Upper cortical layer-driven network impairment in schizophrenia

Batiuk, Mykhailo Y. and Tyler, Teadora and Dragicevic, Katarina and Mei, Shenglin and Rydbirk, Rasmus and Petukhov, Viktor and Deviatiiarov, Ruslan and Sedmak, Dora and Frank, Erzsébet and Fehér, Virgínia and Habek, Nikola and Hu, Qiwen and Igolkina, Anna and Roszík, Lilla and Pfisterer, Ulrich and Garcia-Gonzalez, Diego and Petanjek, Zdravko and Adorján, István and Kharchenko, Peter V. and Khodosevich, Konstantin (2022) Upper cortical layer-driven network impairment in schizophrenia. SCIENCE ADVANCES, 8 (41). No-eabn8367. ISSN 2375-2548

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Abstract

Schizophrenia is one of the most widespread and complex mental disorders. To characterize the impact of schizophrenia, we performed single-nucleus RNA sequencing (snRNA-seq) of >220,000 neurons from the dorsolateral prefrontal cortex of patients with schizophrenia and matched controls. In addition, >115,000 neurons were analyzed topographically by immunohistochemistry. Compositional analysis of snRNA-seq data revealed a reduction in abundance of GABAergic neurons and a concomitant increase in principal neurons, most pronounced for upper cortical layer subtypes, which was substantiated by histological analysis. Many neuronal subtypes showed extensive transcriptomic changes, the most marked in upper-layer GABAergic neurons, including down-regulation in energy metabolism and up-regulation in neurotransmission. Transcription factor network analysis demonstrated a developmental origin of transcriptomic changes. Last, Visium spatial transcriptomics further corroborated upperlayer neuron vulnerability in schizophrenia. Overall, our results point toward general network impairment within upper cortical layers as a core substrate associated with schizophrenia symptomatology.

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