 |
Journal articles
Higher ambient synaptic glutamate at inhibitory versus excitatory neurons differentially impacts NMDA receptor activity
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.
Cited literature [74 references]
https://www.hal.inserm.fr/inserm-02438982
Contributor : Mélissa David Connect in order to contact the contributor
Submitted on : Tuesday, January 14, 2020 - 2:11:42 PM
Last modification on : Wednesday, November 17, 2021 - 12:31:56 PM
Long-term archiving on: : Wednesday, April 15, 2020 - 5:05:16 PM
Contributor : Mélissa David Connect in order to contact the contributor
Submitted on : Tuesday, January 14, 2020 - 2:11:42 PM
Last modification on : Wednesday, November 17, 2021 - 12:31:56 PM
Long-term archiving on: : Wednesday, April 15, 2020 - 5:05:16 PM