Elevated synaptic PKA activity and abnormal striatal dopamine signaling in Akap11 mutant mice, a genetic model of schizophrenia and bipolar disorder

Loss-of-function mutations in AKAP11 (a protein kinase A (PKA)-binding protein) greatly increase the risk of bipolar disorder and schizophrenia. We conducted multi-omic analyses of Akap11 mutant mouse brains and report the neurobiological functions of AKAP11 and the consequences of its absence. AKAP11 interacts with multiple proteins involved in signaling and proteostasis. In Akap11 ^+/- and Akap11 ^-/- synapses, PKA protein levels were markedly elevated, and many synaptic proteins were hyperphosphorylated at PKA substrate sites. Akap11 mutant brains showed extensive transcriptomic changes, prominently in synapse-related gene-sets and most profoundly in neurons of the striatum, a brain region implicated in motivation, cognition and psychiatric disorders. In vivo , real-time measurements of PKA activity in Akap11 ^-/- revealed constitutively elevated kinase activity, which distorts the dynamic range of dopamine to PKA signaling in the striatum. Our work reveals the molecular basis of circuit dysfunction in a genetically valid model of psychotic disorder.