# Project 3

> **NIH NIH P50** · JOHNS HOPKINS UNIVERSITY · 2020 · $264,520

## Abstract

Abstract (Project 3)
Recent clinical studies that examine prodromal subjects and recent-onset schizophrenia (SZ) have indicated
that stress-associated pathways are activated prior to and at the onset of the disease, in contrast to milder
changes of the pathways in the chronic stages. In addition, human postmortem studies have demonstrated
changes in dendritic spines of pyramidal neurons and parvalbumin (PV)-positive interneurons. These are key
neural substrates for the excitatory-inhibitory (E-I) imbalance in prefrontal cortical (PFC) neuronal networks
underlying cognitive deficits in SZ. Our preliminary data show changes in stress-associated molecules and
interneurons in adolescence and young adulthood in mouse models that display altered adult behaviors
relevant to SZ. These models carry genetic perturbations of microtubule-associated molecules and show mild
deficits in early neurodevelopment. Based on this background, we propose the following two Aims: Aim 1 will
determine and characterize the critical periods for changes in stress-associated cascades and E-I imbalance in
several genetic mouse models with mild brain deficits in early development elicited by microtubule-associated
genes; and Aim 2 will study the mechanisms of neurocircuitry-based behavioral changes associated with
medial PFC (mPFC) and orbitofrontal cortex (OFC), such as working memory deficits and behavioral
inflexibility. We will also investigate whether adolescent social isolation exacerbates the pathological
signatures. Finally, we will intervene with the stress pathways in a molecule, cell type and brain region-specific
manner during adolescence to try to rescue adult phenotypes (physiology, behavior). We believe the proposed
study is innovative and will lead to the development of new tools for early diagnosis and intervention in
cognitive deficits relevant to SZ and related mental disorders.

## Key facts

- **NIH application ID:** 9978141
- **Project number:** 5P50MH094268-10
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Akira Sawa
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $264,520
- **Award type:** 5
- **Project period:** 2011-07-12 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9978141

## Citation

> US National Institutes of Health, RePORTER application 9978141, Project 3 (5P50MH094268-10). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9978141. Licensed CC0.

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