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

L.-C. Chiou, H.-J. Lee, M. Ernst, W.-J. Huang, J.-F. Chou, H.-L. Chen, A. Mouri, L.-C. Chen, M. Treven, T. Mamiya, P.-C. Fan, D.E. Knutson, C. Witzigmann, J. Cook, W. Sieghart, T. Nabeshima

Research output: Contribution to journalArticle

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Abstract

Background and Purpose: 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 α6GABAA receptors. Here, using hispidulin and a selective α6GABAA receptor PAM, the pyrazoloquinolinone Compound 6, we revealed an unprecedented role of cerebellar α6GABAA 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 α6β3γ2SGABAA 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 α6GABAA receptor PAMs), but not by diazepam (an α6GABAA receptor-inactive benzodiazepine) and were antagonized by furosemide (i.cb.), an α6GABAA 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 α6β3γ2SGABAA receptor-mediated GABA currents. Conclusions and Implications: Positive allosteric modulation of cerebellar α6GABAA receptors rescued disrupted PPI by attenuating granule cell activity. α6GABAA 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. © 2018 The British Pharmacological Society
Original languageEnglish
Pages (from-to)2414-2427
Number of pages14
JournalBritish Journal of Pharmacology
Volume175
Issue number12
DOIs
Publication statusPublished - 2018

Fingerprint

GABA-A Receptors
Methamphetamine
Sensory Gating
Furosemide
Startle Reflex
Therapeutics
Tics
Phencyclidine
GABA Receptors
Dizocilpine Maleate
Ketamine
Xenopus
N-Methyl-D-Aspartate Receptors
Benzodiazepines
Flavonoids
Oocytes
Prepulse Inhibition
hispidulin
Injections

Keywords

  • 4 aminobutyric acid A receptor alpha6
  • 4 aminobutyric acid A receptor alpha6beta3gamma25
  • 8 azido 5,6 dihydro 5 methyl 6 oxo 4h imidazo[1,5 a][1,4]benzodiazepine 3 carboxylic acid ethyl ester
  • dizocilpine
  • furosemide
  • hispidulin
  • ketamine
  • loreclezole
  • methamphetamine
  • n methyl dextro aspartic acid receptor blocking agent
  • phencyclidine
  • unclassified drug
  • allosterism
  • animal experiment
  • Article
  • controlled study
  • drug antagonism
  • drug potentiation
  • electrophysiology
  • male
  • mouse
  • nonhuman
  • oocyte
  • prepulse inhibition
  • priority journal
  • protein expression
  • protein function
  • protein targeting
  • voltage clamp technique
  • Xenopus laevis

Cite this

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

In: British Journal of Pharmacology, Vol. 175, No. 12, 2018, p. 2414-2427.

