# Genetic and Synaptic Mechanisms of State Representation Impairments in Mice

> **NIH NIH P50** · UNIVERSITY OF MINNESOTA · 2021 · $529,040

## Abstract

PROJECT SUMMARY: PROJECT 2
The purpose of PROJECT 2 is to use mice as an experimental system to investigate cellular and synaptic
neurophysiology that captures core features of medial prefrontal cortex (mPFC) microcircuit dysfunction
that may be related to information processing failures in psychosis. The organizing premise of our Center is
that psychosis involves dysfunctional state representation processes, which we will study across species at
the behavioral level using the Dot Pattern Expectancy (DPX) task and the Bandit probabilistic reversal
learning task. Guided by published neurophysiology findings in the prefrontal cortex of nonhuman primates
after systemic NMDA receptor blockade, we propose to measure the coordinated activity of neuronal
ensembles in the medial prefrontal cortex of mice performing these two tasks.
In Aim 1, we will use genetic manipulations to selectively delete NMDA receptors from the medial
prefrontal cortex, while also testing the same pharmacological manipulation of NMDA receptors used in
PROJECT 1. In Aim 2, we will study mouse lines carrying the three most common genetic variants
associated with psychosis with genome-wide significance. Behavior and neurophysiology data will be
passed to the COMPUTATIONAL CORE, to conduct the same causal discovery analyses and
computational modeling used across all PROJECTS. In Aim 3, we will probe synaptic function in the
medial prefrontal cortex of each mutant mouse line, to determine whether differences in the synaptic
microcircuit (i.e., local connections between excitatory and inhibitory neurons) are related to behavioral and
disease phenotypes. Data from the synaptic level will be used to evaluate and inform the Neurophysiology-
Level attractor network model, which includes synaptic weights as key parameters. Our central hypothesis
is that mutant mice will exhibit synaptic dysfunction and related changes in mPFC neurophysiology, which
we expect to have a negative impact on various state representation processes. We expect to observe
heterogeneous impairments across different genetic manipulations, mirroring the heterogeneity present in
patient populations (PROJECTS 3 & 4), and providing fodder for computational modeling and causal
discovery analyses. Within our Center, these experiments provide a unique opportunity for precise
measurement and manipulation of both disease-related dysfunction and treatment-related plasticity in the
medial prefrontal cortex microcircuit, while translating results across species through computational
analyses.

## Key facts

- **NIH application ID:** 10123006
- **Project number:** 5P50MH119569-02
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Patrick Rothwell
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $529,040
- **Award type:** 5
- **Project period:** 2020-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10123006

## Citation

> US National Institutes of Health, RePORTER application 10123006, Genetic and Synaptic Mechanisms of State Representation Impairments in Mice (5P50MH119569-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10123006. Licensed CC0.

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