Disruptions of social affiliative and emotional behaviors are among the earliest-onset symptoms of schizophrenia, often beginning during adolescence or sometimes late childhood. The neurobiological mechanisms of these lifelong social behavior disabilities of schizophrenia are poorly understood, and effective treatments are lacking. However, multiple lines of evidence suggest that NMDA signaling and epigenetic mechanisms in amygdala circuits play important roles in early social behavior development. Project II will test the overall hypothesis that disruption of NMDA receptor signaling in basolateral amygdala (BLA) will disrupt early development of socioemotional behaviors, and that pharmacologic modulation of GABA signaling or epigenetic marks will rescue sociability development.
Specific Aim 1 : Determine the role of amygdala NMDA signaling in early development of socioemotional behaviors. Using behavioral studies of NMDA NR1 hypomorph mice or mice with amygdala-specific deletions of NMDA NR1, we will test the hypotheses that disruption of NMDA receptors in the amgydala will lead to reduced sociability in the social choice test, impaired fear conditioning, and reduced reward seeking behaviors starting in prepubescence, and that a GABA-B agonist or an HDAC inhibitor will rescue sociability development.
Specific Aim 2 : Determine the role of BLA cell types and epigenetic mechanisms in early development of social affiliative behaviors. Using double-labeling immunohistochemistry (Fos with markers of GABAergic or glutamatergic neurons) and Chip-Seq, we will test the hypothesis that mice with reduced sociability will show reduced activation of BLA GABAergic interneurons during social interactions, as well as increased DNA methylation and decreased histone acetylation in the BLA.
Specific Aim 3 : Determine the physiological activation of BLA in NMDA NR1 mutants across early development. We will test the hypothesis that NMDA NR1 hypomorphs will show decreased inhibition of BLA activity by stimulation of glutamatergic afferents to BLA, and that the relevant afferents will be primarily thalamus-BLA prior to puberty and prefrontal-BLA after puberty. These mechanistic studies may lead to development of novel treatments for negative symptoms of schizophrenia.

Public Health Relevance

Disruptions of social and emotional behaviors are some of the earliest-onset, most disabling, and most difficult-to-treat symptoms of schizophrenia. To better understand the brain mechanisms involved and open up new avenues for treatment, this project will use mouse models to test the role of glutamate signaling in the amygdala in early development of social and emotional behaviors relevant to schizophrenia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Specialized Center (P50)
Project #
5P50MH096891-02
Application #
8536949
Study Section
Special Emphasis Panel (ZMH1-ERB-S)
Project Start
Project End
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
2
Fiscal Year
2013
Total Cost
$320,581
Indirect Cost
$122,691
Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Fromer, Menachem; Roussos, Panos; Sieberts, Solveig K et al. (2016) Gene expression elucidates functional impact of polygenic risk for schizophrenia. Nat Neurosci 19:1442-1453
White, R S; Siegel, S J (2016) Cellular and circuit models of increased resting-state network gamma activity in schizophrenia. Neuroscience 321:66-76
Moore, Tyler M; Reise, Steven P; Roalf, David R et al. (2016) Development of an itemwise efficiency scoring method: Concurrent, convergent, discriminant, and neuroimaging-based predictive validity assessed in a large community sample. Psychol Assess 28:1529-1542
Roalf, David R; Quarmley, Megan; Elliott, Mark A et al. (2016) The impact of quality assurance assessment on diffusion tensor imaging outcomes in a large-scale population-based cohort. Neuroimage 125:903-19
Ferri, Sarah L; Kreibich, Arati S; Torre, Matthew et al. (2016) Activation of basolateral amygdala in juvenile C57BL/6J mice during social approach behavior. Neuroscience 335:184-94
Egbujo, Chijioke N; Sinclair, Duncan; Hahn, Chang-Gyu (2016) Dysregulations of Synaptic Vesicle Trafficking in Schizophrenia. Curr Psychiatry Rep 18:77
Carlson, G C; Lin, R E; Chen, Y et al. (2016) Dexras1 a unique ras-GTPase interacts with NMDA receptor activity and provides a novel dissociation between anxiety, working memory and sensory gating. Neuroscience 322:408-15
Moore, T M; Martin, I K; Gur, O M et al. (2016) Characterizing social environment's association with neurocognition using census and crime data linked to the Philadelphia Neurodevelopmental Cohort. Psychol Med 46:599-610
Gur, Ruben C; Gur, Raquel E (2016) Social cognition as an RDoC domain. Am J Med Genet B Neuropsychiatr Genet 171B:132-41
Barz, Claudia S; Bessaih, Thomas; Abel, Ted et al. (2016) Sensory encoding in Neuregulin 1 mutants. Brain Struct Funct 221:1067-81

Showing the most recent 10 out of 50 publications