A gene-specific cerebral types 1, 2, and 3 RyR protein knockdown induces an antidepressant-like effect in mice

Elevation of baseline intracellular calcium levels was observed in platelets or lymphoblasts of patients with bipolar affective disorders suggesting an altered intracellular Ca2+ homeostasis in the pathophysiology of mood disorders. The role of supraspinal endoplasmic ryanodine receptors (RyRs), which allow mobilization of intracellular Ca2+ stores, in the modulation of depressive states was, then, investigated. Ryanodine and FK506 reduced the immobility time in the mouse forced swimming test showing an antidepressant-like profile comparable with that produced by amitriptyline and clomipramine. We generated types 1, 2, and 3 RyR knockdown mice by using selective antisense oligonucleoticles (aODN) to investigate the role of each RyR isoform. A gene-specific cerebral RyR protein level reduction in knockdown animals was demonstrated by immunoblotting, immunoprecipitation, and immunohistochemical experiments. Repeated intracerebroventricular administration of aODNs complementary to the sequence of the types 1, 2, or 3 RyR produced an antidepressant-like response in the forced swimming test. The aODN-induced reduction of immobility time was temporary and reversible and did not impair motor coordination, spontaneous mobility, and exploratory activity. These findings identify cerebral RyRs as critical targets underlying depressive states and should facilitate the comprehension of the pathophysiology of mood disorders and help developing of new therapeutical strategies.