Bipolar disorder, characterized by extreme manic and depressive moods, is a prevalent debilitating disease of unknown etiology. Because mood stabilizers, antipsychotics, antidepressants, and mood-regulating neuromodulators increase the inhibitory serine-phosphorylation of glycogen synthase kinase-3 (GSK3), we hypothesized that deficient GSK3 serine-phosphorylation may increase vulnerability to mood-related behavioral disturbances. This was tested by measuring behavioral characteristics of GSK3α/β 21A/21A/9A/9A knockin mice with serine-to-alanine mutations to block inhibitory serine-phosphorylation of GSK3. GSK3 knockin mice displayed increased susceptibility to amphetamine-induced hyperactivity and to stress-induced depressive-like behaviors. Furthermore, serine-phosphorylation of GSK3 was reduced during both mood-related behavioral responses in wild-type mouse brain and in blood cells from patients with bipolar disorder. Therefore, proper control of GSK3 by serine-phosphorylation, which is targeted by agents therapeutic for bipolar disorder, is an important mechanism that regulates mood stabilization, and mice with disabled GSK3 serine-phosphorylation may provide a valuable model to study bipolar disorder.