Glutamate and GABAA receptor crosstalk mediates homeostatic regulation of neuronal excitation in the mammalian brain

Maintaining a proper balance between the glutamate receptor-mediated neuronal excitation and the A type of GABA receptor(GABAAR)mediated inhibition is essential for brain functioning;and its imbalance contributes to the pathogenesis of many brain disorders including neurodegenerative diseases and mental illnesses.Here we identify a novel glutamate-GABAAR interaction mediated by a direct glutamate binding of the GABAAR.In HEK293 cells overexpressing recombinant GABAARs,glutamate and its analog ligands,while producing no current on their own,potentiate GABA-evoked currents.This potentiation is mediated by a direct binding at a novel glutamate binding pocket located at theα+/β−subunit interface of the GABAAR.Moreover,the potentiation does not require the presence of aγsubunit,and in fact,the presence ofγsubunit significantly reduces the potency of the glutamate potentiation.In addition,the glutamate-mediated allosteric potentiation occurs on native GABAARs in rat neurons maintained in culture,as evidenced by the potentiation of GABAAR-mediated inhibitory postsynaptic currents and tonic currents.Most importantly,we found that genetic impairment of this glutamate potentiation in knock-in mice resulted in phenotypes of increased neuronal excitability,including decreased thresholds to noxious stimuli and increased seizure susceptibility.These results demonstrate a novel cross-talk between excitatory transmitter glutamate and inhibitory GABAAR.Such a rapid and short feedback loop between the two principal excitatory and inhibitory neurotransmission systems may play a critical homeostatic role in fine-tuning the excitation-inhibition balance(E/I balance),thereby maintaining neuronal excitability in the mammalian brain under both physiological and pathological conditions.