Selective depletion of upper-layer somatostatin interneuron subtypes in schizophrenia

01/10/2026

AI Summary

Subclass-wide reduction of SST mRNA expression within somatostatin interneurons in schizophrenia.
Selective depletion of a subset of upper-layer somatostatin interneurons and increased abundance of L6b excitatory neurons, confirmed by spatial transcriptomics.
Most depleted Sst cells are enriched for schizophrenia genetic risk, express HCN1, map to CALB1 double bouquet cells and are lost early in Alzheimer's disease.

TL;DR (AI Generated)

Here, we harmonized seven prefrontal post-mortem single-nucleus RNA-seq datasets onto a fine-grained taxonomy of cortical cell types and meta-analyzed their gene expression and abundance changes in SCZ (298 controls, 171 SCZ).

Second, we find reduced abundance (depletion) of a subset of upper-layer Sst interneurons and increased abundance of L6b excitatory neurons, with both changes confirmed in spatial transcriptomics (12 controls, 12 SCZ).

Depleted Sst subtypes highly express HCN1 , partially correspond to primate-specialized CALB1 -expressing double-bouquet cells, and are among the cells lost earliest in Alzheimer's disease.

Basic summary

bioRxiv [Preprint]. 2026 Sep 22:2026.09.18.752621. doi: 10.64898/2026.09.18.752621.

ABSTRACT

Schizophrenia (SCZ) is associated with cortical GABAergic dysfunction, but whether inhibitory interneurons are lost or persist in an altered molecular state remains unresolved. Here, we harmonized seven prefrontal post-mortem single-nucleus RNA-seq datasets onto a fine-grained taxonomy of cortical cell types and meta-analyzed their gene expression and abundance changes in SCZ (298 controls, 171 SCZ). First, we find a subclass-wide reduction of SST mRNA within somatostatin (Sst) neurons. Second, we find reduced abundance (depletion) of a subset of upper-layer Sst interneurons and increased abundance of L6b excitatory neurons, with both changes confirmed in spatial transcriptomics (12 controls, 12 SCZ). Notably, SCZ genetic risk is enriched in the most depleted Sst cells. Depleted Sst subtypes highly express HCN1 , partially correspond to primate-specialized CALB1 -expressing double-bouquet cells, and are among the cells lost earliest in Alzheimer’s disease. These upper-layer Sst interneurons constitute an intrinsically vulnerable population and a promising target for neuroprotective and compensatory therapies.

PMID:42818094 | PMC:PMC13622044 | DOI:10.64898/2026.09.18.752621

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