Cerebellar α6 -subunit-containing GABAA receptors: a novel therapeutic target for disrupted prepulse inhibition in neuropsychiatric disorders.

Abstract

The pathophysiological role of α6 -subunit-containing GABAA receptors, which are mainly expressed in cerebellar granule cells, remains unclear. Recently, we demonstrated that hispidulin, a flavonoid isolated from a local herb that remitted a patient's intractable motor tics, attenuated methamphetamine-induced hyperlocomotion in mice as a positive allosteric modulator (PAM) of cerebellar α6 GABAA receptors. Here, using hispidulin and a selective α6 GABAA receptor PAM, the pyrazoloquinolinone Compound 6, we revealed an unprecedented role of cerebellar α6 GABAA receptors in disrupted prepulse inhibition of the startle response (PPI), which reflects sensorimotor gating deficits manifested in several neuropsychiatric disorders. PPI disruptions were induced by methamphetamine and NMDA receptor antagonists in mice. Effects of the tested compounds were measured in Xenopus oocytes expressing recombinant α6 β3 γ2S GABAA receptors. Hispidulin given i.p. or by bilateral intracerebellar (i.cb.) injection rescued PPI disruptions induced by methamphetamine, ketamine, MK-801 and phencyclidine. Intracerebellar effects of hispidulin were mimicked by Ro15-4513 and loreclezole (two α6 GABAA receptor PAMs), but not by diazepam (an α6 GABAA receptor-inactive benzodiazepine) and were antagonized by furosemide (i.cb.), an α6 GABAA receptor antagonist. Importantly, Compound 6 (i.p.) also rescued methamphetamine-induced PPI disruption, an effect prevented by furosemide (i.cb.). Both hispidulin and Compound 6 potentiated α6 β3 γ2S GABAA receptor-mediated GABA currents. Positive allosteric modulation of cerebellar α6 GABAA receptors rescued disrupted PPI by attenuating granule cell activity. α6 GABAA receptor-selective PAMs are potential medicines for treating sensorimotor gating deficits in neuropsychiatric disorders. A mechanistic hypothesis is based on evidence for cerebellar contributions to cognitive functioning including sensorimotor gating.