Research output: Contribution to journalArticle

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, DE, Witzigmann, C, Cook, J, Sieghart, W & Nabeshima, T 2018, 'Cerebellar α6-subunit-containing GABAA 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
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. / Cerebellar α6-subunit-containing GABAA 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 α6-subunit-containing GABAA receptors: a novel therapeutic target for disrupted prepulse inhibition in neuropsychiatric disorders",
abstract = "Background and Purpose: 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 α6GABAA receptors. Here, using hispidulin and a selective α6GABAA receptor PAM, the pyrazoloquinolinone Compound 6, we revealed an unprecedented role of cerebellar α6GABAA 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 α6β3γ2SGABAA 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 α6GABAA receptor PAMs), but not by diazepam (an α6GABAA receptor-inactive benzodiazepine) and were antagonized by furosemide (i.cb.), an α6GABAA 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 α6β3γ2SGABAA receptor-mediated GABA currents. Conclusions and Implications: Positive allosteric modulation of cerebellar α6GABAA receptors rescued disrupted PPI by attenuating granule cell activity. α6GABAA 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. {\circledC} 2018 The British Pharmacological Society",
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author = "L.-C. Chiou and H.-J. Lee and M. Ernst and W.-J. Huang and J.-F. Chou and H.-L. Chen and A. Mouri and L.-C. Chen and M. Treven and T. Mamiya and P.-C. Fan and D.E. Knutson and C. Witzigmann and J. Cook and W. Sieghart and T. Nabeshima",
note = "引用次數:2 Export Date: 25 October 2018 CODEN: BJPCB 通訊地址: Chiou, L.-C.; Graduate Institute of Pharmacology, National Taiwan UniversityTaiwan; 電子郵件: lcchiou@ntu.edu.tw 化學物質/CAS: 8 azido 5,6 dihydro 5 methyl 6 oxo 4h imidazo[1,5 a][1,4]benzodiazepine 3 carboxylic acid ethyl ester, 91917-65-6; dizocilpine, 77086-21-6; furosemide, 54-31-9; hispidulin, 1447-88-7; ketamine, 1867-66-9, 6740-88-1, 81771-21-3; loreclezole, 117857-45-1; methamphetamine, 28297-73-6, 51-57-0, 537-46-2, 7632-10-2; phencyclidine, 77-10-1, 956-90-1 商標: ro 154513, Tocris 製造商: Tocris, United Kingdom; Tocris 出資詳情: MEXT, Ministry of Education, Culture, Sports, Science and Technology 出資詳情: NRPB, National Research Program for Biopharmaceuticals 出資詳情: R01 grants, Nakatomi Foundation 出資詳情: R01 MH096463, Nakatomi Foundation 出資詳情: R01 NS076517, Nakatomi Foundation 出資詳情: Takeda Science Foundation 出資詳情: FWF I 2306, FWF, Austrian Science Fund 出資詳情: 26460240 出資詳情: 16K10195 出資詳情: 15K08218 出資詳情: 17H04252 出資詳情: NHRI-EX107-10733NI, MOST, Ministry of Science and Technology, Taiwan 出資詳情: 104-2325-B002-010 出資詳情: MOST 105-2325-B002-004 出資詳情: NSC 102-2320-B038-019-MY3 出資詳情: MOST 106-2911-I-002-514 出資詳情: 103-2325-B002-037 出資詳情: UNC, University of North Carolina 出資詳情: NIH, National Institutes of Health 出資詳情: 100-2325-B002-050 出資詳情: NSC 102-2325-B002-047 出資詳情: NSC 101-2325-B002-048 出資詳情: JSPS, Japan Society for the Promotion of Science 出資詳情: NSC, National Science Council 出資詳情: MOST 104-2923-B-002-006-MY3, NHRI, National Health Research Institutes 出資詳情: NTU, National Taiwan University 出資詳情: NIMH, National Institute of Mental Health 出資正文: This study was mainly supported by the National Research Program for Biopharmaceuticals (NSC 100-2325-B002-050, NSC 101-2325-B002-048, NSC 102-2325-B002-047, MOST 103-2325-B002-037, MOST 104-2325-B002-010 and MOST 105-2325-B002-004) to L.-C.C. and by the research grant (MOST 106-2911-I-002-514 to L.-C.C., NSC 102-2320-B038-019-MY3 to W.-J.H.) from the National Science Council/ the Ministry of Science and Technology, Taiwan, as well as the Innovative Research Grant (NHRI-EX107-10733NI) from National Health Research Institutes, Taiwan, to L.-C.C from Taiwan. It was also supported by the Taiwan-Austria bilateral international grant (MOST 104-2923-B-002-006-MY3) from the Ministry of Science and Technology to L.-C.C. from Taiwan as well as by the Austrian Science Fund (FWF I 2306) to M.E. from Austria. It was also supported by Grants-in-Aids for Scientific Research (26460240 and 15K08218, 16K10195, 17H04252) from the Japan Society for the Promotion of Science, the Private University Research Branding Project from the Ministry of Education, Culture, Sports, Science and Technology of Japan, Research Grants from Takeda Science Foundation, the Nakatomi Foundation and the Smoking Research Foundation, Japan, to TN from Japan as well as by the R01 grants (R01 NS076517 and R01 MH096463) from the National Institutes of Health, and the Shimadzu Analytical Facility of Southeastern Wisconsin to J.C. from USA. We appreciate the support from the Psychoactive Drug Screening Program, which is funded by the National Institute of Mental Health and run by Dr. Bryan Roth at the University of North Carolina. 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year = "2018",
doi = "10.1111/bph.14198",
language = "English",
volume = "175",
pages = "2414--2427",
journal = "British Journal of Pharmacology",
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publisher = "John Wiley and Sons Inc.",
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}

