Genetic inhibition of glutamate allosteric potentiation of GABA_ARs in mice results in hyperexcitability, leading to neurobehavioral abnormalities

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 (GABA_AR)-glutamate allosteric potentiation of GABA_AR functions through a direct binding of glutamate to the GABA_AR itself. Here, we investigated the physiological significance and pathological implications of this cross-talk by generating the β3_E182G knock-in (KI) mice. We found that β3_E182G KI, while had little effect on basal GABA_AR-mediated synaptic transmission, significantly reduced glutamate potentiation of GABA_AR-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 β3-containing GABA_ARs was sufficient to rescue the deficits of glutamate potentiation of GABA_AR-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 GABA_AR functions as a homeostatic mechanism in fine-tuning neuronal E/I balance, thereby playing an essential role in ensuring normal brain functioning.