This project aims to investigate genomic underpinnings for NMDAR hypofunction in schizophrenia and its possible association with the behavioral phenotypes of asociality during development. NMDARs exist as a macromolecular complex, in which members of various pathways can interact and influence NMDAR funcfion. Thus, the NMDAR pathway could be a molecular substrate for convergent interacfions of genefic variants that can lead to behavioral phenotypes of schizophrenia. We hypothesize that the NMDAR pathway as a whole may contain common and rare genetic variants that are enriched in schizophrenia. Some of these variants may impact the function of basolateral amygdala (BLA) via modulation of gene transcripts. As such, they may play a critical role for the expression of behavioral traits of asociality during development. The NMDAR pathway is highly represented in the BLA transcriptome and our recent GWAS study has shown that common variants of the NMDAR pathways as a whole were associated with schizophrenia. To assess the genomic impact of NMDAR pathway on negative symptoms, we will conduct deep sequencing for NMDAR pathway genes in DNAs from 100 patients with schizophrenia. To assess their roles in BLA function, we will analyze the transcriptome of postmortem BLAs of 50 schizophrenia patients and their matched controls using RNA-Seq, which will then be tested for their association with DNA variants. Genetic variants linked to transcript alterations in the BLA with may play a role in the expression of schizophrenia phenotypes during development. We will assess the association between NMDAR pathway genetic variants that can modulate BLA transcripts with asociality behavioral phenotypes of 1000 adolescents who have been examined by GWAS and behavioral phenotypes.

Public Health Relevance

This project aims to investigate genomic underpinnings for NMDAR hypofunction in schizophrenia and its possible association with the behavioral phenotypes of asociality during development. NMDARs exist as a macromolecular complex, in which members of various pathways can interact and influence NMDAR function. Thus, the NMDAR pathway could be a molecular substrate for convergent interactions of genetic variants that can lead to behavioral phenotypes of schizophrenia.

Agency
National Institute of Health (NIH)
Type
Specialized Center (P50)
Project #
5P50MH096891-03
Application #
8704389
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