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
N1 - Funding Information:
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. We thank the help from Ms. Kuan-Ling Lu in preparing this manuscript and the support from Behavior Core, Neurobiology and Cognitive Center, National Taiwan University.
PY - 2018/6
Y1 - 2018/6
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.
UR - http://www.scopus.com/inward/record.url?scp=85044219476&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85044219476&partnerID=8YFLogxK
U2 - 10.1111/bph.14198
DO - 10.1111/bph.14198
M3 - Article
C2 - 29518821
AN - SCOPUS:85044219476
VL - 175
SP - 2414
EP - 2427
JO - British Journal of Pharmacology
JF - British Journal of Pharmacology
SN - 0007-1188
IS - 12
ER -