Dataset Information

Cerebellar ?₆ -subunit-containing GABA_A receptors: a novel therapeutic target for disrupted prepulse inhibition in neuropsychiatric disorders.

ABSTRACT:

Background and purpose

The pathophysiological role of ?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 ?₆ GABA_A receptors. Here, using hispidulin and a selective ?₆ GABA_A receptor PAM, the pyrazoloquinolinone Compound 6, we revealed an unprecedented role of cerebellar ?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 ?₆ ?₃ ?_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 ?₆ GABA_A receptor PAMs), but not by diazepam (an ?₆ GABA_A receptor-inactive benzodiazepine) and were antagonized by furosemide (i.cb.), an ?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 ?₆ ?₃ ?_2S GABA_A receptor-mediated GABA currents.

Conclusions and implications

Positive allosteric modulation of cerebellar ?₆ GABA_A receptors rescued disrupted PPI by attenuating granule cell activity. ?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.

SUBMITTER: Chiou LC

PROVIDER: S-EPMC5980635 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Publications

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

Chiou Lih-Chu LC Lee Hsin-Jung HJ Ernst Margot M Huang Wei-Jan WJ Chou Jui-Feng JF Chen Hon-Lie HL Mouri Akihiro A Chen Liang-Chieh LC Treven Marco M Mamiya Takayoshi T Fan Pi-Chuan PC Knutson Daniel E DE Witzigmann Chris C Cook James J Sieghart Werner W Nabeshima Toshitaka T

British journal of pharmacology 20180510 12

<h4>Background and purpose</h4>The pathophysiological role of α6 -subunit-containing GABAA 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 GABAA receptors. Here, using his ...[more]

PMID: 29518821

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Dataset Information

Cerebellar ?₆ -subunit-containing GABA_A receptors: a novel therapeutic target for disrupted prepulse inhibition in neuropsychiatric disorders.

Background and purpose

Experimental approach

Key results

Conclusions and implications

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Cerebellar ?6 -subunit-containing GABAA receptors: a novel therapeutic target for disrupted prepulse inhibition in neuropsychiatric disorders.

Background and purpose

Experimental approach

Key results

Conclusions and implications

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Cerebellar ?₆ -subunit-containing GABA_A receptors: a novel therapeutic target for disrupted prepulse inhibition in neuropsychiatric disorders.