Selective depletion of upper-layer somatostatin interneuron subtypes in schizophrenia
- 1Centre for Addiction and Mental Health
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.
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BibTeX
@misc{endresz2026selective,
title = {{Selective depletion of upper-layer somatostatin interneuron subtypes in schizophrenia}},
author = {N. Endresz and M. E. Fafouti and K. Arbabi and X. Zhou and T. DeLong and G. Gonzalez-Burgos and L. Duncan and E. Sibille and S. J. Tripathy},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.18.752621},
url = {https://www.biorxiv.org/content/10.64898/2026.09.18.752621v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Selective depletion of upper-layer somatostatin interneuron subtypes in schizophrenia
AU - N. Endresz
AU - M. E. Fafouti
AU - K. Arbabi
AU - X. Zhou
AU - T. DeLong
AU - G. Gonzalez-Burgos
AU - L. Duncan
AU - E. Sibille
AU - S. J. Tripathy
PY - 2026
DA - 2026/09/18
PB - bioRxiv
DO - 10.64898/2026.09.18.752621
UR - https://www.biorxiv.org/content/10.64898/2026.09.18.752621v1
AB - 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.
ER -