Scientific Understanding of Consciousness
Depression Core Symptoms Mediated by Lateral Habenula
Science 30 August 2013: Vol. 341 no. 6149 pp. 1016-1020
βCaMKII in Lateral Habenula Mediates Core Symptoms of Depression
Kun Li, Tao Zhou, Lujian Liao, Zhongfei Yang, Catherine Wong, Fritz Henn, Roberto Malinow, John R. Yates III, Hailan Hu
Institute of Neuroscience and State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, P. R. China.
Graduate School of Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, P. R. China.
The Scripps Research Institute, Department of Molecular and Cellular Neurobiology, La Jolla, CA 92037, USA.
Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA.
University of California at San Diego, La Jolla, CA, 92093, USA.
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.
Major depressive disorder (MDD), one of the most prevalent and disabling mental disorders, is characterized by low mood, loss of motivation, feelings of despair, and an inability to feel pleasure, also known as anhedonia. Modern views on the cause of MDD suggest that the neural activities of specific brain circuits are altered in response to external stimuli, such as stress, as a result of maladaptive molecular and cellular changes. Recently, the lateral habenula (LHb), a nucleus that relays information from the limbic forebrain to multiple monoamine centers, has emerged as a key brain region in aversive behaviors and the pathophysiology of depression. LHb neurons are activated by aversive emotional cues, including stress, disappointment, fear, or anticipation of a negative reward. Consistently, neuroimaging studies have identified heightened habenula activity in the depressed state.
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