The cerebellar α6 subunit-containing GABAA receptor: A novel therapeutic target for disrupted prepulse inhibition in neuropsychiatric disorders

[Speaker] Lih-Chu Chiou:1,2,3
[Co-author] Hsin-Jung Lee:1, Margot Ernst:4, Wei-Jan Huang:5, Akihiro Mouri:6,7, Marco Treven:4, Takayoshi Mamiya:6, James Cook:8, Werner Sieghart:4, Toshitaka Nabeshima:6,7,9
1:Department of Pharmacology, College of Medicine, National Taiwan University, Taiwan, 2:Graduate Institute of Brain and Mind Sciences, College of Medicine, National Taiwan University, Taipei, Taiwan, 3:Research Center for Chinese Medicine and Acupuncture, China Medical University, Taichung, Taiwan, 4:Center for Brain Research, Department of Molecular Neurosciences, Medical University Vienna, Austria, 5:Graduate Institute of Pharmacognosy, Taipei Medical University, Taipei, Taiwan, 6:Department of Chemical Pharmacology, Faculty of Pharmacy, Meijo University, Nagoya, Japan, 7:Advanced Diagnostic System Research Laboratory, Fujita Health University, Graduate School of Health Sciences, Toyoake, Japan, 8:Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI, USA, 9:Aino University, Ibaraki, Japan

The pathophysiological role of the 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 by acting as a positive allosteric modulator (PAM) of the cerebellar α6GABAARs (1). Here, using hispidulin and a recently identified selective α6GABAAR PAM, the pyrazoloquinolinone Compound 6 (2), we revealed an unprecedented role of cerebellar α6GABAARs in disrupted prepulse inhibition (PPI). PPI disruption can be measured in animals and humans, and reflects the sensorimotor gating deficits manifested in several neuropsychiatric disorders, such as schizophrenia, Tourette syndrome, attention deficit disorders, obsessive compulsive disorder and so on. We induced PPI disruptions in mice by methamphetamine and several NMDA receptor blockers. GABAAR modulatory effects of tested compounds were measured in Xenopus oocytes expressing recombinant α6β3γ2s GABAARs. 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 α6β3γ2s GABAAR-mediated GABA currents. 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.

1. Liao YH, Lee HJ, Huang WJ, Fan PC, Chiou LC (2016). Hispidulin alleviated methamphetamine-induced hyperlocomotion by acting at alpha6 subunit-containing GABAA receptors in the cerebellum. Psychopharmacology 233: 3187-3199.
2. Varagic Z, Ramerstorfer J, Huang S, Rallapalli S, Sarto-Jackson I, Cook J, Sieghart W, Ernst M (2013). Subtype selectivity of alpha+beta- site ligands of GABAA receptors: identification of the first highly specific positive modulators at alpha6beta2/3gamma2 receptors. Br J Pharmacol 169: 384-399.

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