Elevated PKA activity at synapses and broad molecular disturbances in the striatum of Akap11 mutant mice, a genetic model of schizophrenia and bipolar disorder [bulk RNA-Seq]

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 analysis of Akap11 mutant mouse brains, and report that AKAP11 interacts with multiple proteins involved in signaling and proteostasis. In Akap11+/- and Akap11-/- synapses, PKA protein levels were markedly elevated, and many proteins (eg GluA1) were hyperphosphorylated at PKA 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. Widespread misexpression and differential phosphorylation of neuromodulation-related genes indicated perturbed function and altered organization of the striatum. Our work reveals the molecular mechanism and a potential circuit basis of brain dysfunction in a genetically valid model of psychotic disorder. Comparative gene expression profiling analysis of RNA-seq data from prefrontal cortex (PFC), somatosensory cortex (SSC), hippocampus (HP), striatum (ST), Thalamus (TH) and substantia nigra (SN) at 4, and12 weeks of age in Akap11 mutant mice.