Upper cortical layer-driven network impairment in schizophrenia

Area of Science:

• Neuroscience
• Genomics
• Psychiatry

Background:

• Schizophrenia is a complex mental disorder with significant societal impact.
• Understanding the cellular and molecular underpinnings of schizophrenia is crucial for developing effective treatments.

Purpose of the Study:

• To investigate the impact of schizophrenia on neuronal populations in the dorsolateral prefrontal cortex.
• To identify transcriptomic and compositional changes in neurons from schizophrenia patients.

Main Methods:

• Single-nucleus RNA sequencing (snRNA-seq) of over 220,000 neurons.
• Immunohistochemistry analysis of over 115,000 neurons.
• Visium spatial transcriptomics for topographical analysis.

Main Results:

• A reduction in GABAergic neurons and an increase in principal neurons, especially in upper cortical layers.
• Extensive transcriptomic alterations in neuronal subtypes, notably in upper-layer GABAergic neurons (decreased energy metabolism, increased neurotransmission).
• Evidence of a developmental origin for observed transcriptomic changes.

Conclusions:

• Schizophrenia is associated with significant alterations in neuronal composition and function within the upper cortical layers.
• These changes suggest impaired neural network function in upper cortical layers as a key substrate for schizophrenia.
• Findings highlight the vulnerability of upper cortical neurons in schizophrenia.