Enhancing NMDA Receptor Function: Recent Progress on Allosteric Modulators

Abstract

The N-methyl-D-aspartate receptors (NMDARs) are subtype glutamate receptors that play important roles in excitatory neurotransmission and synaptic plasticity. Their hypo- or hyperactivation are proposed to contribute to the genesis or progression of various brain diseases, including stroke, schizophrenia, depression, and Alzheimer's disease. Past efforts in targeting NMDARs for therapeutic intervention have largely been on inhibitors of NMDARs. In light of the discovery of NMDAR hypofunction in psychiatric disorders and perhaps Alzheimer's disease, efforts in boosting NMDAR activity/functions have surged in recent years. In this review, we will focus on enhancing NMDAR functions, especially on the recent progress in the generation of subunit-selective, allosteric positive modulators (PAMs) of NMDARs. We shall also discuss the usefulness of these newly developed NMDAR-PAMs.

Figure 1

Cell type-specific effects of NMDAR-PAMs. (a) GNE-8324 has no effect on NMDAR EPSPs recorded from CA1 pyramidal neurons in acute brain slices. (b) In contrast, GNE-6901 showed robust potentiation on NMDAR EPSPs under the same condition. (c, d) Robust potentiation of both GNE-8324 and GNE-6901 on NMDAR EPSCs recorded in the inhibitory neurons in the hippocampus. Modified from [28].

Figure 2

Differential effects on NMDARs underlie different modification of synaptic plasticity by GNE-PAMs. (a) NMDAR-mediated responses during TBS were calculated and showed differences between GNE-8324 and GNE-6901 which further depends on whether inhibition is present. With intact inhibition, GNE-6901 enhanced while GNE-8324 reduced NMDAR responses, compared to controls. When inhibition was absent, GNE-8324 showed a small, nonsignificant enhancement. (b) Consistent with the above effects on NMDAR responses, GNE-6901 enhanced LTP regardless of whether inhibition was present, while GNE-8324 enhanced LTP in the absence of inhibition but reduced LTP when inhibition was intact. Modified from [28].