TY - JOUR

T1 - Cerebellar α6-subunit-containing GABAA receptors: a novel therapeutic target for disrupted prepulse inhibition in neuropsychiatric disorders

AU - Chiou, L.-C.

AU - Lee, H.-J.

AU - Ernst, M.

AU - Huang, W.-J.

AU - Chou, J.-F.

AU - Chen, H.-L.

AU - Mouri, A.

AU - Chen, L.-C.

AU - Treven, M.

AU - Mamiya, T.

AU - Fan, P.-C.

AU - Knutson, D.E.

AU - Witzigmann, C.

AU - Cook, J.

AU - Sieghart, W.

AU - Nabeshima, T.

N1 - 引用次數:2 Export Date: 25 October 2018 CODEN: BJPCB 通訊地址: Chiou, L.-C.; Graduate Institute of Pharmacology, National Taiwan UniversityTaiwan; 電子郵件: lcchiou@ntu.edu.tw 化學物質/CAS: 8 azido 5,6 dihydro 5 methyl 6 oxo 4h imidazo[1,5 a][1,4]benzodiazepine 3 carboxylic acid ethyl ester, 91917-65-6; dizocilpine, 77086-21-6; furosemide, 54-31-9; hispidulin, 1447-88-7; ketamine, 1867-66-9, 6740-88-1, 81771-21-3; loreclezole, 117857-45-1; methamphetamine, 28297-73-6, 51-57-0, 537-46-2, 7632-10-2; phencyclidine, 77-10-1, 956-90-1 商標: ro 154513, Tocris 製造商: Tocris, United Kingdom; Tocris 出資詳情: MEXT, Ministry of Education, Culture, Sports, Science and Technology 出資詳情: NRPB, National Research Program for Biopharmaceuticals 出資詳情: R01 grants, Nakatomi Foundation 出資詳情: R01 MH096463, Nakatomi Foundation 出資詳情: R01 NS076517, Nakatomi Foundation 出資詳情: Takeda Science Foundation 出資詳情: FWF I 2306, FWF, Austrian Science Fund 出資詳情: 26460240 出資詳情: 16K10195 出資詳情: 15K08218 出資詳情: 17H04252 出資詳情: NHRI-EX107-10733NI, MOST, Ministry of Science and Technology, Taiwan 出資詳情: 104-2325-B002-010 出資詳情: MOST 105-2325-B002-004 出資詳情: NSC 102-2320-B038-019-MY3 出資詳情: MOST 106-2911-I-002-514 出資詳情: 103-2325-B002-037 出資詳情: UNC, University of North Carolina 出資詳情: NIH, National Institutes of Health 出資詳情: 100-2325-B002-050 出資詳情: NSC 102-2325-B002-047 出資詳情: NSC 101-2325-B002-048 出資詳情: JSPS, Japan Society for the Promotion of Science 出資詳情: NSC, National Science Council 出資詳情: MOST 104-2923-B-002-006-MY3, NHRI, National Health Research Institutes 出資詳情: NTU, National Taiwan University 出資詳情: NIMH, National Institute of Mental Health 出資正文: This study was mainly supported by the National Research Program for Biopharmaceuticals (NSC 100-2325-B002-050, NSC 101-2325-B002-048, NSC 102-2325-B002-047, MOST 103-2325-B002-037, MOST 104-2325-B002-010 and MOST 105-2325-B002-004) to L.-C.C. and by the research grant (MOST 106-2911-I-002-514 to L.-C.C., NSC 102-2320-B038-019-MY3 to W.-J.H.) from the National Science Council/ the Ministry of Science and Technology, Taiwan, as well as the Innovative Research Grant (NHRI-EX107-10733NI) from National Health Research Institutes, Taiwan, to L.-C.C from Taiwan. It was also supported by the Taiwan-Austria bilateral international grant (MOST 104-2923-B-002-006-MY3) from the Ministry of Science and Technology to L.-C.C. from Taiwan as well as by the Austrian Science Fund (FWF I 2306) to M.E. from Austria. It was also supported by Grants-in-Aids for Scientific Research (26460240 and 15K08218, 16K10195, 17H04252) from the Japan Society for the Promotion of Science, the Private University Research Branding Project from the Ministry of Education, Culture, Sports, Science and Technology of Japan, Research Grants from Takeda Science Foundation, the Nakatomi Foundation and the Smoking Research Foundation, Japan, to TN from Japan as well as by the R01 grants (R01 NS076517 and R01 MH096463) from the National Institutes of Health, and the Shimadzu Analytical Facility of Southeastern Wisconsin to J.C. from USA. We appreciate the support from the Psychoactive Drug Screening Program, which is funded by the National Institute of Mental Health and run by Dr. Bryan Roth at the University of North Carolina. 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PY - 2018

