Chronic activation of the small-conductance, calcium-activated potassium channel precipitates age-dependent depressive-like behavior and cognitive deficits and reduces klotho concentration.

Abstract

Depression is a common mood disorder with a multifaceted, complex pathophysiology. An abnormal level of corticosteroids in the brain can cause structural change in the hippocampus. It may cause an imbalance in calcium homeostasis leading to functional impairment in the activity of the voltage-insensitive, small conductance, calcium-activated potassium channel (SKC). Deficit in the longevity protein klotho is also implicated in stress-induced depression. We ascertained whether chronic activation of SKCs can cause age-dependent depressive-like behavior and cognitive deficits, accompanied by disturbances in klotho concentration. We tested the effect of repeated activation of SKCs by the potent SKC agonist, 1-EBIO (1.0 mg/kg, IP, once daily for 15 days) in young (3 months) and mid-life (12 months) male BALB/c mice. We conducted a battery of behavioral tests to investigate depressive-like behavior and cognitive functions. Then, we used an enzyme-linked immunosorbent assay (ELISA) on brain homogenates to determine the change in total klotho concentration in the prefrontal cortex, hippocampus, and dorsal raphe. We found that chronic 1-EBIO treatment decreased locomotor activity, sucrose preference, and alternation index in an age-dependent manner. The drug does not affect stress-coping behavior in the forced swim test. The behavioral deficits were accompanied by a significant decrease in total klotho concentration in the hippocampus but not in the prefrontal cortex or dorsal raphe, observed in an age-dependent manner. Based on these results, we surmise that chronic activation of SKCs results in concurrent cognitive and depressive-like phenotypes in mid-aged mice. Therefore, this could represent a putative therapeutic target for age-related psycho-affective disorders.