Activity-dependent synaptic plasticity of NMDA receptors

Abstract

Activity-dependent, bidirectional control of synaptic efficacy is thought to contribute to many forms of experience-dependent plasticity, including learning and memory. Although most excitatory synapses contain both AMPA and N-methyl-d-aspartate receptors (AMPARs and NMDARs), most studies have focused on the plasticity of synaptic AMPARs, and on the pivotal role of NMDA receptors for its induction. Here we review evidence that synaptic NMDARs themselves are subject to long-term activity-dependent changes by mechanisms that may differ from that of synaptic AMPARs. The bidirectional modulation of NMDAR-mediated synaptic responses is likely to have important functional implications for NMDAR-dependent forms of synaptic plasticity.

Christophe Mulle is a cellular neurobiologist with expertise in cellular electrophysiology of synaptic transmission and plasticity, receptor cell biology and the generation of transgenic mice. Since 1995 he has worked at a CNRS laboratory he established in Bordeaux, with interests in the cellular biology and pathophysiology of glutamatergic synaptic transmission and plasticity. He trained in the laboratory of Jean-Pierre Changeux to characterize functional nicotinic receptors in the mammalian brain and in the laboratory of Mircea Steriade and Martin Deschênes, and of Steve Heinemann at the Salk Institute in San Diego. He trained in molecular biology techniques and generated knock-out mice for kainate receptor subunits, which have proved to be instrumental for the understanding the function of these elusive glutamate receptors. In addition he has provided insights into the molecular events that govern polarized trafficking of kainate receptors. More recently he has unravelled novel forms of synaptic plasticity in the hippocampus, and has ambitions to answer questions related to cell biology of glutamate receptors, and to synaptic function, integration and plasticity.

Figure 1. Examples of LTP and LTD of NMDARs

Tetanic stimulation consisting of eight trains each of eight pulses at 200 Hz, inter-train interval 2 s, applied under current clamp configuration at resting membrane potential during tetanus induces LTP of NMDA-EPSCs in dentate gyrus granule cells (reproduced from O’Connor et al. 1994 with permission from Nature Publishing Group). On the other hand, a 1 Hz stimulation for 10 min while holding the cells at −40 mV induces LTD of NMDA-EPSCs in CA1 area of the hippocampus (reproduced from Selig et al. 1995 with permission from Elsevier).

Figure 2. Schematic illustration of LTP of NMDARs at hippocampal mossy fibre synapses

Short bursts of stimulation of mossy fibres lead to the activation of NMDA, mGluR5 and adenosine A_2A receptors that jointly induce LTP of NMDA-EPSCs in CA3 pyramidal neurons. mGluR5 couples to phospholipase C (PLC) via a Gq protein, which promotes the formation of inositol 1,4,5-trisphosphate (IP₃) and diacylglycerol (DAG). IP₃ triggers Ca²⁺ release from intracellular stores, and both Ca²⁺ and DAG activate protein kinase C. Once activated, PKC can also activate Src kinases. PKC or Src may trigger the SNARE-dependent insertion of new NMDARs into the postsynaptic membrane. PKC or Src kinases can also enhance open probability of postsynaptic NMDARs, increasing postsynaptic Ca²⁺ rise and thus favouring LTP induction. The role of adenosine A_2A receptors in LTP of NMDAR induction is not clear but could rely on an increase in postsynaptic Ca²⁺ rise through direct coupling of A_2A receptors to the PLC pathway or on a potentiation of mGluR5 function. Additionally, activation of Src kinase by A_2A receptors might also facilitate the induction of LTP of NMDA-EPSCs.