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

  • Nat Commun. 2018 Oct 1;9(1):4000. doi: 10.1038/s41467-018-06512-7.
Lulu Yao  1 ,  Teddy Grand  2 ,  Jesse E Hanson  3 ,  Pierre Paoletti  2 ,  Qiang Zhou  4
Affiliations
  • 1. School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, 518055, Shenzhen, China.
  • 2. Institut de Biologie de l'Ecole Normale Supérieure (IBENS), Ecole Normale Supérieure, CNRS, INSERM, Université PSL, 46 rue d'Ulm, 75005, Paris, France.
  • 3. Department of Neuroscience, Genentech, Inc., South San Francisco, 94080, CA, USA.
  • 4. School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, 518055, Shenzhen, China. [email protected].
PMID: 30275542 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.

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