Schizophrenia-associated changes in neuronal subpopulations in the human midbrain

Area of Science:

• Neuroscience
• Genomics
• Psychiatry

Background:

• Schizophrenia is associated with dysfunctional GABAergic and dopaminergic neurons in the ventral midbrain.
• Transcriptional changes in these neurons are not well-localized to specific subsets.
• Ventral midbrain dopaminergic activity is modulated by excitatory (glutamate) and inhibitory (GABA) inputs.

Purpose of the Study:

• To characterize transcriptional diversity of neuronal populations in the human ventral midbrain.
• To identify schizophrenia-associated changes in neuronal subset proportions and gene activity.
• To elucidate neuron pathology at the single-cell level in schizophrenia.

Main Methods:

• Single nucleus RNA-sequencing (snRNA-seq) of 31,669 NEUN+ nuclei from human ventral midbrain.
• Fluorescence-activated sorting (FAS) of NEUN+ nuclei.
• Orthogonal validation using immunohistochemical stainings.

Main Results:

• 18 transcriptionally distinct neuronal populations identified, including two 'mixed' populations.
• 16 additional subpopulations classified as excitatory or inhibitory upon subclustering.
• Potential alterations in proportions of excitatory, inhibitory, mixed, and TH-expressing neuron subpopulations in schizophrenia.
• 99 differentially expressed genes detected in schizophrenia patients within mixed populations, with 67 in small GABAergic subpopulations.

Conclusions:

• Single-nucleus transcriptomic analysis reveals high diversity of GABAergic neurons in the human ventral midbrain.
• Putative shifts in neuronal subpopulation proportions and gene expression in schizophrenia.
• Evidence suggests dysfunction of specific GABAergic subpopulations in schizophrenia, warranting further investigation.