Abstract

Astrocyte dysfunction in bipolar disorder and schizophrenia differs from major depressive disorder

Medina A, Hagenauer MH, Krolweski DM, Hughes E, Thew Forrester LC, Waselus M, Walsh DM, Richardson E, Turner CA, Cartagena P, Thompson RC, Vawter MP, Bunney B, Sequeira A, Myers R, Barchas JD, Lee FS, Schatzberg AF, Bunney WE, Akil H, Watson SJ
51st Annual Meeting of the Society for Neuroscience. 2022.

Astrocytes are fundamental in maintaining and modulating brain function at the cellular level. Their activity regulates different aspects of neurotransmission, and dysfunction of the glial syncytium may underlie the pathophysiology of mental illness. Previous studies from our group showed that several aspects of the glial function are affected by Major Depressive Disorder (MDD), most of them related to the modulation of glutamate neurotransmission and the resetting of the synaptic environment after its excitatory activity, functions that are mediated by astrocytes. Those results showed the downregulation of genes involved in glutamate re-uptake, post-excitatory water and potassium siphoning, and the gap junction elements necessary to maintain the syncytial function of astrocytes. This study explored the effect of two other diagnoses, Bipolar Disorder (BP) and Schizophrenia (SZ), on the astrocyte network. We hypothesize that astrocyte function may also be affected in these two diseases, however, since the etiological theories for BP and SZ differ from those described for MDD, there could also be differences in the glial mechanisms associated with these disorders. Methods: Human brain samples from the frontopolar cortex (Brodmann area 10, BA10) were obtained through the University of California, Irvine (UCI)-Pritzker Brain Bank. The subjects included in the schizophrenia and bipolar disorder groups met diagnostic criteria from the Diagnostics and Statistical Manual of Mental Disorders (DSM-V). The control group showed no evidence of psychiatric or neurological disorders. Covariates that could affect gene expression were accounted for including gender, age, and postmortem interval. All subjects used in the study had cerebellar tissue pH above 6.5 and agonal factor scores (AFS) of zero. After performing RNA extraction and adequate quality control, we used TaqMan® Gene Expression Custom Array Cards to perform qPCR analysis of genes related to astrocyte function. The results were then bolstered by performing a meta-analysis of publicly released BA10 microarray data to find points of convergence with our qPCR results. Results: our study showed alterations of genes related to astrocyte function in BP and SZ compared to controls. However, the altered molecules did not overlap with the list of candidate genes based on previously reported findings in MDD. There was a strong correlation between the BP and SZ results, suggesting pathophysiological commonalities between the two diagnoses.