# Reverse Translation of Psychosis - associated Hippocampal Hyperactivity in the mouse

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $410,000

## Abstract

ABSTRACT
The hippocampus has been implicated in numerous functions related to normal memory and its dysfunction in
several diseases. Our lab has investigated the hippocampus in relation to schizophrenia (SZ) pathophysiology
using cognitive and behavioral outcomes(1-3) and brain image analyses(4-6). These consistently show that
hippocampal (Hipp) activity is elevated in schizophrenic psychosis (SZ), especially in early illness. To test the
molecular basis of this hyperactivity, we examined human postmortem hippocampal tissue by subfield,
contrasting healthy and schizophrenia cases, using excitatory and inhibitory synaptic markers and Golgi. We
found a reduction in GluN1 limited to dentate gyrus (DG) and an increase in markers of synaptic strength in CA3
in the SZ tissue; these changes are consistent with the observations that Lee et al(7) reported in hippocampal
cell cultures (see A.1). Lee showed that CA3 pyramidal cell sensitivity is inversely and powerfully controlled by
afferent input from DG, with decreased afferent input associated with increased pyramidal cell activity. We have
been able to recapitulate this human-specific SZ pathology in a mouse using a DG-selective GluN1 knock out
(KO)(8). This back-translation mouse KO demonstrated Hipp hyperactivity and alterations in Hipp-mediated
behaviors (8). We are piloting an inhibitory DREADD technique in DG to mimic the DG-selective GluN1 KO
mouse and saw evidence of a sensitive period during ‘adolescence’, when reduced DG activity could stimulate
hyperactivity in CA3/CA1. This time phase cannot be resolved in the KO animal, so we had not seen it before
and can only study it using DREADDs. The goal of these experiments are to causally define the mechanisms
underlying the neurobiological outcomes of temporary DG hypofunction in mouse using DREADD constructs,
and to show the extent, development, and critical periods of vulnerability of brain-wide changes. Having found
a discrete circuit of Hipp projection regions hyperactive in the KO mouse, we will test human SZ vs HC tissue in
these regions for evidence of hyperactivity and coherence with Hipp. The goal is to build a model of how
hippocampal hyperactivity affects behavior and brain pathology, and specifically how this tissue pathology could
support aberrant memories with psychotic content.

## Key facts

- **NIH application ID:** 10873761
- **Project number:** 5R01MH123479-04
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Carol A Tamminga
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $410,000
- **Award type:** 5
- **Project period:** 2021-09-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10873761

## Citation

> US National Institutes of Health, RePORTER application 10873761, Reverse Translation of Psychosis - associated Hippocampal Hyperactivity in the mouse (5R01MH123479-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10873761. Licensed CC0.

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