Perisomatic changes in h-channels regulate depressive behaviors following chronic unpredictable stress

Chronic stress can be a precipitating factor in the onset of depression. Lentiviral-mediated knockdown of HCN1 protein expression and reduction of functional I(h) produce antidepressant behavior. However, whether h-channels are altered in an animal model of depression is not known. We found that perisomatic HCN1 protein expression and I(h)-sensitive physiological measurements were significantly increased in dorsal but not in ventral CA1 region/neurons following chronic unpredictable stress (CUS), a widely accepted model for major depressive disorder. Cell-attached patch clamp recordings confirmed that perisomatic I(h) was increased in dorsal CA1 neurons following CUS. Furthermore, when dorsal CA1 I(h) was reduced by shRNA-HCN1, the CUS-induced behavioral deficits were prevented. Finally, rats infused in the dorsal CA1 region with thapsigargin, an irreversible inhibitor of the SERCA pump, exhibited anxiogenic-like behaviors and increased I(h), similar to that observed following CUS. Our results suggest that CUS, but not acute stress, leads to an increase in perisomatic I(h) in dorsal CA1 neurons and that HCN channels represent a potential target for the treatment of major depressive disorder.