Cerebellar α ₆ -subunit-containing GABA _A receptors: a novel therapeutic target for disrupted prepulse inhibition in neuropsychiatric disorders

Background and Purpose: The pathophysiological role of α ₆ -subunit-containing GABA _A 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 α ₆ GABA _A receptors. Here, using hispidulin and a selective α ₆ GABA _A receptor PAM, the pyrazoloquinolinone Compound 6, we revealed an unprecedented role of cerebellar α ₆ GABA _A receptors in disrupted prepulse inhibition of the startle response (PPI), which reflects sensorimotor gating deficits manifested in several neuropsychiatric disorders. Experimental Approach: PPI disruptions were induced by methamphetamine and NMDA receptor antagonists in mice. Effects of the tested compounds were measured in Xenopus oocytes expressing recombinant α ₆ β ₃ γ _2S GABA _A receptors. Key Results: 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 α ₆ GABA _A receptor PAMs), but not by diazepam (an α ₆ GABA _A receptor-inactive benzodiazepine) and were antagonized by furosemide (i.cb.), an α ₆ GABA _A 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 α ₆ β ₃ γ _2S GABA _A receptor-mediated GABA currents. Conclusions and Implications: Positive allosteric modulation of cerebellar α ₆ GABA _A receptors rescued disrupted PPI by attenuating granule cell activity. α ₆ GABA _A 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.