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

Lih Chu Chiou, Hsin Jung Lee, Margot Ernst, Wei Jan Huang, Jui Feng Chou, Hon Lie Chen, Akihiro Mouri, Liang Chieh Chen, Marco Treven, Takayoshi Mamiya, Pi Chuan Fan, Daniel E. Knutson, Chris Witzigmann, James Cook, Werner Sieghart, Toshitaka Nabeshima

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Abstract

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.

Original languageEnglish
Pages (from-to)2414-2427
Number of pages14
JournalBritish Journal of Pharmacology
Volume175
Issue number12
DOIs
Publication statusPublished - 06-2018

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All Science Journal Classification (ASJC) codes

  • Pharmacology

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Chiou, L. C., Lee, H. J., Ernst, M., Huang, W. J., Chou, J. F., Chen, H. L., Mouri, A., Chen, L. C., Treven, M., Mamiya, T., Fan, P. C., Knutson, D. E., Witzigmann, C., Cook, J., Sieghart, W., & Nabeshima, T. (2018). Cerebellar α 6 -subunit-containing GABA A receptors: a novel therapeutic target for disrupted prepulse inhibition in neuropsychiatric disorders. British Journal of Pharmacology, 175(12), 2414-2427. https://doi.org/10.1111/bph.14198