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 βCaMII expression was significantly upregulated in the LHb of animal models of depression, and downregulated by antidepressants. Increasing the levels of 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. Downregulation of βCaMKII levels, blocking its activity or its target molecule GluR1, reversed the depressive symptoms. These results identify βCaMKII as a powerful regulator of LHb neuron function and a key molecular determinant of depression.
Mental strength and history of winning play an important role in the determination of social dominance. However, the neural circuits mediating these intrinsic and extrinsic factors have remained unclear. Working in mice, we identified a dorsomedial prefrontal cortex (dmPFC) neural population showing "effort"-related firing during moment-to-moment competition in the dominance tube test. Activation or inhibition of the dmPFC induces instant winning or losing, respectively. In vivo optogenetic-based long-term potentiation and depression experiments establish that the mediodorsal thalamic input to the dmPFC mediates long-lasting changes in the social dominance status that are affected by history of winning. The same neural circuit also underlies transfer of dominance between different social contests. These results provide a framework for understanding the circuit basis of adaptive and pathological social behaviors.
Mutations in the proline-rich transmembrane protein 2 (PRRT2) are associated with paroxysmal kinesigenic dyskinesia (PKD) and several other paroxysmal neurological diseases, but the PRRT2 function and pathogenic mechanisms remain largely obscure. Here we show that PRRT2 is a presynaptic protein that interacts with components of the SNARE complex and downregulates its formation. Loss-of-function mutant mice showed PKD-like phenotypes triggered by generalized seizures, hyperthermia, or optogenetic stimulation of the cerebellum. Mutant mice with specific PRRT2 deletion in cerebellar granule cells (GCs) recapitulate the behavioral phenotypes seen in Prrt2-null mice. Furthermore, recording made in cerebellar slices showed that optogenetic stimulation of GCs results in transient elevation followed by suppression of Purkinje cell firing. The anticonvulsant drug carbamazepine used in PKD treatment also relieved PKD-like behaviors in mutant mice. Together, our findings identify PRRT2 as a novel regulator of the SNARE complex and provide a circuit mechanism underlying the PRRT2-related behaviors.
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