249. ELEVATED LEVELS OF AKT-INTERACTING PROTEIN IN THE FRONTAL POLE REVEALS MOLECULAR PATHOLOGY SPECIFIC TO A SUBTYPE OF PEOPLE WITH SCHIZOPHRENIA

Abstract Background Schizophrenia is a syndrome with complex and heterogeneous pathologies. We are studying the molecular pathology of one subtype of schizophrenia (∼ 25%), termed Muscarinic Receptor Deficit Schizophrenia (MRDS), who have very low levels of cortical cholinergic muscarinic M1 receptors (CHRM1). Our transcriptomic data revealed altered levels of AKT-interacting protein (AKTIP) RNA in the frontal pole (Brodmann’s area (BA) 10) from people with schizophrenia, but not in the other cortical regions studied (including the dorsolateral prefrontal cortex (BA9)) or in mood disorders. Further, AKTIP RNA levels were changed in the cortex of the CHRM1-/- mouse (a molecular model of aberrant CHRM1 signaling). Based on these data, we predicted that changes in AKTIP protein levels would be specific to BA10 from people with MRDS, providing novel insights into the molecular pathology involving the AKT-signaling pathway in schizophrenia. Aims & Objectives This study investigated the AKT-signaling pathway, specifically assessing levels of AKTIP protein in postmortem cortical brain samples from people with schizophrenia and mood disorders. We also investigated levels of AKT1 (total and phosphorylated) and PDK1 proteins due to their functional association with AKTIP within the AKT-signaling pathway. Method We used western blotting to measure levels of AKTIP protein in BA9 and BA10 from people with schizophrenia (n=36 (n=18 MRDS, n=18 non-MRDS)) and controls (n=18), as well as levels of AKT1 and PDK1 proteins in BA10 from the same cohort. We also measured levels of AKTIP protein in BA10 from people with mood disorders (n=12 bipolar disorder, n=12 major depressive disorder) and controls (n=12). Results Compared to controls, levels of AKTIP protein were 41% higher in BA10 from people with schizophrenia (Cohen's d=0.73; p=0.02), but not in BA9 or in people with mood disorders. Notably, this change in levels of AKTIP protein was specific to the MRDS subtype (+54%; Cohen's d=0.80; p=0.03), with no differences between non-MRDS and controls. There were no differences in levels of total AKT1 and PDK1 proteins between groups, consistent with our transcriptomic data. Discussion & Conclusions Our work is the first to show that levels of AKTIP protein are selectively altered in BA10 from people with MRDS. These findings provide insights to better understand the nature of aberrant AKT-signaling in schizophrenia and uncover why people with MRDS who have altered CHRM1 signaling may be more susceptible to dysfunction in the AKT-signaling pathway. Our study also highlights the necessity of studying subtypes within schizophrenia to disentangle its complex molecular pathologies, and therefore, better inform treatment selection and efficacy.