Decoding frontotemporal and cell type-specific vulnerabilities to neuropsychiatric disorders and psychoactive drugs

Abstract Abnormalities in temporal and frontal lobes (TL and FL) have been linked to cognition and neuropsychiatric disorders. While structural and functional differences between the brain lobes have been documented in disease, the cellular heterogeneity in FL and TL and its impact to the vulnerability to genetic risk factors for neuropsychiatric disorders is not well studied. We hypothesize that intrinsic cellular-level differences between TL and FL explain the vulnerability of specific cell types to genetic risk factors and psychoactive drugs. To test this, we integrated single-nucleus transcriptome analysis in fresh human FL and TL with data related to genetic susceptibility and gene dysregulation in neuropsychiatric disease, and response to psychoactive drugs. We also investigate how these differences are associated with gene dysregulation in disease brain. Neuronal cell populations were the most vulnerable to psychiatric genetic risk factors, and more specifically parvalbumin interneurons (PVALB neurons). These PVALB-expressed genetic risk factors were mostly upregulated in the TL compared with FL, and dysregulated in the brain of patients with obsessive-compulsive disorder, bipolar disorder and schizophrenia. We found GRIN2A and HCN1 , implicated in schizophrenia by genome-wide association studies, to be significantly upregulated in PVLAB from the TL and in brain cortex from schizophrenia patients. Our analysis provides comprehensive evidence for PVALB neurons as the most vulnerable cell type that is implicated in several psychiatric disorders. PVALB neurons showed the highest vulnerability to psychoactive drug response, which was 3.6-fold higher than the vulnerability to genetic risk factors. In summary, we show high vulnerability of PVALB neurons that is specific to the temporal lobe, implying that differences between TL and FL greatly influence the cell vulnerability to genetic risk factors as well as the response to psychoactive drugs. These findings offer insights into how regional brain differences affect the cell type vulnerabilities in neuropsychiatric disorders.