Upper cortical layer–driven network impairment in schizophrenia

• DOI: 10.1126/sciadv.abn8367
• Publication Date: 2022-10-12T17:57:16Z
• Authors: Mykhailo Y. Batiuk; Teadora Tyler; Katarina Dragicevic; Shenglin Mei; Rasmus Rydbirk; Viktor Petukhov; Ruslan Deviatiiarov; Dora Sedmak; Erzsebet Frank; Virginia Feher; Nikola Habek; Qiwen Hu; Anna Igolkina; Lilla Roszik; Ulrich Pfisterer; Diego Garcia-Gonz...; Zdravko Petanjek; Istvan Adorjan; Peter V. Kharchenko; Konstantin Khodos...
• Keywords: Neurons; 0301 basic medicine; neurológia; Transcription Factors / metabolism; QH3015 Molecular biology / molekuláris biológia; GABAergic Neurons / metabolism; Prefrontal Cortex; RNA sequencing; Mental disorders; Schizophrenia / pathology; Biología y Biomedicina / Biología; RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry / idegkórtan; 3. Good health; 03 medical and health sciences; Prefrontal Cortex / metabolism; cerebral cortex, interneurons, mental disorders; pszichiátria; RNA, Small Nuclear; Schizophrenia; Humans; RNA, Small Nuclear / metabolism; GABAergic Neurons; Neuroscience; Transcription Factors

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