| First Author | Yao L | Year | 2018 |
| Journal | Nat Commun | Volume | 9 |
| Issue | 1 | Pages | 4000 |
| PubMed ID | 30275542 | Mgi Jnum | J:267589 |
| Mgi Id | MGI:6267740 | Doi | 10.1038/s41467-018-06512-7 |
| Citation | Yao L, et al. (2018) Higher ambient synaptic glutamate at inhibitory versus excitatory neurons differentially impacts NMDA receptor activity. Nat Commun 9(1):4000 |
| abstractText | 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. |
