Distinct regulation of tonic GABAergic inhibition by NMDA receptor subtypes.
Cell Rep
; 37(6): 109960, 2021 11 09.
Article
in En
| MEDLINE
| ID: mdl-34758303
ABSTRACT
Tonic inhibition mediated by extrasynaptic GABAARs regulates various brain functions. However, the mechanisms that regulate tonic inhibition remain largely unclear. Here, we report distinct actions of GluN2A- and GluN2B-NMDA receptors (NMDARs) on tonic inhibition in hippocampal neurons under basal and high activity conditions. Specifically, overexpression of GluN2B, but not GluN2A, reduces α5-GABAAR surface expression and tonic currents. Additionally, knockout of GluN2A and GluN2B decreases and increases tonic currents, respectively. Mechanistically, GluN2A-NMDARs inhibit and GluN2B-NMDARs promote α5-GABAAR internalization, resulting in increased and decreased surface α5-GABAAR expression, respectively. Furthermore, GluN2A-NMDARs, but not GluN2B-NMDARs, are required for homeostatic potentiation of tonic inhibition induced by prolonged increase of neuronal activity. Last, tonic inhibition decreases during acute seizures, whereas it increases 24 h later, involving GluN2-NMDAR-dependent signaling. Collectively, these data reveal an NMDAR subunit-specific regulation of tonic inhibition in physiological and pathological conditions and provide mechanistic insight into activity-dependent modulation of tonic inhibition.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Seizures
/
Receptors, N-Methyl-D-Aspartate
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GABAergic Neurons
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Hippocampus
/
Neural Inhibition
Limits:
Animals
Language:
En
Journal:
Cell Rep
Year:
2021
Document type:
Article
Affiliation country: