Higher ambient synaptic glutamate at inhibitory versus excitatory neurons differentially impacts NMDA receptor activity

Lulu Yao,Teddy Grand,Pierre Paoletti,Qiang Zhou,Jesse E Hanson

doi:10.1038/s41467-018-06512-7

Abstract

Selective disruption of synaptic drive to inhibitory neurons could contribute to the pathophysiology of various brain disorders. We have previously identified a GluN2A-selective positive allosteric modulator, GNE-8324, that selectively enhances N-methyl-d-aspartate receptor (NMDAR)-mediated synaptic responses in inhibitory but not excitatory neurons. Here, we demonstrate that differences in NMDAR subunit composition do not underlie this selective potentiation. Rather, a higher ambient glutamate level in the synaptic cleft of excitatory synapses on inhibitory neurons is a key factor. We show that increasing expression of glutamate transporter 1 (GLT-1) eliminates GNE-8324 potentiation in inhibitory neurons, while decreasing GLT-1 activity enables potentiation in excitatory neurons. Our results reveal an unsuspected difference between excitatory synapses onto different neuronal types, and a more prominent activation of synaptic NMDARs by ambient glutamate in inhibitory than excitatory neurons. This difference has implications for tonic NMDAR activity/signaling and the selective modulation of inhibitory neuron activity to treat brain disorders.

Highlights

Selective disruption of synaptic drive to inhibitory neurons could contribute to the pathophysiology of various brain disorders
We found an absence of GNE-8324 potentiation of N-methyl-D-aspartate receptor (NMDAR) excitatory postsynaptic currents (EPSCs) in excitatory neurons in the prefrontal cortex (PFC) and extended our previous observation in the hippocampus (Fig. 1a, b; GNE-8324 + Ext, 91.83 ± 3.27%, 99.88 ± 3.89%, N = 7; Veh + Ext, 86.75 ± 3.27%, 90.24 ± 12.6%, N = 5)
The selective potentiation of postsynaptic NMDAR responses in inhibitory neurons by GNE-8324 does not seem to involve presynaptic NMDARs or metabotropic glutamate receptors as there was no change in paired-pulse ratio (Supplementary Figure 2) after bath application of GNE-8324 and potentiation was observed in the presence of a broadspectrum mGluR blocker (S)-MCPG ((S)-α-methyl-4-carboxyphenylglycine) (500 μM) (Supplementary Figure 3)

Summary

Introduction

Selective disruption of synaptic drive to inhibitory neurons could contribute to the pathophysiology of various brain disorders. Our results reveal an unsuspected difference between excitatory synapses onto different neuronal types, and a more prominent activation of synaptic NMDARs by ambient glutamate in inhibitory than excitatory neurons This difference has implications for tonic NMDAR activity/signaling and the selective modulation of inhibitory neuron activity to treat brain disorders. We have recently identified a new series of small-molecule positive allosteric modulators (PAMs) that selectively enhance GluN2A subunit-containing NMDAR currents[16] Among these PAMs, GNE-8324 is of particular interest since it enhances synaptic NMDAR responses in inhibitory neurons but not excitatory neurons during low-frequency stimulation[16]. That the microenvironment at glutamatergic synapses differs between excitatory and inhibitory neurons has broad implications for understanding basic neurophysiology and mechanisms of drug action

Methods

Results

Conclusion