# Somatostatin Interneurons in Prefrontal Cortical Microcircuits in Schizophrenia

> **NIH NIH F30** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $47,232

## Abstract

Project Summary
Developing novel therapeutics to treat the core cognitive deficits (e.g. working memory) in individuals with
schizophrenia (SZ) remains a major unmet need. Working memory depends, in part, on properly timed activation
of layer 3 pyramidal neurons in the dorsolateral prefrontal cortex (DLPFC). In particular, this DLPFC microcircuit
appears to be crucial for filtering out distracting stimuli during working memory tasks. Convergent experimental
and computational data suggest that successful filtering of distractors occurs through inhibition onto pyramidal
neuron dendrites by somatostatin (SOM)-expressing GABA neurons. Thus, the widely replicated findings of
lower SOM mRNA expression in gray matter samples from SZ subjects implicate altered GABA signaling from
SOM neurons as potential contributors to the neural basis for working memory dysfunction in the illness. The
few studies which have been conducted on SOM neurons in SZ consistently demonstrate lower SOM mRNA
expression in total gray matter DLPFC samples as well as a lower density of neurons positive for SOM mRNA.
These prior findings raise key questions about these alterations: first, does a lower density of SOM-expressing
neurons in the DLPFC of SZ subjects reflect fewer total SOM neurons in the illness or a failure of a subset of
these neurons to express SOM mRNA? Second, do SOM neurons exhibit a diminished capacity to synthesize
GABA, indexed by lower expression of the principal GABA synthesizing enzyme, GAD67? We propose to
address these questions utilizing novel multiplex fluorescent in-situ hybridization, relying on the use of Sox6 as
a proxy marker for SOM neurons while measuring SOM and GAD67 mRNA levels in a cell-type specific manner.
We predict that the density of SOM neurons is unaltered in SZ and that SOM and GAD67 mRNA levels per
neuron are lower (Aim 1). Third, upstream factors which contribute to lower SOM mRNA in SOM neurons residing
in layers 2-superficial 3, but not those not deep 6-white matter, are unknown, but likely reflect microcircuit
abnormalities. Both SOM and GAD67 mRNA expression levels are positively associated with activity levels.
Layer 3 pyramidal neurons, which furnish the majority of excitatory inputs onto SOM neurons in the superficial
layers, but not those in deeper layers or white matter, are hypoactive in the illness. Thus, we will test the
hypothesis that SOM neuron abnormalities in SZ are secondary to weaker excitatory drive from layer 3 pyramidal
neurons. We will perform RNAseq on SOM neurons in the superficial gray matter layers and superficial white
matter and measure levels of activity-associated transcripts, predicting lower expression of these transcripts in
SOM neurons from the superficial gray matter (Aim 2). A primate model of the DLPFC microcircuitry will be
employed to provide direct experimental evidence that lower activity of layer 3 pyramidal neurons contributes to
the observed SOM alterations in SZ (Aim 3). The results of th...

## Key facts

- **NIH application ID:** 10219793
- **Project number:** 5F30MH124329-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Samuel James Dienel
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $47,232
- **Award type:** 5
- **Project period:** 2020-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10219793

## Citation

> US National Institutes of Health, RePORTER application 10219793, Somatostatin Interneurons in Prefrontal Cortical Microcircuits in Schizophrenia (5F30MH124329-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10219793. Licensed CC0.

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