βCaMKII in Lateral Habenula Mediates Core Symptoms of Depression

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/calm...

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Published in:	Science (American Association for the Advancement of Science) 2013-08, Vol.341 (6149), p.1016-1020
Main Authors:	Li, Kun, Zhou, Tao, Liao, Lujian, Yang, Zhongfei, Wong, Catherine, Henn, Fritz, Malinow, Roberto, Yates, John R., Hu, Hailan
Format:	Article
Language:	eng
Subjects:	Adaptation Animal models Animals Antidepressants Antidepressive Agents - pharmacology Brain Calcium-Calmodulin-Dependent Protein Kinase Type 2 - antagonists & inhibitors Calcium-Calmodulin-Dependent Protein Kinase Type 2 - biosynthesis Calcium-Calmodulin-Dependent Protein Kinase Type 2 - genetics Depression Depressive Disorder, Major - enzymology Depressive Disorder, Major - genetics Depressive Disorder, Major - psychology Depressive disorders Disease Models, Animal Enzymes Firing Gene Knockdown Techniques Habenula Habenula - drug effects Habenula - enzymology Humans Infections Lithium Male Mice Mice, Inbred C57BL Neurons Neurons - drug effects Neurons - enzymology Promoter Regions, Genetic Proteomics Rats Rats, Sprague-Dawley Receptors Rodents Viruses
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Summary:	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 (βCaMKII) 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.
ISSN:	0036-8075 1095-9203