Enhancement of hippocampal interneuron excitability by NMDA receptor positive allosteric modulation.

Abstract

N-Methyl-d-aspartate receptors (NMDARs) are known for their role in mediating a calcium-permeable, slow component of excitatory synaptic transmission. These receptors play important roles in multiple facets of brain functions, and their dysfunction has been implicated in neurological disease aetiology. Here, we describe the actions of a positive allosteric modulator (PAM), EU1622-240, on NMDARs within the hippocampal circuit. EU1622-240 is a pan-PAM that enhances the function of all GluN2 subunit-containing NMDARs with submicromolar potency, with the strongest effects on GluN2C- and GluN2D-containing NMDARs. Previously, we have shown that EU1622-240 enhances the maximal response, prolongs the response time course, enhances agonist potency and reduces single channel conductance. Using whole-cell patch-clamp recordings, we evaluated the effects of this PAM on both CA1 pyramidal cells and CA1 stratum radiatum interneurons in immature hippocampus. Although we observed potentiation of evoked NMDAR-mediated EPSCs on both CA1 pyramidal cells and interneurons, the PAM preferentially enhanced interneuron excitability owing to the expression of GluN2D in interneurons and increased the ratio of inhibition to excitation. This appears to result from cellular depolarization, increased spike firing and enhanced NMDAR-mediated current charge transfer in interneurons. In contrast, EU1622-240 did not detectably depolarize CA1 pyramidal cells in slices but did have modest effects when bicuculline was used to block GABAergic signalling. We also observed EU1622-240 enhancement of AMPA receptor synaptic signalling in a manner reminiscent of long-term potentiation. These data support the idea that EU1622-240 enhances interneuron function, with modest effects on the CA1 pyramidal cells, providing therapeutically beneficial effects in situations where interneuron output is diminished. KEY POINTS: EU1622-240 is a potent positive allosteric modulator of all GluN2-containing NMDA receptors. EU1622-240 is active at native receptors in acute brain slices, increasing NMDA receptor-mediated charge transfer onto both CA1 principal cells and interneurons. Despite its actions on principal cells, EU1622-240 appears to drive preferential enhancement of interneuron function within the hippocampal network. EU1622-240 is also capable of increasing calcium flow into cultured hippocampal neurons, in addition to influencing AMPA receptor-mediated EPSPs that occlude conventional theta-burst-driven long-term potentiation.