| Learning and memory requires discernible mechanisms for the spatial and temporal regulation of synaptic activity. Modifications to synaptic strength through changes in the expression and composition of ionotropic glutamate receptors at the synapse have been implicated in a dynamic range of physiological responses as well as pathological conditions throughout the brain. NMDA-type glutamate receptors, in particular, are the predominant effectors of synaptic change and investigations into their regulation at the synapse are fundamental to understanding the relationship between synaptic plasticity, cellular physiology, and behavioral learning. We are interested in the regulation and expression of NMDA receptors by proteins of the postsynaptic density (PSD) in synapses of hippocampus. These proteins form massive macromolecular complexes with NMDA receptors to translate presynaptic signals into postsynaptic modifications through downstream signaling pathways. Consequently, NMDA receptor complexes not only play a critical role in determining the strength of synaptic connections through morphological changes of the spine and dendrite, but also affect the physiological response of neurons in response to stimuli, underlying the mechanisms of learning and memory.; Our study aims to determine interactions of synaptic proteins responsible for different forms of synaptic plasticity imparted by the subunit-specific regulation of NMDA receptors at the synapse. Using postembedding immunogold electron microscopy, the present study establishes subunit-specific effects of NMDA receptor subunits, NR2A and NR2B, in CA1 hippocampus of transgenic mice with contrasting phenotypes. In PSD-95PDZ12 mutant mice lacking LTD but with enhanced LTP, NR2B subunits are preferentially redistributed from the synaptic membrane into internal compartments of the PSD and cytoplasm of the spine. In support of functional overlap and compensation by homologous MAGUK proteins, NR2B is redistributed in approximately the same magnitude and direction in SAP102 knockout mice. In stark contrast to MAGUK-dependent regulation of NR2B-containing NMDA receptors, NR2A is selectively reduced at the synapse and throughout dendritic spines of CaMKIIT305D mutant mice, with severe decrements in LTP yet robust LTD. Moreover, PSD-95 distribution in CaMKIIT305D mutant mice did not change and, conversely, neither was alphaCaMKII distribution affected in PSD-95 PDZ12 mutant mice, indicating highly independent and separable interactions for the differential regulation of NR2B and NR2A-containing NMDA receptors. |
