βCaMKII in Lateral Habenula Mediates Core Symptoms of Depression

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Science  30 Aug 2013:
Vol. 341, Issue 6149, pp. 1016-1020
DOI: 10.1126/science.1240729

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Depression and the Habenula

The lateral habenula (LHb) appears to have a role in depression. However, the underlying mechanisms are poorly understood, and by using multiple rodent models of depression, Li et al. (p. 1016) identified a signaling pathway and associated neuronal adaptations in which the enzyme βCaMKII was selectively up-regulated in the LHb. Manipulations that enhanced βCaMKII levels increased depression-related phenotypes, and RNA interference of CaMKIIb blunted depression. Enhanced βCaMKII levels in the habenula promoted excitatory synaptic transmission on these neurons and increased action potential firing mediated by an up-regulation of a specific subtype of glutamate receptors.


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.

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