Cyclin-dependent kinase 5 in the ventral tegmental area regulates depression-related behaviors.
Dopamine neurons in the ventral tegmental area (VTA) govern reward and motivation and dysregulated dopaminergic transmission may account for anhedonia and other symptoms of depression. Cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine/threonine kinase that regulates a broad range of brain functions through phosphorylation of a myriad of substrates, including tyrosine hydroxylase (TH), the rate-limiting enzyme for dopamine synthesis. We investigated whether and how Cdk5 activity in VTA dopamine neurons regulated depression-related behaviors in mice. Using the Cre/LoxP system to selectively delete Cdk5 in the VTA or in midbrain dopamine neurons in Cdk5(loxP/loxP) mice, we showed that Cdk5 loss of function in the VTA induced anxiety- and depressive-like behaviors that were associated with decreases in TH phosphorylation at Ser31 and Ser40 in the VTA and dopamine release in its target region, the nucleus accumbens. The decreased phosphorylation of TH at Ser31 was a direct effect of Cdk5 deletion, whereas decreased phosphorylation of TH at Ser40 was likely caused by impaired cAMP/protein kinase A (PKA) signaling, because Cdk5 deletion decreased cAMP and phosphorylated cAMP response element-binding protein (p-CREB) levels in the VTA. Using Designer Receptors Exclusively Activated by Designer Drugs (DREADD) technology, we showed that selectively increasing cAMP levels in VTA dopamine neurons increased phosphorylation of TH at Ser40 and CREB at Ser133 and reversed behavioral deficits induced by Cdk5 deletion. The results suggest that Cdk5 in the VTA regulates cAMP/PKA signaling, dopaminergic neurotransmission, and depression-related behaviors.
Department of Pharmacology and Toxicology and Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, and Department of Geriatrics, Qi-Lu Hospital of Shandong University, Key Laboratory of Proteomics of Shandong Province, Jinan, Shandong, China.
Peng
P
Zhong
Xiaojie
X
Liu
Zhen
Z
Zhang
Ying
Y
Hu
Sarah J
SJ
Liu
Martha
M
Lezama-Ruiz
Milan
M
Joksimovic
Qing-song
QS
Liu
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D050882:CREB-Binding Protein / Q000378:metabolism; D003024:Clozapine / Q000031:analogs & derivatives / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics / Q000378:metabolism*; D003863:Depression / Q000235:genetics* / Q000378:metabolism*; D004195:Disease Models, Animal; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics; D005106:Exploratory Behavior / Q000502:physiology; D005518:Food Preferences / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D066298:In Vitro Techniques; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D022661:RNA, Untranslated / Q000235:genetics; D012694:Serine / Q000378:metabolism; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000378:metabolism*
D014150:Antipsychotic Agents; D050483:Dopamine Plasma Membrane Transport Proteins; C110853:Gt(ROSA)26Sor non-coding RNA, mouse; D022661:RNA, Untranslated; D049452:Green Fluorescent Proteins; D012694:Serine; D000242:Cyclic AMP; D050882:CREB-Binding Protein; D051360:Cyclin-Dependent Kinase 5; D003024:Clozapine; C079149:clozapine N-oxide
Cdk5; DREADD; cAMP; depression; dopamine; tyrosine hydroxylase