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. To determine the neurobiological
functions of AKAP11, we conduct multi-omic and neurobiological analyses of Akap11 mutant
mouse brains. We find that AKAP11 is a key regulator of PKA proteostasis in the brain whose
loss leads to dramatically increased levels of PKA subunits and phosphorylated PKA substrates,
especially in synapses. Akap11 mutant mice show extensive transcriptomic changes throughout
the brain, including prominent decreases in synapse-related genes sets. Gene expression is highly
impacted in spiny projection neurons of the striatum, a brain region implicated in motivation,
cognition and psychotic disorders. Real-time measurements of PKA activity reveal elevated
basal PKA activity in striatum of Akap11 38 -/- mice, with exaggerated additional response to
dopamine receptor antagonists. Behaviorally, Akap11 mutant mice show abnormally prolonged
locomotor response to amphetamine, deficits in associative learning and contextual
discrimination, as well as depression-like behaviors. Our study connects molecular changes to
circuit dysfunction and behavioral disturbance in a genetically valid animal model of psychotic
disorder.