Quercetin Reduces Cortical GABAergic Transmission and Alleviates MK-801-Induced Hyperactivity
Hui-Ran Fan,
Wei-Feng Du,
Tao Zhu,
Yan-Jiao Wu,
Yan-Mei Liu,
Qi Wang,
Qin Wang,
Xue Gu,
Xingyue Shan,
Shining Deng,
Tailin Zhu,
Tian-Le Xu,
Wei-Hong Ge,
Wei-Guang Li,
Fei Li
Affiliations
Hui-Ran Fan
Department of Chinese Materia Medica, College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou 310053, China; Developmental and Behavioral Pediatric Department, Ministry of Education-Shanghai Key Laboratory of Children's Environmental Health, Shanghai Institute for Pediatric Research, Xin Hua Hospital Affiliated Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China; Collaborative Innovation Center for Brain Science, Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
Wei-Feng Du
Department of Chinese Materia Medica, College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou 310053, China
Tao Zhu
Department of Chinese Materia Medica, College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou 310053, China
Yan-Jiao Wu
Collaborative Innovation Center for Brain Science, Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
Yan-Mei Liu
Developmental and Behavioral Pediatric Department, Ministry of Education-Shanghai Key Laboratory of Children's Environmental Health, Shanghai Institute for Pediatric Research, Xin Hua Hospital Affiliated Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
Qi Wang
Collaborative Innovation Center for Brain Science, Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
Qin Wang
Collaborative Innovation Center for Brain Science, Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
Xue Gu
Collaborative Innovation Center for Brain Science, Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
Xingyue Shan
Developmental and Behavioral Pediatric Department, Ministry of Education-Shanghai Key Laboratory of Children's Environmental Health, Shanghai Institute for Pediatric Research, Xin Hua Hospital Affiliated Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
Shining Deng
Developmental and Behavioral Pediatric Department, Ministry of Education-Shanghai Key Laboratory of Children's Environmental Health, Shanghai Institute for Pediatric Research, Xin Hua Hospital Affiliated Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
Tailin Zhu
Developmental and Behavioral Pediatric Department, Ministry of Education-Shanghai Key Laboratory of Children's Environmental Health, Shanghai Institute for Pediatric Research, Xin Hua Hospital Affiliated Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
Tian-Le Xu
Collaborative Innovation Center for Brain Science, Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
Wei-Hong Ge
Department of Chinese Materia Medica, College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou 310053, China
Wei-Guang Li
Collaborative Innovation Center for Brain Science, Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Correspondence to: W.G. Li, Collaborative Innovation Center for Brain Science, Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China.
Fei Li
Developmental and Behavioral Pediatric Department, Ministry of Education-Shanghai Key Laboratory of Children's Environmental Health, Shanghai Institute for Pediatric Research, Xin Hua Hospital Affiliated Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China; Correspondence to: F. Li, Developmental and Behavioral Pediatric Department, Ministry of Education-Shanghai Key Laboratory of Children's Environmental Health, Shanghai Institute for Pediatric Research, Xin Hua Hospital Affiliated Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China.
An imbalance between neuronal excitation and inhibition represents a core feature in multiple neuropsychiatry disorders, necessitating the development of novel strategies to calibrate the excitatory–inhibitory balance of therapeutics. Here we identify a natural compound quercetin that reduces prefrontal cortical GABAergic transmission and alleviates the hyperactivity induced by glutamatergic N-methyl-d-aspartate receptor antagonist MK-801. Quercetin markedly reduced the GABA-activated currents in a noncompetitive manner in cultured cortical neurons, and moderately inhibited spontaneous and electrically-evoked GABAergic inhibitory postsynaptic current in mouse prefrontal cortical slices. Notably, systemic and prefrontal-specific delivery of quercetin reduced basal locomotor activity in addition to alleviated the MK-801-induced hyperactivity. The effects of quercetin were not exclusively dependent on α5-subunit-containing A type GABA receptors (GABAARs), as viral-mediated, region-specific genetic knockdown of the α5-subunit in prefrontal cortex improved the MK-801-evoked psychotic symptom but reserved the pharmacological responsivity to quercetin. Both interventions together completely normalized the locomotor activity. Together, quercetin as a negative allosteric GABAAR modulator exerted antipsychotic activity, facilitating further therapeutic development for the excitatory–inhibitory imbalance disorders. Keywords: Antipsychotic, Excitatory–inhibitory imbalance disorders, GABAAR, Prefrontal transmission, Quercetin
