Upper cortical layer–driven network impairment in schizophrenia

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 upper-layer neuron vulnerability in schizophrenia. Overall, our results point toward general network impairment within upper cortical layers as a core substrate associated with schizophrenia symptomatology.

Integrated single cell and unsupervised spatial transcriptomic analysis defines molecular anatomy of the human dorsolateral prefrontal cortex

“…Recent single nucleus RNA-sequencing (snRNA-seq) analyses, including those in companion PsychENCODE studies, are defining transcriptionally distinct DLPFC cell types and revealing cell type-specific changes associated with neurodevelopmental and neuropsychiatric disorders, such as schizophrenia (SCZ), autism spectrum disorder (ASD), major depressive disorder (MDD) and post-traumatic stress disorder (PTSD) (13)(14)(15)(16). However, snRNA-seq data lack spatial context, which when retained during molecular profiling, can provide important insights into cell-cell communication and disease pathogenesis.…”

Associations of psychiatric disease and aging onFKBP5expression converge on cortical supragranular neurons

“…In (c) Cohort 5 and ( d ) Cohort 6, bar plots show the average FKBP5 gene expression per cell-type cluster, as well as FKBP5 expression across cell clusters. ( e ) Bar plots showing the average FKBP5 gene expression per cell type cluster in previously published datasets Habib et al [1] and Lake et al [2] (f) Co-localisation of FKBP51 protein expression (green) with nuclear marker DAPI (blue) and: (i) NeuN+ neurons (red) in the supragranular layer; (ii) NeuN+ neurons in the infragranular layer; (iii) GAD67+ neurons; (iv-v) GFAP+ astrocytes (top showing no colocalization and bottom showing strong colocalization); (vi) TMEM119+ microglia. Scale bar for all images = 20µm.…”

“…Our group and others have also reported that FKBP5 levels in the postmortem orbitofrontal cortex are inversely correlated with dendritic mushroom spine density in post-traumatic stress disorder [53] and in mixed psychiatric cases with a history of severely stressful life events [19]. Interestingly, both excitatory and inhibitory supragranular neurons in the dorsolateral prefrontal cortex were recently reported to be vulnerable to the effects of psychopathology in schizophrenia, indicating a core network impairment in this sub-region that may originate from gene × environment interactions during development [2]. Our study may indicate that FKBP5 is a contributor in this process given FKBP5 is governed by gene × environment interactions, and its expression is increased via epigenetic mechanisms in the presence of early life adversity [31].…”

Variant-risk-exon interplay impacts circadian rhythm and dopamine signaling pathway in severe psychiatric disorders

“…We showed that our core gene set which implicated circadian rhythms is enriched in excitatory neuron subtypes of BA6, 10 and 11. Projections from the orbitofrontal cortex to cholecystokinin-expressing neurons of the suprachiasmatic nucleus have been previously reported 77 and several studies have also highlighted the impact of different cortical layer subtypes in schizophrenia 78 , which has been linked to cognitive function 79 . Cortical neurons also appear to be vulnerable to the effects of stress in psychopathology 80 , relevant given the implication of cortisol in our core gene set, and is likely linked to circadian entrainment.…”