Quercetin Reduces Cortical GABAergic Transmission and Alleviates MK-801-Induced Hyperactivity.

ABSTRACT: An imbalance between neuronal excitation and inhibition represents a core feature in multiple neuropsychiatry disorders, necessitating the development of novel strategies to calibrate the excitatory-inhibitory balance of therapeutics. Here we identify a natural compound quercetin that reduces prefrontal cortical GABAergic transmission and alleviates the hyperactivity induced by glutamatergic N-methyl-d-aspartate receptor antagonist MK-801. Quercetin markedly reduced the GABA-activated currents in a noncompetitive manner in cultured cortical neurons, and moderately inhibited spontaneous and electrically-evoked GABAergic inhibitory postsynaptic current in mouse prefrontal cortical slices. Notably, systemic and prefrontal-specific delivery of quercetin reduced basal locomotor activity in addition to alleviated the MK-801-induced hyperactivity. The effects of quercetin were not exclusively dependent on ?5-subunit-containing A type GABA receptors (GABA_ARs), as viral-mediated, region-specific genetic knockdown of the ?5-subunit in prefrontal cortex improved the MK-801-evoked psychotic symptom but reserved the pharmacological responsivity to quercetin. Both interventions together completely normalized the locomotor activity. Together, quercetin as a negative allosteric GABA_AR modulator exerted antipsychotic activity, facilitating further therapeutic development for the excitatory-inhibitory imbalance disorders.

SUBMITTER: Fan HR 

PROVIDER: S-EPMC6116474 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature