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

Background and purpose The pathophysiological role of α6 subunit-containing GABAA receptors (α6GABAARs), 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 α6GABAARs. Here, using hispidulin and a selective α6GABAAR PAM, the pyrazoloquinolinone Compound 6, we revealed an unprecedented role of cerebellar α6GABAARs in disrupted prepulse inhibition (PPI), which reflects sensorimotor gating deficits manifested in several neuropsychiatric disorders. Experimental approach PPI disruptions were induced by methamphetamine and NMDA receptor blockers in mice. GABAAR modulatory effects of tested compounds were measured in Xenopus oocytes expressing recombinant α6β3γ2sGABAARs. Key results Hispidulin given by i.p. or bilateral intra-cerebellar (i.cb.) injection significantly rescued PPI disruptions induced by methamphetamine, ketamine, MK-801 and phencyclidine. Intra-cerebellar effects of hispidulin were mimicked by Ro15-4513 and loreclezole (two α6GABAAR PAMs), but not by diazepam (an α6GABAAR-insensitive benzodiazepine), and were antagonized by furosemide (i.cb.), an α6GABAAR antagonist. Importantly, Compound 6 (i.p.) also significantly rescued methamphetamine-induced PPI disruption in a manner prevented by furosemide (i.cb.). Both hispidulin and Compound 6 significantly potentiated α6β3γ2sGABAAR-mediated GABA currents. Conclusions and implications These results suggest that positively modulating cerebellar α6GABAARs can rescue disrupted PPI via attenuating granule cell activity, and α6GABAAR-selective PAMs are potential medicines for treating sensorimotor gating deficits in neuropsychiatric disorders. A mechanistic hypothesis is provided based on increasing evidence for a cerebellar contribution in cognitive functioning including sensorimotor gating.