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

Background and purpose: The pathophysiological role of α₆ -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 α₆ GABA_A receptors. Here, using hispidulin and a selective α₆ GABA_A receptor PAM, the pyrazoloquinolinone Compound 6, we revealed an unprecedented role of cerebellar α₆ 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 α₆ β₃ 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 α₆ GABA_A receptor PAMs), but not by diazepam (an α₆ GABA_A receptor-inactive benzodiazepine) and were antagonized by furosemide (i.cb.), an α₆ 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 α₆ β₃ γ_2S GABA_A receptor-mediated GABA currents.

Conclusions and implications: Positive allosteric modulation of cerebellar α₆ GABA_A receptors rescued disrupted PPI by attenuating granule cell activity. α₆ 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.