Single-cell nuclear sequencing reveals brain damage in patients with schizophrenia

Animal model studies have found perturbations in several types of brain cells in people with schizophrenia, including GABAergic interneurons, but researchers at the University of Copenhagen believe these studies have focused on
a small number of neuronal subtypes.

Konstantin Khodosevich of the University of Copenhagen and colleagues have published a new study
in the journal Science Advances.
They isolated more than 220,000
neurons of various types from the dorsolateral prefrontal cortex of schizophrenia patients and controls.
Single-cell nuclear RNA sequencing revealed changes in the number of GABAERGIC interneurons and master neurons in patients and changes
in gene expression in these cells.

"Our study shows that the associated changes in schizophrenia affect not only specific neuronal families, but also multiple neuronal subtypes, suggesting the presence of pervasive network damage
," the researchers wrote.
”

Khodosevich and colleagues analyzed tissue samples from the dorsolateral prefrontal cortex of nine patients with schizophrenia and 14 patients with no history of mental illness, specifically in Brodmann zone
9.
Previous functional and anatomical studies have suggested that this brain region is associated with
schizophrenia.

For each sample, the researchers first isolated the nuclei of neurons based on the expression of the neuronal marker NeuN, then prepared and sequenced
libraries on 10x Genomics' Chromium Controller system.
In total, they sequenced 225,000 nuclei, of which 209,000 passed quality control analysis
.

In general, the composition of neurons in the cerebral cortex of people with schizophrenia is different
.
There are fewer GABAergic interneurons, especially those belonging to the PVALB, SST and VIP subtypes, but the proportion of primary neurons belonging to L2_3_CUX2 families and L4_5_FEZF2_LRRK1 subtypes increases
.
Transcriptional analysis also found that gene expression in the L2_3_CUX2_LAMP5 subfamily of main neurons and the PVALB subfamily of GABAergic interneurons in patients with schizophrenia was very different
from that of controls.

However, the researchers also noted that schizophrenia is a highly variable disorder that varies widely
between individuals.
When they compared the size of the transcriptional differences between the patients and the controls, they found that the control samples were tightly clustered, while the schizophrenia samples were less concentrated and more dispersed
.

Still, the researchers found differentially expressed genes
in each neuronal subtype.
These genes tend to influence certain pathways: genes associated with energy metabolism and protein synthesis pathways are down-regulated, and genes involved in neurotransmission, plasticity, and developmental processes are upregulated
.

"Our data support the theory that developmental events associated with schizophrenia occur in the dorsolateral prefrontal cortex during the third trimester of pregnancy, due to the arrival of GABAergic interneurons to cortical circuits and disturbances
in primary neuronal differentiation," they note in the paper.
”

However, single-cell nuclei studies like this have only drawn conclusions
from a small sample of patients.
The researchers note that future studies will need to analyze a large number of samples to gain insight into how potential covariates affect cell abundance and gene expression
.

Original text search

Upper cortical layer–driven network impairment in schizophrenia

SCIENCE ADVANCES 12 Oct 2022 Vol 8, Issue 41
DOI: 10.
1126/sciadv.
abn83