
European Journal of Neuroscience | Year: 2013

The insular cortex (IC) is known to play important roles in higher brain functions such as memory and pain. Activity-dependent long-term depression (LTD) is a major form of synaptic plasticity related to memory and chronic pain. Previous studies of LTD have mainly focused on the hippocampus, and no study in the IC has been reported. In this study, using a 64-channel recording system, we show for the first time that repetitive low-frequency stimulation (LFS) can elicit frequency-dependent LTD of glutamate receptor-mediated excitatory synaptic transmission in both superficial and deep layers of the IC of adult mice. The induction of LTD in the IC required activation of the N-methyl-d-aspartate (NMDA) receptor, metabotropic glutamate receptor (mGluR)5, and L-type voltage-gated calcium channel. Protein phosphatase 1/2A and endocannabinoid signaling are also critical for the induction of LTD. In contrast, inhibiting protein kinase C, protein kinase A, protein kinase Mζ or calcium/calmodulin-dependent protein kinase II did not affect LFS-evoked LTD in the IC. Bath application of the group I mGluR agonist (RS)-3,5-dihydroxyphenylglycine produced another form of LTD in the IC, which was NMDA receptor-independent and could not be occluded by LFS-induced LTD. Our studies have characterised the basic mechanisms of LTD in the IC at the network level, and suggest that two different forms of LTD may co-exist in the same population of IC synapses. © 2013 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Park P.,Seoul National University | Park P.,Center for Synaptic Plasticity | Sanderson T.M.,Seoul National University | Sanderson T.M.,Center for Synaptic Plasticity | And 10 more authors.
Journal of Neuroscience | Year: 2016

Two forms of NMDA receptor (NMDAR)-dependent long-term potentiation (LTP) at hippocampal CA1 synapses can be distinguished based on their sensitivity to inhibitors of protein kinase A (PKA). The PKA-dependent form requires multiple episodes of high-frequency stimulation (HFS) or theta burst stimuli (TBS) with a spacing between episodes in the order of minutes. To investigate the mechanism by which spaced episodes induce the PKA-dependent form of LTP, we have compared, in interleaved experiments, spaced (s) and compressed (c) TBS protocols in the rat CA1 synapses. We find that LTP induced by sTBS, but not that induced by cTBS, involves the insertion of calcium-permeable (CP) AMPARs, as assessed using pharmacological and electrophysiological criteria. Furthermore, a single TBS when paired with rolipram [4-(3-(cyclopentyloxy)-4-methoxyphenyl)pyrrolidin-2-one], to activate PKA, generates an LTP that also involves the insertion of CP-AMPARs. These data demonstrate that the involvement of CP-AMPARs in LTP is critically determined by the timing of the induction trigger and is associated specifically with the PKA-dependent form of LTP. © 2016 Park et al.

Kim J.-I.,Seoul National University | Lee H.-R.,Seoul National University | Sim S.-E.,Seoul National University | Baek J.,Seoul National University | And 21 more authors.
Nature Neuroscience | Year: 2011

Phosphatidylinositol 3-kinase (PI3K) has been implicated in synaptic plasticity and other neural functions in the brain. However, the role of individual PI3K isoforms in the brain is unclear. We investigated the role of PI3KÎ 3 in hippocampal-dependent synaptic plasticity and cognitive functions. We found that PI3KÎ 3 has a crucial and specific role in NMDA receptor (NMDAR)-mediated synaptic plasticity at mouse Schaffer collateralg - commissural synapses. Both genetic deletion and pharmacological inhibition of PI3KÎ 3 disrupted NMDAR long-term depression (LTD) while leaving other forms of synaptic plasticity intact. Accompanying this physiological deficit, the impairment of NMDAR LTD by PI3KÎ 3 blockade was specifically correlated with deficits in behavioral flexibility. These findings suggest that a specific PI3K isoform, PI3KÎ 3, is critical for NMDAR LTD and some forms of cognitive function. Thus, individual isoforms of PI3Ks may have distinct roles in different types of synaptic plasticity and may therefore influence various kinds of behavior. © 2011 Nature America, Inc. All rights reserved.

