title: Increased Cdk5/p35 activity in the dentate gyrus mediates depressive-like behaviour in rats.
abstract: Depression is one of the most pervasive and debilitating psychiatric diseases, and the molecular mechanisms underlying the pathophysiology of depression have not been elucidated. Cyclin-dependent kinase 5 (Cdk5) has been implicated in synaptic plasticity underlying learning, memory, and neuropsychiatric disorders. However, whether Cdk5 participates in the development of depressive diseases has not been examined. Using the chronic mild stress (CMS) procedure, we examined the effects of Cdk5/p35 activity in the hippocampus on depressive-like behaviour in rats. We found that CMS increased Cdk5 activity in the hippocampus, accompanied by translocation of neuronal-specific activator p35 from the cytosol to the membrane in the dentate gyrus (DG) subregion. Inhibition of Cdk5 in DG but not in the cornu ammonis 1 (CA1) or CA3 hippocampal subregions inhibited the development of depressive-like symptoms. Overexpression of p35 in DG blocked the antidepressant-like effect of venlafaxine in the CMS model. Moreover, the antidepressants venlafaxine and mirtazapine, but not the antipsychotic aripiprazole, reduced Cdk5 activity through the redistribution of p35 from the membrane to the cytosol in DG. Our results showed that the development of depressive-like behaviour is associated with increased Cdk5 activity in the hippocampus and that the Cdk5/p35 complex plays a key role in the regulation of depressive-like behaviour and antidepressant actions.
authors.affiliation: National Institute on Drug Dependence, Peking University, Beijing, China. zhu_wl@bjmu.edu.cn
authors.forename: Wei-Li
authors.initials: WL
authors.lastname: Zhu
authors.forename: Hai-Shui
authors.initials: HS
authors.lastname: Shi
authors.forename: Shen-Jun
authors.initials: SJ
authors.lastname: Wang
authors.forename: Chun-Mei
authors.initials: CM
authors.lastname: Xu
authors.forename: Wen-Gao
authors.initials: WG
authors.lastname: Jiang
authors.forename: Xi
authors.initials: X
authors.lastname: Wang
authors.forename: Ping
authors.initials: P
authors.lastname: Wu
authors.forename: Qian-Qian
authors.initials: QQ
authors.lastname: Li
authors.forename: Zeng-Bo
authors.initials: ZB
authors.lastname: Ding
authors.forename: Lin
authors.initials: L
authors.lastname: Lu
mesh_terms: D015107:4-Butyrolactone / Q000494:pharmacology; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D003080:Cold Temperature / Q000009:adverse effects; D018891:Dentate Gyrus / Q000187:drug effects / Q000201:enzymology*; D003863:Depression / Q000188:drug therapy / Q000201:enzymology* / Q000209:etiology / Q000473:pathology*; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D005106:Exploratory Behavior / Q000187:drug effects; D005518:Food Preferences / Q000187:drug effects; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D007276:Injections, Intraventricular; D008297:Male; D010770:Phosphotransferases / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013315:Stress, Psychological / Q000209:etiology; D013395:Sucrose / Q000008:administration & dosage; D013997:Time Factors; D014161:Transduction, Genetic
chemical_list: D000928:Antidepressive Agents; C492235:Cdk5r1 protein, rat; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D013395:Sucrose; D010770:Phosphotransferases; D015107:4-Butyrolactone