title: βCaMKII in lateral habenula mediates core symptoms of depression.
abstract: The lateral habenula (LHb) has recently emerged as a key brain region in the pathophysiology of depression. However, the molecular mechanism by which LHb becomes hyperactive in depression remains unknown. Through a quantitative proteomic screen, we found that expression of the β form of calcium/calmodulin-dependent protein kinase type II (βCaMΚΙΙ) was significantly up-regulated in the LHb of animal models of depression and down-regulated by antidepressants. Increasing β-, but not α-, CaMKII in the LHb strongly enhanced the synaptic efficacy and spike output of LHb neurons and was sufficient to produce profound depressive symptoms, including anhedonia and behavioral despair. Down-regulation of βCaMKII levels, blocking its activity or its target molecule the glutamate receptor GluR1 reversed the depressive symptoms. These results identify βCaMKII as a powerful regulator of LHb neuron function and a key molecular determinant of depression.
authors.affiliation: Institute of Neuroscience and State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, P R China.
authors.forename: Kun
authors.initials: K
authors.lastname: Li
authors.forename: Tao
authors.initials: T
authors.lastname: Zhou
authors.forename: Lujian
authors.initials: L
authors.lastname: Liao
authors.forename: Zhongfei
authors.initials: Z
authors.lastname: Yang
authors.forename: Catherine
authors.initials: C
authors.lastname: Wong
authors.forename: Fritz
authors.initials: F
authors.lastname: Henn
authors.forename: Roberto
authors.initials: R
authors.lastname: Malinow
authors.forename: John R
authors.initials: JR
authors.lastname: Yates
authors.forename: Hailan
authors.initials: H
authors.lastname: Hu
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D003865:Major Depressive Disorder / Q000201:enzymology* / Q000235:genetics / Q000523:psychology; D004195:Disease Models, Animal; D055785:Gene Knockdown Techniques; D019262:Habenula / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000201:enzymology; D011401:Promoter Regions, Genetic; D040901:Proteomics; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000928:Antidepressive Agents; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2