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.
We are trying to understand how different inhibitory brain cell types control various behaviors, focusing on those with different mechanisms of action. Furthermore, we are trying to understand how this process is influenced by prenatal maternal immune challenge. We are taking advantage of a novel transgenic mouse technology developed in the previous grant cycle.
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