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

Research output: Contribution to journalArticle

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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 - 01-06-2018

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GABA-A Receptors
Methamphetamine
Sensory Gating
Therapeutics
Furosemide
Startle Reflex
Prepulse Inhibition
GABA-A Receptor Antagonists
Tics
Phencyclidine
Dizocilpine Maleate
Ketamine
Diazepam
Xenopus
N-Methyl-D-Aspartate Receptors
Benzodiazepines
Flavonoids
gamma-Aminobutyric Acid
Oocytes
hispidulin

All Science Journal Classification (ASJC) codes

  • Pharmacology

Cite this

Chiou, Lih Chu ; Lee, Hsin Jung ; Ernst, Margot ; Huang, Wei Jan ; Chou, Jui Feng ; Chen, Hon Lie ; Mouri, Akihiro ; Chen, Liang Chieh ; Treven, Marco ; Mamiya, Takayoshi ; Fan, Pi Chuan ; Knutson, Daniel E. ; Witzigmann, Chris ; Cook, James ; Sieghart, Werner ; Nabeshima, Toshitaka. / Cerebellar α 6 -subunit-containing GABA A receptors : a novel therapeutic target for disrupted prepulse inhibition in neuropsychiatric disorders. In: British Journal of Pharmacology. 2018 ; Vol. 175, No. 12. pp. 2414-2427.
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title = "Cerebellar α 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 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.",
author = "Chiou, {Lih Chu} and Lee, {Hsin Jung} and Margot Ernst and Huang, {Wei Jan} and Chou, {Jui Feng} and Chen, {Hon Lie} and Akihiro Mouri and Chen, {Liang Chieh} and Marco Treven and Takayoshi Mamiya and Fan, {Pi Chuan} and Knutson, {Daniel E.} and Chris Witzigmann and James Cook and Werner Sieghart and Toshitaka Nabeshima",
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Chiou, LC, Lee, HJ, Ernst, M, Huang, WJ, Chou, JF, Chen, HL, Mouri, A, Chen, LC, Treven, M, Mamiya, T, Fan, PC, Knutson, DE, 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, vol. 175, no. 12, pp. 2414-2427. https://doi.org/10.1111/bph.14198

Cerebellar α 6 -subunit-containing GABA A receptors : a novel therapeutic target for disrupted prepulse inhibition in neuropsychiatric disorders. / Chiou, Lih Chu; Lee, Hsin Jung; Ernst, Margot; Huang, Wei Jan; Chou, Jui Feng; Chen, Hon Lie; Mouri, Akihiro; Chen, Liang Chieh; Treven, Marco; Mamiya, Takayoshi; Fan, Pi Chuan; Knutson, Daniel E.; Witzigmann, Chris; Cook, James; Sieghart, Werner; Nabeshima, Toshitaka.

In: British Journal of Pharmacology, Vol. 175, No. 12, 01.06.2018, p. 2414-2427.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Cerebellar α 6 -subunit-containing GABA A receptors

T2 - a novel therapeutic target for disrupted prepulse inhibition in neuropsychiatric disorders

AU - Chiou, Lih Chu

AU - Lee, Hsin Jung

AU - Ernst, Margot

AU - Huang, Wei Jan

AU - Chou, Jui Feng

AU - Chen, Hon Lie

AU - Mouri, Akihiro

AU - Chen, Liang Chieh

AU - Treven, Marco

AU - Mamiya, Takayoshi

AU - Fan, Pi Chuan

AU - Knutson, Daniel E.

AU - Witzigmann, Chris

AU - Cook, James

AU - Sieghart, Werner

AU - Nabeshima, Toshitaka

PY - 2018/6/1

Y1 - 2018/6/1

N2 - 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.

AB - 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.

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