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PSD-MAGUK-specific developmetal regulation of AMPA receptor synaptic expression
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
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