Brown M.W.,Center for Synaptic Plasticity | Warburton E.C.,Center for Synaptic Plasticity | Aggleton J.P.,University of Cardiff
Hippocampus | Year: 2010

The proposal that a system centering on the perirhinal cortex is responsible for familiarity discrimination, particularly for single items, whereas a system centering on the hippocampus is responsible for recollective and more complex associational aspects of recognition memory is reviewed in the light of recent findings. In particular, the proposal is reviewed in relation to recent animal work with rats and results from human clinical studies. Notably, progress has been made in determining potential neural memory substrate mechanisms within the perirhinal cortex in rats. Recent findings have emphasized the importance of specifying the type of material, the type of test, and the strategy used by subjects to solve recognition memory tests if substrates are to be accurately inferred. It is to be expected that the default condition is that both the hippocampal and perirhinal systems will contribute to recognition memory performance. Indeed, rat lesion experiments provide examples of where cooperation between both systems is essential. Nevertheless, there remain examples of the independent operation of the hippocampal and perirhinal systems. Overall, it is concluded that most, though not all, of the recent findings are in support of the proposal. However, there is also evidence that the systems involved in recognition memory need to include structures outside the medial temporal lobe: there are significant but as yet only partially defined roles for the prefrontal cortex and sensory association cortices in recognition memory processes. © 2010 Wiley-Liss, Inc.

Srivastava R.,French Institute of Health and Medical Research | Srivastava R.,University Paris Diderot | Srivastava R.,National Brain Research Center | Kumar M.,French Institute of Health and Medical Research | And 13 more authors.
Stem Cells | Year: 2013

Directing differentiation of embryonic stem cells (ESCs) to specific neuronal subtype is critical for modeling disease pathology in vitro. An attractive means of action would be to combine regulatory differentiation factors and extrinsic inductive signals added to the culture medium. In this study, we have generated mature cerebellar granule neurons by combining a temporally controlled transient expression of Math1, a master gene in granule neuron differentiation, with inductive extrinsic factors involved in cerebellar development. Using a Tetracyclin-On transactivation system, we overexpressed Math1 at various stages of ESCs differentiation and found that the yield of progenitors was considerably increased when Math1 was induced during embryonic body stage. Math1 triggered expression of Mbh1 and Mbh2, two target genes directly involved in granule neuron precursor formation and strong expression of early cerebellar territory markers En1 and NeuroD1. Three weeks after induction, we observed a decrease in the number of glial cells and an increase in that of neurons albeit still immature. Combining Math1 induction with extrinsic factors specifically increased the number of neurons that expressed Pde1c, Zic1, and GABAa6R characteristic of mature granule neurons, formed "T-shaped" axons typical of granule neurons, and generated synaptic contacts and action potentials in vitro. Finally, in vivo implantation of Math1-induced progenitors into young adult mice resulted in cell migration and settling of newly generated neurons in the cerebellum. These results show that conditional induction of Math1 drives ESCs toward the cerebellar fate and indicate that acting on both intrinsic and extrinsic factors is a powerful means to modulate ESCs differentiation and maturation into a specific neuronal lineage. © AlphaMed Press.

Affaticati P.,French National Institute for Agricultural Research | Affaticati P.,University Paris - Sud | Mignen O.,French National Institute for Agricultural Research | Mignen O.,University Paris - Sud | And 20 more authors.
Cell Death and Differentiation | Year: 2011

L-glutamate, the major excitatory neurotransmitter, also has a role in non-neuronal tissues and modulates immune responses. Whether NMDA receptor (NMDAR) signalling is involved in T-cell development is unknown. In this study, we show that mouse thymocytes expressed an array of glutamate receptors, including NMDARs subunits. Sustained calcium (Ca2+) signals and caspase-3 activation in thymocytes were induced by interaction with antigen-pulsed dendritic cells (DCs) and were inhibited by NMDAR antagonists MK801 and memantine. NMDARs were transiently activated, triggered the sustained Ca2+ signal and were corecruited with the PDZ-domain adaptor postsynaptic density (PSD)-95 to thymocyte-DC contact zones. Although T-cell receptor (TCR) activation was sufficient for relocalization of NMDAR and PSD-95 at the contact zone, NMDAR could be activated only in a synaptic context. In these T-DC contacts, thymocyte activation occurred in the absence of exogenous glutamate, indicating that DCs could be a physiological source of glutamate. DCs expressed glutamate, glutamate-specific vesicular glutamate transporters and were capable of fast glutamate release through a Ca2+-dependent mechanism. We suggest that glutamate released by DCs could elicit focal responses through NMDAR-signalling in T cells undergoing apoptosis. Thus, synapses between T and DCs could provide a functional platform for coupling TCR activation and NMDAR signalling, which might reflect on T-cell development and modulation of the immune response. © 2011 Macmillan Publishers Limited All rights reserved.

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