- Email: [email protected]
Synaptic plasticity in learning and memory
492
Symposia & Short Talk Abstracts / Int. J. Devl Neuroscience 24 (2006) 471–493
SHP-2 enhanced neurogenesis and suppressed gliogenesis. Blockade of MAP kinase activity inhibited the SHP-2mediated increase in neurogenesis, indicating that this is the likely pathway used by NS SHP-2. Together, these results indicate that SHP-2 plays a key role in integrating extrinsic signals, and functions to promote neurogenesis at the same time that it inhibits gliogenesis. We are currently investigating whether the neuronal versus glial ratio is altered in a mouse model of Noonan syndrome, with the ultimate goal of determining whether this accounts for the cognitive impairments in NS patients.
doi:10.1016/j.ijdevneu.2006.09.054 Cellular mechanisms regulating neural plasticity
stabilization of the active one through TrkB. Muscle activity drives the secretion of proBDNF, which is converted to mBDNF by proteases selectively expressed by the active, presynaptic terminal. These results demonstrate that the activity-dependent conversion of proBDNF to mBDNF is critical for synaptic competition and elimination during development. doi:10.1016/j.ijdevneu.2006.09.055 [S46] Otx2 homeoprotein specifies critical period plasticity in mouse visual cortex T.K. Hensch 1,*, S. Sugiyama 1, A. Prochiantz 2 1
[S45] Role of proteolytic conversion of proBDNF to mBDNF in synaptic development and plasticity B. Lu Gene, Cognition and Psychosis (GCAP) Program, NIMH, NIH, USA BDNF has recently emerged as a key regulator for synaptic development and plasticity. In a recent study, we examined the role of BDNF in late-phase LTP (L-LTP). We demonstrate that the extracellular protease tPA converts the precursor proBDNF to the mature BDNF (mBDNF) in the hippocampus, and such conversion is critical for L-LTP. Furthermore, application of mBDNF allows L-LTP to occur when protein synthesis is blocked and converts early-phase LTP to L-LTP, suggesting that mBDNF is the key protein synthesis product responsible for LLTP expression. Our study has identified tPA/plasmin as an endogenous enzyme system that converts proBDNF to mBDNF in the hippocampus, and provided a mechanistic link between tPA and BDNF in L-LTP. ProBDNF and mBDNF are thought to bind to two distinct receptors: the pan neurotrophin receptor p75 (p75NTR) and the TrkB tyrosine kinase, respectively. Previous, studies indicate that mBDNF facilitates LTP through TrkB. We show that the proBDNF, by activating its preferred receptor p75NTR, selectively enhances the NMDA-dependent form of LTD at the hippocampal synapses. Together with the finding that mBDNF promotes LTP, our results support a Yin-Yang model in which proBDNF promotes LTD whereas mBDNF facilitates LTP. Thus, extracellular cleavage of proBDNF becomes a key step that controls the direction of BDNF regulation. ProBDNF ! mBDNF conversion may also play a role in synapse development. Using a cell culture system in which a single myocyte is innervated by two spinal neurons, proBDNF induces retraction of the less active terminal by activating p75NTR, whereas mature BDNF (mBDNF) facilitates the
RIKEN Brain Science Institute, Japan; 2 CNRS UMR 8542, Ecole Normale Superieure, France Brain functions are shaped by sensory experience during early postnatal life. We have found that the critical period for binocular vision is triggered by specific GABAergic connections in the neocortex. Maturation of these interneurons (and hence, plasticity onset) was surprisingly specified by the noncell autonomous expression of a homeoprotein, Otx2. Binocular enucleation or dark-rearing from birth prevented the normal accumulation of Otx2 within parvalbumin-positive interneurons. Directly reducing the intercellular transfer or Otx2 synthesis in non-GABAergic cells prevented visual cortical plasticity. Conversely, cortical infusion of exogenous Otx2 accelerated the maturation of the GABAergic network mediating critical period timing. Our findings indicate a physiological role for the experience-dependent passage of a homeodomain transcription factor in vivo and reveal embryonic factors to guide the later postnatal plasticity of neural circuits along specific sensory pathways. doi:10.1016/j.ijdevneu.2006.09.056 [S47] Synaptic plasticity in learning and memory Y.-T. Wang University of British Columbia, Canada Dynamic modification of the efficacy of synaptic transmission between neurons in the brain is considered one of the essential mechanisms underlying learning and memory. The most extensively studied examples of such synaptic plasticity have been long-term potentiation (LTP) and long-term depression (LTD) observed at the glutamatergic synapses of the CA1 region of the hippocampus. However, evidence for a definitive role of either LTP or LTD in learning and memory remains missing due to the lack of the specific inhibitor for LTP or LTD. It is generally accepted that the induction of both LTP
