Neurotransmission-Related Gene Expression in the Frontal Pole (Brodmann Area 10) is Altered in Subjects with Bipolar Disorder and Schizophrenia

Brodmann Area 10 (BA10) is the largest cytoarchitectonic region of the human cortex, performing complex integrative functions. BA10 undergoes intensive adolescent grey matter pruning around the average age of onset for Bipolar disorder (BP) and Schizophrenia (SCHIZ), and its dysfunction is likely to underly aspects of their shared symptomology. In this study, we investigated the role of BA10 neurotransmission-related gene expression in BP and SCHIZ. We performed qPCR to measure the expression of 115 neurotransmission-related targets in control, BP, and SCHIZ post-mortem samples ( n =72). We chose this method for its high sensitivity to detect low-level expression. We then bolstered our findings by performing a meta-analysis of publicly-released BA10 microarray data ( n =101) and identified sources of convergence with our qPCR results. To improve interpretation, we compiled an unusually large database of clinical metadata for our samples. We used this data to explore the relationship between BA10 gene expression, therapeutics, substances of abuse, and symptom profiles, and validated these findings with publicly-available datasets. Using these convergent sources of evidence, we identified 20 neurotransmission-related genes that were differentially expressed in BP and SCHIZ in BA10. These results included a large diagnosis-related decrease in two important therapeutic targets with low-levels of expression, HTR2B and DRD4, as well as other findings related to dopaminergic, GABA-ergic and astrocytic function. We also observed that therapeutics may produce differential expression that opposes the effects of diagnosis. In contrast, substances of abuse showed similar effects on BA10 gene expression as BP and SCHIZ, potentially amplifying diagnosis-related dysregulation. ### Competing Interest Statement All authors are members of the Pritzker Neuropsychiatric Disorders Research Consortium, which is supported by Pritzker Neuropsychiatric Disorders Research Fund. A shared intellectual property agreement exists between the academic and philanthropic entities of the consortium. All authors report no biomedical financial interests or potential conflicts of interest. ### Funding Statement This work was primarily supported by the Pritzker Neuropsychiatric Disorders Research Consortium [to HA and SJW]. This work was further supported by grants from the Hope for Depression Research Foundation (RGA No. DTF Phase II [D]), National Institute on Drug Abuse (Grant #U01-DA043098 [to HA]), Office of Naval Research (Grant # 00014-19-1-2149 [to HA]), and National Institute of Mental Health (Grant # R01-MH-08580 [to MPV]). Research training for LTF and ER was supported by the Undergraduate Research Opportunity Program at the University of Michigan. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Institutional Review Board for the University of Michigan and the Institutional Review Board for the University of California-Irvine gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced will be available online on FigShare following publication.