Genetic inhibition of glutamate allosteric potentiation of GABAARs in mice results in hyperexcitability, leading to neurobehavioral abnormalities.
MedComm (2020)
; 4(3): e235, 2023 Jun.
Article
en En
| MEDLINE
| ID: mdl-37101797
The imbalance between neuronal excitation and inhibition (E/I) in neural circuit has been considered to be at the root of numerous brain disorders. We recently reported a novel feedback crosstalk between the excitatory neurotransmitter glutamate and inhibitory γ-aminobutyric acid type A receptor (GABAAR)-glutamate allosteric potentiation of GABAAR functions through a direct binding of glutamate to the GABAAR itself. Here, we investigated the physiological significance and pathological implications of this cross-talk by generating the ß3E182G knock-in (KI) mice. We found that ß3E182G KI, while had little effect on basal GABAAR-mediated synaptic transmission, significantly reduced glutamate potentiation of GABAAR-mediated responses. These KI mice displayed lower thresholds for noxious stimuli, higher susceptibility to seizures and enhanced hippocampus-related learning and memory. Additionally, the KI mice exhibited impaired social interactions and decreased anxiety-like behaviors. Importantly, hippocampal overexpression of wild-type ß3-containing GABAARs was sufficient to rescue the deficits of glutamate potentiation of GABAAR-mediated responses, hippocampus-related behavioral abnormalities of increased epileptic susceptibility, and impaired social interactions. Our data indicate that the novel crosstalk among excitatory glutamate and inhibitory GABAAR functions as a homeostatic mechanism in fine-tuning neuronal E/I balance, thereby playing an essential role in ensuring normal brain functioning.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Idioma:
En
Revista:
MedComm (2020)
Año:
2023
Tipo del documento:
Article
Pais de publicación:
China