Symposia & Short Talk Abstracts / Int. J. Devl Neuroscience 24 (2006) 471–493
and LTD at the CA1 synapse is postsynaptic and dependent upon Ca2+ influx through activated N-methyl-D-aspartate subtype glutamate receptors (NMDARs). However, the mechanisms underlying the expression of LTP and LTD remain hotly debated, and likely involve both a presynaptic component via alteration of transmitter release and a postsynaptic one through the modification of (-amino-3hydroxy-5-methylisoxazole-4-propionic acid subtype glutamate receptors (AMPARs). Traditionally, modifications of postsynaptic AMPARs has been thought to be achieved mainly by altering the channel gating properties or conductance of the receptors. Recent studies from many laboratories including our own have provided substantial evidence suggesting that AMPARs are continuously cycling between the plasma membrane and intracellular compartments via vesicle fusion mediated plasma membrane insertion and clathrin dependent endocytosis and that facilitated AMPAR insertion and endocytosis at postsynaptic membranes contributes to the expression of LTP and LTD, respectively. Using a combination of recombinant receptor expression systems and hippocampal brain slice preparations, we were able to demonstrate that facilitated endocytosis of postsynaptic AMPAR during LTD is AMPAR GluR2 subunit-specific. These studies have lead us to develop a GluR2-derived interference peptide that, when delivered into neurons in the brain, can specifically block the expression of LTD without affecting normal functioning of either NMDAR or AMPAR and hence, basal synaptic transmission in many regions of the brain. Using the membrane-permeate form of the GluR2 peptide as a specific inhibitor of LTD, we were able to probe the role of LTD in freely moving rats with unprecedented specificity and thereby provide evidence for the involvement of LTD in a number of learning and memory-related behaviours. Our work not only provides the first evidence for a definitive role of LTD in learning and memory, but also demonstrates the utility of peptides that disrupt the AMPAR trafficking, the final step in the expression of synaptic plasticity, as tools to examine the critical role of LTD and/or LTP in specific aspects of learning and memory in conscious animals. doi:10.1016/j.ijdevneu.2006.09.057
493
[ST8] PSD-MAGUK-specific developmetal regulation of AMPA receptor synaptic expression G.M. Elias 1,a,*, L. Funke 1,3,a, V. Stein 1, S.G. Grant 2, D.S. Bredt 1, R.A. Nicoll 1 1
University of California San Francisco, USA; 2 Wellcome Trust Sanger Institute, UK; 3 Freie Universitaet, Germany E-mail address: [email protected] (G.M. Elias). a Equal contribution authors. The trafficking of AMPA receptors to and from synapses controls the strength of excitatory synaptic transmission. However, the proteins responsible for maintaining AMPA receptors at the synapse at different developmental stages are poorly understood. Here, we show that the PSD-95-like MAGUK (PSD-MAGUK) subfamily of scaffolding proteins is essential for this synaptic clustering and uncover a remarkable redundancy of function among this family of proteins. Based on a combination of experimental approaches designed to manipulate endogenously expressed neuronal PSD-MAGUKs, independent of functional compensation by redundancy among PSD-MAGUK isoforms, we demonstrate that PSD95 and PSD-93 are primarily responsible for AMPA receptor clustering at mature synapses. These studies also reveal unanticipated synapse heterogeneity, in which loss of either PSD-95 or PSD-93 causes the silencing of non-overlapping populations of excitatory synapses. At immature synapses PSD-95 and PSD-93 play little role in synaptic AMPA receptor clustering, whereas SAP-102 plays a dominant role. In mature mice lacking both PSD-95 and PSD-93, SAP-102 is upregulated and functionally compensates to cluster the remaining synaptic AMPA receptors. These studies establish a PSD-MAGUK-specific developmental regulation of AMPA receptor synaptic expression that is essential for establishing and maintaining transmission at central glutamatergic synapses. doi:10.1016/j.ijdevneu.2006.09.058
Symposia & Short Talk Abstracts / Int. J. Devl Neuroscience 24 (2006) 471–493
SHP-2 enhanced neurogenesis and suppressed gliogenesis. Blockade of MAP kinase activity inhibited the SHP-2mediated increase in neurogenesis, indicating that this is the likely pathway used by NS SHP-2. Together, these results indicate that SHP-2 plays a key role in integrating extrinsic signals, and functions to promote neurogenesis at the same time that it inhibits gliogenesis. We are currently investigating whether the neuronal versus glial ratio is altered in a mouse model of Noonan syndrome, with the ultimate goal of determining whether this accounts for the cognitive impairments in NS patients.
