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)
Type
Specialized Center (P50)
Project #
5P50MH096891-03
Application #
8704386
Study Section
Special Emphasis Panel (ZMH1)
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Type
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Tatard-Leitman, Valerie M; Jutzeler, Catherine R; Suh, Jimmy et al. (2015) Pyramidal cell selective ablation of N-methyl-D-aspartate receptor 1 causes increase in cellular and network excitability. Biol Psychiatry 77:556-68
Billingslea, Eddie N; Tatard-Leitman, Valerie M; Anguiano, Jaynie et al. (2014) Parvalbumin cell ablation of NMDA-R1 causes increased resting network excitability with associated social and self-care deficits. Neuropsychopharmacology 39:1603-13
Stujenske, Joseph M; Likhtik, Ekaterina; Topiwala, Mihir A et al. (2014) Fear and safety engage competing patterns of theta-gamma coupling in the basolateral amygdala. Neuron 83:919-33
Likhtik, Ekaterina; Gordon, Joshua A (2014) Circuits in sync: decoding theta communication in fear and safety. Neuropsychopharmacology 39:235-6
Kumar, Manoj; Duda, Jeffery T; Hwang, Wei-Ting et al. (2014) High resolution magnetic resonance imaging for characterization of the neuroligin-3 knock-in mouse model associated with autism spectrum disorder. PLoS One 9:e109872
Likhtik, Ekaterina; Stujenske, Joseph M; Topiwala, Mihir A et al. (2014) Prefrontal entrainment of amygdala activity signals safety in learned fear and innate anxiety. Nat Neurosci 17:106-13
Duman, Ronald S (2014) Pathophysiology of depression and innovative treatments: remodeling glutamatergic synaptic connections. Dialogues Clin Neurosci 16:11-27