UCSF

At Schaffer collateral synapses in area CA1 of the hippocampus, presynaptically released glutamate activates two types of postsynaptic ionotropic receptors, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPAR) and N-methyl-D-asparate (NMDAR) receptors. The trafficking of AMPA and NMDA receptors to and from synapses controls excitatory synaptic transmission. The molecular mechanisms regulating this trafficking remain largely unknown. I show that members of the family of PSD-95-like membrane associated guanylate kinases (PSD-MAGUK) scaffolding protein mediate the synaptic targeting of AMPARs in the adult hippocampus, and uncover a remarkable functional redundancy within this protein family. PSD-95 and PSD-93 independently mediate AMPAR trafficking at mature synapses. These studies also reveal unanticipated synapse heterogeneity as loss of either PSD-95 or PSD-93 silences largely non-overlapping populations of excitatory synapses. In adult mice lacking PSD-95 and PSD-93, SAP102 is up-regulated and compensates for the loss of synaptic AMPARs. These studies establish a PSD-MAGUK-specific regulation of AMPAR synaptic trafficking that maintains synaptic transmission in the adult mammalian brain. The development of synapses involves a change in the number and type of glutamate receptors. To elucidate the molecular mechanisms controlling this process in vivo I combine, for the first time, in utero intraventricular injection and electroporation of constructs that alter the molecular composition of developing synapses, with simultaneous dual whole-cell recordings in acute hippocampal slices. I find that SAP102 mediates synaptic trafficking of AMPARs and NR2B-containing NMDARs (NR2B-NMDARs) during synaptogenesis. After synaptogenesis, PSD-95 assumes the functions of SAP102 and is necessary for both the developmental increase in AMPAR-mediated transmission and the replacement of NR2B-NMDARs with NR2A-NMDARs. In mice lacking PSD-95 and PSD-93 the maturational replacement of NR2B- with NR2A-NMDARs fails to occur, and PSD-95 expression in these mice fully rescues this deficit. Thus, SAP102 and PSD-95 regulate the synaptic trafficking of distinct glutamate receptor subtypes at different developmental stages thereby playing a necessary role in excitatory synapse development. These studies establish an essential role for PSD-MAGUK scaffolding proteins in the synaptic targeting of glutamate receptors during the development and maintenance of excitatory synaptic transmission in a mammalian brain circuit for learning and memory.