Synapse-specific regulation of AMPA receptor function by PSD-95

Abstract

PSD-95 is a major protein found in virtually all mature excitatory glutamatergic synapses in the brain. Here, we have addressed the role of PSD-95 in controlling glutamatergic synapse function by generating and characterizing a PSD-95 KO mouse. We found that the ␣-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) subtype of glutamate receptor (AMPAR)-mediated synaptic transmission was reduced in these mice. Two-photon (2P) uncaging of MNI-glutamate onto individual spines suggested that the decrease in AMPAR function in the PSD-95 KO mouse stems from an increase in the proportion of ''silent'' synapses i.e., synapses containing N-methyl-D-aspartate (NMDA) receptors (NMDARs) but no AMPARs. Unexpectedly, the silent synapses in the KO mouse were located onto morphologically mature spines. We also observed that a significant population of synapses appeared unaffected by PSD-95 gene deletion, suggesting that the functional role of PSD-95 displays synapse-specificity. In addition, we report that the decay of NMDAR-mediated current was slower in KO mice: The contribution of NR2B subunit containing receptors to the NMDARmediated synaptic current was greater in KO mice. The greater occurrence of silent synapses might be related to the greater magnitude of potentiation after long-term potentiation induction observed in these mice. Together, these results suggest a synapsespecific role for PSD-95 in controlling synaptic function that is independent of spine morphology.glutamate receptors ͉ hippocampus ͉ spines ͉ synaptic transmission ͉ two-photon uncaging G lutamate, the major excitatory neurotransmitter in the brain, activates ionotropic glutamate receptors of the ␣-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), N-methyl-D-aspartate (NMDA), and kainate subtypes. There is considerable interest in elucidating the molecular mechanisms that controls synaptic targeting and trafficking of these receptors, in part because of their role in the induction and expression of various forms of synaptic plasticity (1). These receptors are imbedded in an electron-dense structure, the postsynaptic density (PSD), which is believed to contain key molecules involved in the regulation of glutamate receptor targeting and trafficking. PSD-95, a member of the membraneassociated guanylate kinase (MAGUK) superfamily of proteins, is a core component of the PSD and is thought to be important in the control of excitatory synapse function (2, 3). Because of its interaction with the cytoplasmic domains of NMDA receptor (NMDAR) subunits, it has long been suspected that PSD-95 might control the synaptic targeting of NMDARs (4, 5). However, more recent studies based on sustained or transient overexpression of PSD-95 in neurons have forced a reassessment of this view by suggesting that the primary role of PSD-95 is restricted to controlling AMPAR synaptic expression (6-10). Intriguingly, previous work on a PSD-95 KO mouse, reported no apparent changes in either AMPAR or NMDAR function (11). The interpretation of these data are, however, ...

Regulation of AMPA receptors and synaptic plasticity

“…An enhancement of LTP is also observed in PSD-95 knockout mice (Migaud et al, 1998), and similar findings were reported in another deletion mutant of PSD-95 (Beique et al, 2006). This suggests that the activity-dependent delivery of AMPARs to the synapse during LTP may occur in the absence of PSD-95, and may be mediated, for example, by Stargazin, which binds both AMPARs and PSD-95 (Schnell et al, 2002).…”

Trimethylamine‐N‐oxide promotes brain aging and cognitive impairment in mice

“…Because of its role in long‐term potentiation (LTP), NMDAR1 is believed to strengthen synaptic plasticity, which is considered the molecular basis of learning and memory (Lau, Saha, Faris & Russek, 2004). PSD‐95 is a core component of postsynaptic density (PSD) and is thought to be important in the control of excitatory synapse function (Béïque et al., 2006; Vickers et al., 2006). Reduced expression of PSD‐95 induces cognitive and memory dysfunction (Migaud et al., 1998).…”

Differential trafficking of AMPA and NMDA receptors by SAP102 and PSD-95 underlies synapse development

“…The PSD-95-like subfamily of neuronal MAGUKs (PSD-MAGUKs) includes PSD-93, SAP102, and SAP97 (15)(16)(17). Comparative studies emphasize the remarkable similarities among PSD-MAGUKs in terms of protein-protein interactions (18,19) and overlapping functions in synaptic trafficking of AMPARs at mature synapses (20)(21)(22)(23)(24). On the other hand, the temporal coincidence of the early postnatal developmental switch from NR2B-to NR2A-NMDARs with the switch from SAP102 to PSD-95 expression raises the possibility that the two processes are related (25).…”