doi:10.1016/j.ijdevneu.2006.09.054 Cellular mechanisms regulating neural plasticity
stabilization of the active one through TrkB. Muscle activity drives the secretion of proBDNF, which is converted to mBDNF by proteases selectively expressed by the active, presynaptic terminal. These results demonstrate that the activity-dependent conversion of proBDNF to mBDNF is critical for synaptic competition and elimination during development. doi:10.1016/j.ijdevneu.2006.09.055 [S46] Otx2 homeoprotein specifies critical period plasticity in mouse visual cortex T.K. Hensch 1,*, S. Sugiyama 1, A. Prochiantz 2 1
[S45] Role of proteolytic conversion of proBDNF to mBDNF in synaptic development and plasticity B. Lu Gene, Cognition and Psychosis (GCAP) Program, NIMH, NIH, USA BDNF has recently emerged as a key regulator for synaptic development and plasticity. In a recent study, we examined the role of BDNF in late-phase LTP (L-LTP). We demonstrate that the extracellular protease tPA converts the precursor proBDNF to the mature BDNF (mBDNF) in the hippocampus, and such conversion is critical for L-LTP. Furthermore, application of mBDNF allows L-LTP to occur when protein synthesis is blocked and converts early-phase LTP to L-LTP, suggesting that mBDNF is the key protein synthesis product responsible for LLTP expression. Our study has identified tPA/plasmin as an endogenous enzyme system that converts proBDNF to mBDNF in the hippocampus, and provided a mechanistic link between tPA and BDNF in L-LTP. ProBDNF and mBDNF are thought to bind to two distinct receptors: the pan neurotrophin receptor p75 (p75NTR) and the TrkB tyrosine kinase, respectively. Previous, studies indicate that mBDNF facilitates LTP through TrkB. We show that the proBDNF, by activating its preferred receptor p75NTR, selectively enhances the NMDA-dependent form of LTD at the hippocampal synapses. Together with the finding that mBDNF promotes LTP, our results support a Yin-Yang model in which proBDNF promotes LTD whereas mBDNF facilitates LTP. Thus, extracellular cleavage of proBDNF becomes a key step that controls the direction of BDNF regulation. ProBDNF ! mBDNF conversion may also play a role in synapse development. Using a cell culture system in which a single myocyte is innervated by two spinal neurons, proBDNF induces retraction of the less active terminal by activating p75NTR, whereas mature BDNF (mBDNF) facilitates the
RIKEN Brain Science Institute, Japan; 2 CNRS UMR 8542, Ecole Normale Superieure, France Brain functions are shaped by sensory experience during early postnatal life. We have found that the critical period for binocular vision is triggered by specific GABAergic connections in the neocortex. Maturation of these interneurons (and hence, plasticity onset) was surprisingly specified by the noncell autonomous expression of a homeoprotein, Otx2. Binocular enucleation or dark-rearing from birth prevented the normal accumulation of Otx2 within parvalbumin-positive interneurons. Directly reducing the intercellular transfer or Otx2 synthesis in non-GABAergic cells prevented visual cortical plasticity. Conversely, cortical infusion of exogenous Otx2 accelerated the maturation of the GABAergic network mediating critical period timing. Our findings indicate a physiological role for the experience-dependent passage of a homeodomain transcription factor in vivo and reveal embryonic factors to guide the later postnatal plasticity of neural circuits along specific sensory pathways. doi:10.1016/j.ijdevneu.2006.09.056 [S47] Synaptic plasticity in learning and memory Y.-T. Wang University of British Columbia, Canada Dynamic modification of the efficacy of synaptic transmission between neurons in the brain is considered one of the essential mechanisms underlying learning and memory. The most extensively studied examples of such synaptic plasticity have been long-term potentiation (LTP) and long-term depression (LTD) observed at the glutamatergic synapses of the CA1 region of the hippocampus. However, evidence for a definitive role of either LTP or LTD in learning and memory remains missing due to the lack of the specific inhibitor for LTP or LTD. It is generally accepted that the induction of both LTP
