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.