title: Mice heterozygous for cathepsin D deficiency exhibit mania-related behavior and stress-induced depression.
abstract: Mutations in cathepsin D (CTSD), an aspartic protease in the endosomal-lysosomal system, underlie congenital neuronal ceroid-lipofuscinosis (cNCL, also known as CLN10), a devastating neurodegenerative disease. CLN10 patients die within the first few days of life, and in the few patients who live into adulthood psychopathological symptoms have not been reported. Extensive neuropathology and altered neurotransmission have been reported in CTSD-deficient mice; however signs of neuropsychiatric behavior in these mice are not well characterized due to the severe movement disorder and premature death of the animal. In the present study, we show that heterozygous CTSD-deficient (CTSD HET) mice display an overall behavioral profile that is similar to human mania, including hyperlocomotion, d-amphetamine-induced hyperactivity, sleep-disturbance, and reduced anxiety-like behavior. However, under stressful conditions CTSD HET mice manifest depressive-like behavior, including anhedonia, behavioral despair, and enhanced learned helplessness. Chronic administration of lithium chloride or valproic acid, two clinically effective mood stabilizers, reverses the majority of these behavioral abnormalities. In addition, CTSD HET mice display stress-induced hypersecretion of corticosterone. These findings suggest an important role for CTSD in the regulation of mood stabilization.
authors.affiliation: Department of Neurobiology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Key Laboratory of Neurobiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Zhou
authors.affiliation: Department of Neurobiology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Key Laboratory of Neurobiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Neurobiology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Key Laboratory of Neurobiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Han
authors.affiliation: Department of Neurobiology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Key Laboratory of Neurobiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Neurobiology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Key Laboratory of Neurobiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
authors.forename: Huifang
authors.initials: H
authors.lastname: Lou
authors.affiliation: Department of Neurobiology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Key Laboratory of Neurobiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
authors.forename: Liya
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Department of Pharmacology, Shanghai Institute of Materia Medica, CAS, China; Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China.
authors.forename: Xuechu
authors.initials: X
authors.lastname: Zhen
authors.affiliation: Department of Neurobiology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Key Laboratory of Neurobiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China. Electronic address: duanshumin@zju.edu.cn.
authors.forename: Shumin
authors.initials: S
authors.lastname: Duan
mesh_terms: D000221:Adaptation, Ocular / Q000187:drug effects / Q000235:genetics; D000818:Animals; D000928:Antidepressive Agents / Q000627:therapeutic use; D001714:Bipolar Disorder / Q000209:etiology* / Q000235:genetics*; D002402:Cathepsin D / Q000172:deficiency* / Q000235:genetics; D003345:Corticosterone / Q000097:blood; D003863:Depression / Q000209:etiology* / Q000235:genetics*; D003913:Dextroamphetamine / Q000494:pharmacology; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000187:drug effects; D005260:Female; D005518:Food Preferences / Q000187:drug effects; D006948:Hyperkinesis / Q000188:drug therapy / Q000235:genetics; D018021:Lithium Chloride / Q000627:therapeutic use; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009472:Neuronal Ceroid-Lipofuscinoses / Q000150:complications*; D012893:Sleep Wake Disorders / Q000209:etiology; D013550:Swimming / Q000523:psychology; D014635:Valproic Acid / Q000627:therapeutic use
chemical_list: D000928:Antidepressive Agents; D014635:Valproic Acid; D002402:Cathepsin D; C533923:Ctsd protein, mouse; D018021:Lithium Chloride; D003913:Dextroamphetamine; D003345:Corticosterone
keywords: Animal Disease Model; Bipolar Disorder; Cathepsin D; Congenital Neuronal Ceroid-lipofuscinosis