Potassium Release From the Habenular Astrocytes Induces Depressive-Like Behaviors in Mice

The habenula has been implicated in psychiatric disorders such as depression, primarily because of its role in the modulation of the dopaminergic and serotonergic systems, which play a role in the pathophysiology of these disorders. Despite growing evidence supporting the role of the habenula in behavioral regulation, the process by which neural cells develop in the habenula remains elusive. Since the habenular anlage is found in the prosomere 2 domain expressing transcription factor Dbx1 in mouse embryos, we hypothesized that the Dbx1-expressing prosomere domain is a source of astrocytes that modulate neuronal activity in the habenula. To address this, we examined the cell lineage generated from Dbx1-expressing cells in male mice using tamoxifen-inducible Cre recombinase under the control of the Dbx1 promoter. Perinatal induction of Cre activity labeled cells migrating radially from the ventricular zone to the pial side of the habenular anlage, and eventually showed astrocyte-like morphology with expression of the marker protein, S100β, for mature astrocytes in the habenula of the adult mouse. Photostimulation of astrocytes expressing ChR2 released potassium ions into the extracellular space, which in turn excited the neurons with an increased firing rate in the lateral habenula. Finally, photostimulation of habenular astrocytes exacerbated depression-like phenotypes with reduced locomotor activity, exaggerated despair behavior and impaired sucrose preference in open-field, tail suspension and sucrose preference tests, respectively. These results indicated that the Dbx1-expressing perinatal domain generated astrocytes that modulated neuronal activity via the regulation of extracellular potassium levels.