# Towards understanding cellular mechanisms of positive symptoms of schizophrenia

> **NIH NIH R01** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 2021 · $470,098

## Abstract

Schizophrenia (SCZ) affects about 1% of the world’s population and is characterized by symptoms
that include hallucinations and delusions (positive symptoms); antisocial behavior and blunted emotions
(negative symptoms); and deficits in working memory, executive function, and learning and memory (cognitive
symptoms). Antipsychotics primarily acting through dopamine receptors (Drd2s) alleviate positive symptoms,
some negative symptoms, and are mostly ineffective for cognitive symptoms. Thus, multiple neural circuits and
mechanisms are implicated in SCZ symptom categories. Because the etiology of SCZ is unknown and valid SCZ
mouse models are not available, we focus on 22q11.2 deletion syndrome (22q11DS), the most common
microdeletion syndrome in humans, which increases the risk of SCZ 30 fold. Psychotic symptoms are clinically
indistinguishable in patients with SCZ with or without 22q11DS and usually appear during late adolescence/early
adulthood. Mouse models of 22q11DS (22q11DS mice) have been constructed and validated. Using these mice,
we and others have identified cellular and molecular mechanisms underlying some cognitive and negative
symptoms of 22q11DS. During the previous funding period, we also identified disrupted synaptic transmission
in thalamocortical (TC) projections between the auditory thalamus and auditory cortex (ACx) in 22q11DS mice.
Abnormal activity in these brain regions in humans is associated with auditory hallucinations. Disruption of TC
projections occurs in mice at 3.5 months, which corresponds to late adolescence/early adulthood in humans, the
age of positive symptom onset, and is rescued by antipsychotics and specific inhibitors of Drd2s. Our studies
revealed that the TC deficit is caused by reduced glutamate release from thalamic afferents, resulting from the
haploinsufficiency of the 22q11DS gene Dgcr8, which mediates microRNA (miR) biosynthesis. Dgcr8
haploinsufficiency leads to depletion of miR-338-3p, which in turn, elevates Drd2 levels in thalamic relay neurons.
Elevated Drd2s decrease glutamate release in thalamic neurons. The expression of miR-338-3p is enriched in
the thalamus and declines with age, which may underlie thalamus specificity and the mechanism of late onset
of TC disruption. Although the TC mechanism appears to satisfy requirements for mediating positive symptoms,
how it affects network activity in the ACx and auditory thalamus is unclear. In this competitive renewal application,
we propose to analyze abnormal spontaneous activity in neuronal ensembles in the ACx and auditory thalamus
in behaving mice. For the ACx, we will use 2-photon imaging through a cranial window, and for the auditory
thalamus, we will use a head-attached miniscope (1-photon imaging) or 2-photon imaging through graded index
lenses. We will also study the mechanisms underlying age-dependent decline in the expression of miR-338-3p
and connect it to the late onset of abnormal synchronicity in the ACx of 22q11DS models. This work...

## Key facts

- **NIH application ID:** 10148811
- **Project number:** 5R01MH097742-08
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL
- **Principal Investigator:** Stanislav S Zakharenko
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $470,098
- **Award type:** 5
- **Project period:** 2013-07-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10148811

## Citation

> US National Institutes of Health, RePORTER application 10148811, Towards understanding cellular mechanisms of positive symptoms of schizophrenia (5R01MH097742-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10148811. Licensed CC0.

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