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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
2R01MH067234-11A1
Application #
9243758
Study Section
Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
Program Officer
Meinecke, Douglas L
Project Start
2003-07-01
Project End
2022-02-28
Budget Start
2017-03-01
Budget End
2018-02-28
Support Year
11
Fiscal Year
2017
Total Cost
$405,043
Indirect Cost
$128,435
Name
University of Nebraska Medical Center
Department
Psychiatry
Type
Schools of Medicine
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
Garbett, Krassimira A; Vereczkei, Andrea; Kálmán, Sára et al. (2015) Coordinated messenger RNA/microRNA changes in fibroblasts of patients with major depression. Biol Psychiatry 77:256-65
Brown, J A; Ramikie, T S; Schmidt, M J et al. (2015) Inhibition of parvalbumin-expressing interneurons results in complex behavioral changes. Mol Psychiatry 20:1499-507
Schmidt, Martin J; Mirnics, Karoly (2015) Neurodevelopment, GABA system dysfunction, and schizophrenia. Neuropsychopharmacology 40:190-206
Horváth, Szatmár; Mirnics, Károly (2015) Schizophrenia as a disorder of molecular pathways. Biol Psychiatry 77:22-8
Garbett, K A; Vereczkei, A; Kálmán, S et al. (2015) Fibroblasts from patients with major depressive disorder show distinct transcriptional response to metabolic stressors. Transl Psychiatry 5:e523
Kalman, Sara; Garbett, Krassimira A; Vereczkei, Andrea et al. (2014) Metabolic stress-induced microRNA and mRNA expression profiles of human fibroblasts. Exp Cell Res 320:343-53
Korade, Zeljka; Mirnics, Károly (2014) Programmed to be human? Neuron 81:224-6
Horváth, Szatmár; Mirnics, Károly (2014) Clues from the cloud. Am J Psychiatry 171:705-8
Horvath, Szatmar; Mirnics, Karoly (2014) Immune system disturbances in schizophrenia. Biol Psychiatry 75:316-23
Brown, Jacquelyn A; Horvath, Szatmar; Garbett, Krassimira A et al. (2014) The role of cannabinoid 1 receptor expressing interneurons in behavior. Neurobiol Dis 63:210-21

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