# Effects Of Environmental Challenges On Genetically Modified Interneuronal Subpopulations

> **NIH NIH R01** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2021 · $384,790

## Abstract

Reduction of the transcript encoding glutamic acid decarboxylase 67kDa (GAD67, encoded by the Gad1 gene)
is perhaps the most robust and consistently replicated finding across different cohorts of schizophrenia. Yet
this downregulation is complex: GAD67, the critical GABA synthesis enzyme in the brain, is simultaneously
reduced in distinct interneuron populations of the human cortex. Over the last 5 years we generated and
characterized five distinct, GFP/RFP-labeled, Gad1 hypomorph mice under the control of Sst, Npy, Cck, Cnr1
and Pvalb BAC promoters. Although the same gene was downregulated (Gad1), the five transgenic mice
showed distinct, well-defined behavioral phenotypes depending on which interneuronal subpopulation was
targeted. In this application we selected two animal lines for further follow-up. The Pvalb-driven/Gad1-
hypomorph (Pvalb/Gad1) and Npy-driven/Gad1-hypomorph (Npy/Gad1) transgenic mice were chosen based
on literature findings, their reported behavioral phenotypes, as well as their different mechanism of inhibition
(synaptic vs. volumetric). These two mouse lines showed divergent behavioral phenotypes: the Npy/Gad1
animals were hypersensitive to amphetamine challenge, while fear and novelty seeking were the primarily
impacted behavioral domains in the Pvalb/Gad1 animals. This proposal focuses on Gene*Environment (G*E)
interaction, and asks how does the transgenic mouse phenotypes change when we expose them to
schizophrenia-predisposing environmental challenges. We hypothesize that Pvalb/Gad1 and Npy/Gad1
transgenic mice will show enhanced susceptibility when exposed to maternal immune activation,
resulting in emergence of novel, disease-relevant phenotypes. In Aim 1 we will perform maternal immune
activation (MIA) of Pvalb/Gad1 transgenic mice and matched controls, and establish their molecular/behavioral
phenotype at adulthood using RNA-seq, neurochemical measures in striatum, hippocampus and frontal cortex,
a battery of behavioral tests at baseline and under challenge with ketamine and amphetamine, and a rescue of
phenotype will be attempted by clozapine. In Aim 2 will perform the same experiments using Npy/Gad1
transgenic muse model and establish the resulting molecular/behavioral phenotypes with methods described in
Aim 1. Finally, Aim 3 will compare the obtained transcriptome findings in Aims 1-2 to human postmortem
datasets from patients with neuropsychiatric and neurodevelopmental disorders. The significance of the
proposal comes from our approach, which is trying to understand the cell-type specific building blocks of
behavior (especially those that show alteration in schizophrenia) and how are they influenced by environmental
factors. We are also taking advantage of a novel technology developed in the previous grant cycle, and use
our unique BAC-driven/miRNA-mediated silencing mice as a novel model for ascertaining of the environmental
effects on brain function and behavior.

## Key facts

- **NIH application ID:** 10111560
- **Project number:** 5R01MH067234-15
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Karoly Mirnics
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $384,790
- **Award type:** 5
- **Project period:** 2003-07-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10111560

## Citation

> US National Institutes of Health, RePORTER application 10111560, Effects Of Environmental Challenges On Genetically Modified Interneuronal Subpopulations (5R01MH067234-15). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10111560. Licensed CC0.

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