Symposia & Short Talk Abstracts / Int. J. Devl Neuroscience 24 (2006) 471–493
and LTD at the CA1 synapse is postsynaptic and dependent upon Ca2+ influx through activated N-methyl-D-aspartate subtype glutamate receptors (NMDARs). However, the mechanisms underlying the expression of LTP and LTD remain hotly debated, and likely involve both a presynaptic component via alteration of transmitter release and a postsynaptic one through the modification of (-amino-3hydroxy-5-methylisoxazole-4-propionic acid subtype glutamate receptors (AMPARs). Traditionally, modifications of postsynaptic AMPARs has been thought to be achieved mainly by altering the channel gating properties or conductance of the receptors. Recent studies from many laboratories including our own have provided substantial evidence suggesting that AMPARs are continuously cycling between the plasma membrane and intracellular compartments via vesicle fusion mediated plasma membrane insertion and clathrin dependent endocytosis and that facilitated AMPAR insertion and endocytosis at postsynaptic membranes contributes to the expression of LTP and LTD, respectively. Using a combination of recombinant receptor expression systems and hippocampal brain slice preparations, we were able to demonstrate that facilitated endocytosis of postsynaptic AMPAR during LTD is AMPAR GluR2 subunit-specific. These studies have lead us to develop a GluR2-derived interference peptide that, when delivered into neurons in the brain, can specifically block the expression of LTD without affecting normal functioning of either NMDAR or AMPAR and hence, basal synaptic transmission in many regions of the brain. Using the membrane-permeate form of the GluR2 peptide as a specific inhibitor of LTD, we were able to probe the role of LTD in freely moving rats with unprecedented specificity and thereby provide evidence for the involvement of LTD in a number of learning and memory-related behaviours. Our work not only provides the first evidence for a definitive role of LTD in learning and memory, but also demonstrates the utility of peptides that disrupt the AMPAR trafficking, the final step in the expression of synaptic plasticity, as tools to examine the critical role of LTD and/or LTP in specific aspects of learning and memory in conscious animals. doi:10.1016/j.ijdevneu.2006.09.057
493
[ST8] PSD-MAGUK-specific developmetal regulation of AMPA receptor synaptic expression G.M. Elias 1,a,*, L. Funke 1,3,a, V. Stein 1, S.G. Grant 2, D.S. Bredt 1, R.A. Nicoll 1 1
University of California San Francisco, USA; 2 Wellcome Trust Sanger Institute, UK; 3 Freie Universitaet, Germany E-mail address: [email protected] (G.M. Elias). a Equal contribution authors. The trafficking of AMPA receptors to and from synapses controls the strength of excitatory synaptic transmission. However, the proteins responsible for maintaining AMPA receptors at the synapse at different developmental stages are poorly understood. Here, we show that the PSD-95-like MAGUK (PSD-MAGUK) subfamily of scaffolding proteins is essential for this synaptic clustering and uncover a remarkable redundancy of function among this family of proteins. Based on a combination of experimental approaches designed to manipulate endogenously expressed neuronal PSD-MAGUKs, independent of functional compensation by redundancy among PSD-MAGUK isoforms, we demonstrate that PSD95 and PSD-93 are primarily responsible for AMPA receptor clustering at mature synapses. These studies also reveal unanticipated synapse heterogeneity, in which loss of either PSD-95 or PSD-93 causes the silencing of non-overlapping populations of excitatory synapses. At immature synapses PSD-95 and PSD-93 play little role in synaptic AMPA receptor clustering, whereas SAP-102 plays a dominant role. In mature mice lacking both PSD-95 and PSD-93, SAP-102 is upregulated and functionally compensates to cluster the remaining synaptic AMPA receptors. These studies establish a PSD-MAGUK-specific developmental regulation of AMPA receptor synaptic expression that is essential for establishing and maintaining transmission at central glutamatergic synapses. doi:10.1016/j.ijdevneu.2006.09.058