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The membrane-associated guanylate kinases (MAGUKs) PSD-95, PSD-93 and SAP102 are thought to have crucial roles in both AMPA receptor trafficking and formation of NMDA receptor-associated signalling complexes involved in synaptic plasticity. While PSD-95, PSD-93, and SAP102 appear to have similar roles in AMPA receptor trafficking, it is not known whether these MAGUKs also have functionally similar roles in synaptic plasticity. To explore this issue we examined several properties of basal synaptic transmission in the hippocampal CA1 region of PSD-93 and PSD-95 mutant mice and compared the ability of a number of different synaptic stimulation protocols to induce long-term potentiation (LTP) and long-term depression (LTD) in these mutants. We find that while both AMPA and NMDA receptor-mediated synaptic transmission are normal in PSD-93 mutants, PSD-95 mutant mice exhibit clear deficits in AMPA receptor-mediated transmission. Moreover, in contrast to the facilitation of LTP induction and disruption of LTD observed in PSD-95 mutant mice, PSD-93 mutant mice exhibit deficits in LTP and normal LTD. Our results suggest that PSD-95 has a unique role in AMPA receptor trafficking at excitatory synapses in the hippocampus of adult mice and indicate that PSD-93 and PSD-95 have essentially opposite roles in LTP, perhaps because these MAGUKs form distinct NMDA receptor signalling complexes that differentially regulate the induction of LTP by different patterns of synaptic activity.
Pubmed ID: 18936077 RIS Download
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A neuroscience research program that studies genes, the brain and behavior in an integrated manner, established to elucidate the molecular mechanisms of learning and memory, and shed light on the pathogenesis of disorders of cognition. Central to G2C investigations is the NMDA receptor complex (NRC/MASC), that is found at the synapses in the central nervous system which constitute the functional connections between neurons. Changes in the receptor and associated components are thought to be in a large part responsible for the phenomenon of synaptic plasticity, that may underlie learning and memory. G2C is addressing the function of synapse proteins using large scale approaches combining genomics, proteomics and genetic methods with electrophysiological and behavioral studies. This is incorporated with computational models of the organization of molecular networks at the synapse. These combined approaches provide a powerful and unique opportunity to understand the mechanisms of disease genes in behavior and brain pathology as well as provide fundamental insights into the complexity of the human brain. Additionally, Genes to Cognition makes available its biological resources, including gene-targeting vectors, ES cell lines, antibodies, and transgenic mice, generated for its phenotyping pipeline. The resources are freely-available to interested researchers.
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