Grant: CIHR Fellowship

Schizophrenia and bipolar disorder share common genetic determinants and are both associated with altered reward motivation, including elevated or blunted motivation to seek out rewards. Mutations in one gene called AKAP11 have recently been discovered to increase risk of developing both diseases in humans. To understand the mechanisms contributing to bipolar disorder and schizophrenia, we conducted experiments using transgenic mice lacking one or both copies of the AKAP11 gene. We discovered that in the mutant animals missing copies of AKAP11, the expression of a protein called protein kinase A is dramatically increased. Previous research suggests that protein kinase A plays a critical role in reward processing together with neuromodulator dopamine, in a brain region important for reward processing and motivation. Hence, we hypothesize that protein kinase A activities are dysregulated in this brain region of Akap11 mutant mice and contribute to their abnormalities in reward motivation. To test our hypothesis, we will inject viruses in the brains of Akap11 mice to express a sensor that reports the activity of protein kinase A by light. We will first examine how protein kinase A activity in the brains of mutant mice is abnormal in response to dopamine receptor activation induced by drug infusion or natural rewards (food pellets). Following that, we will determine how Akap11 mice perform during a behavioral test that measures reward motivation and investigate whether manipulating the protein kinase A activity will reverse their reward motivation abnormalities. Our studies will identify the mechanisms underlying how AKAP11 mutations contribute to altered motivation in patients with schizophrenia and bipolar disorder, providing insight into the pathological mechanisms and new treatment targets of these diseases.