Y1 - 2018

N2 - Background and Purpose: 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 α6GABAA receptors. Here, using hispidulin and a selective α6GABAA receptor PAM, the pyrazoloquinolinone Compound 6, we revealed an unprecedented role of cerebellar α6GABAA 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 α6β3γ2SGABAA 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 α6GABAA receptor PAMs), but not by diazepam (an α6GABAA receptor-inactive benzodiazepine) and were antagonized by furosemide (i.cb.), an α6GABAA 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 α6β3γ2SGABAA receptor-mediated GABA currents. Conclusions and Implications: Positive allosteric modulation of cerebellar α6GABAA receptors rescued disrupted PPI by attenuating granule cell activity. α6GABAA 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. © 2018 The British Pharmacological Society

AB - Background and Purpose: 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 α6GABAA receptors. Here, using hispidulin and a selective α6GABAA receptor PAM, the pyrazoloquinolinone Compound 6, we revealed an unprecedented role of cerebellar α6GABAA 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 α6β3γ2SGABAA 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 α6GABAA receptor PAMs), but not by diazepam (an α6GABAA receptor-inactive benzodiazepine) and were antagonized by furosemide (i.cb.), an α6GABAA 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 α6β3γ2SGABAA receptor-mediated GABA currents. Conclusions and Implications: Positive allosteric modulation of cerebellar α6GABAA receptors rescued disrupted PPI by attenuating granule cell activity. α6GABAA 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. © 2018 The British Pharmacological Society

KW - 4 aminobutyric acid A receptor alpha6

KW - 4 aminobutyric acid A receptor alpha6beta3gamma25

KW - 8 azido 5,6 dihydro 5 methyl 6 oxo 4h imidazo[1,5 a][1,4]benzodiazepine 3 carboxylic acid ethyl ester

KW - dizocilpine

KW - furosemide

KW - hispidulin

KW - ketamine

KW - loreclezole

KW - methamphetamine

KW - n methyl dextro aspartic acid receptor blocking agent

KW - phencyclidine

KW - unclassified drug

KW - allosterism

KW - animal experiment

KW - Article

KW - controlled study

KW - drug antagonism

KW - drug potentiation

KW - electrophysiology

KW - male

KW - mouse

KW - nonhuman

KW - oocyte

KW - prepulse inhibition

KW - priority journal

KW - protein expression

KW - protein function

KW - protein targeting

KW - voltage clamp technique

KW - Xenopus laevis

U2 - 10.1111/bph.14198

DO - 10.1111/bph.14198

M3 - Article

VL - 175

SP - 2414

EP - 2427

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

SN - 0007-1188

IS - 12

ER -