Abstract

This Research Career Development plan proposes a program of training and research designed to clarify the in vivo biological impact of variations in the gene encoding regulator of G-protein signaling subtype 4 (RGS4) polymorphisms in schizophrenia patients, individuals at risk for schizophrenia and matched healthy subjects. Demonstrating an association between genetic variations and intermediate phenotypes provides an important additional support for genetic association. RGS4 underexpression in the dorsolateral prefrontal cortex (DLPFC) of schizophrenia patients is reported. Subsequently, an association of RGS4 gene with schizophrenia has been reported in 7 independently ascertained populations in USA, Europe, india and Brazil. Our preliminary studies showed smaller DLPFC in schizophrenia patients homozygous for allele T of SNP4 and allele A of SNP18 but not in healthy subjects suggesting an interaction with other illness related variables. According to the neurodevelopmental hypothesis of schizophrenia pathogenic process starts prior to the emergence of clinical symptoms. Therefore, studying cerebral changes in persons at genetically high risk for developing schizophrenia who have not yet manifested the illness could minimize the confounds due to the illness. Smaller DLPFC was also observed in schizophrenia subjects homozygous for Val allele of the COMT gene that has also been associated with schizophrenia. The proposed study plans to utilize structural MRI and phosphorus magnetic resonance spectroscopy to characterize the differences in morphometry and membrane chemical (phosphomonoesters and phosphodiesters) concentrations associated with RGS4 variations in these study groups. We will explore the associations of these imaging measures with COMT polymorphisms. Characterizing intermediate phenotypes using """"""""cross-longitudinal"""""""" design helps in delineating longitudinal trajectory of cerebral correlates of genetic polymorphisms, designing novel medications and early detection.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23MH072995-02
Application #
7107958
Study Section
Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
Program Officer
Chavez, Mark
Project Start
2005-08-05
Project End
2010-07-31
Budget Start
2006-08-01
Budget End
2007-07-31
Support Year
2
Fiscal Year
2006
Total Cost
$175,375
Indirect Cost

  Institution

Name
University of Pittsburgh
Department
Psychiatry
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213

  Publications

Prasad, Konasale M; Chowdari, Kodavali V; D'Aiuto, Leonardo A et al. (2018) Neuropil contraction in relation to Complement C4 gene copy numbers in independent cohorts of adolescent-onset and young adult-onset schizophrenia patients-a pilot study. Transl Psychiatry 8:134
Prasad, Konasale M; Burgess, Ashley M; Keshavan, Matcheri S et al. (2016) Neuropil pruning in Early-Course Schizophrenia: Immunological, Clinical, and Neurocognitive Correlates. Biol Psychiatry Cogn Neurosci Neuroimaging 1:528-538
D'Aiuto, Leonardo; Prasad, Konasale M; Upton, Catherine H et al. (2015) Persistent infection by HSV-1 is associated with changes in functional architecture of iPSC-derived neurons and brain activation patterns underlying working memory performance. Schizophr Bull 41:123-32
Prasad, Konasale M; Upton, Catherine H; Nimgaonkar, Vishwajit L et al. (2015) Differential susceptibility of white matter tracts to inflammatory mediators in schizophrenia: an integrated DTI study. Schizophr Res 161:119-25
Prasad, Konasale M; Upton, Catherine H; Schirda, Claudiu S et al. (2015) White matter diffusivity and microarchitecture among schizophrenia subjects and first-degree relatives. Schizophr Res 161:70-5
Lener, M S; Goodnow, S J; Wood, J A et al. (2013) RGS4 and COMT risk variants are associated with brain structural alterations. Schizophr Res 150:321-2
Prasad, Konasale M; Eack, Shaun M; Keshavan, Matcheri S et al. (2013) Antiherpes virus-specific treatment and cognition in schizophrenia: a test-of-concept randomized double-blind placebo-controlled trial. Schizophr Bull 39:857-66
Yokley, Jessica L; Prasad, Konasale M; Chowdari, Kodavali V et al. (2012) Genetic associations between neuregulin-1 SNPs and neurocognitive function in multigenerational, multiplex schizophrenia families. Psychiatr Genet 22:70-81
Prasad, Konasale M; Watson, Annie M M; Dickerson, Faith B et al. (2012) Exposure to herpes simplex virus type 1 and cognitive impairments in individuals with schizophrenia. Schizophr Bull 38:1137-48
Stolz, Erin; Pancholi, Krishna M; Goradia, Dhruman D et al. (2012) Brain activation patterns during visual episodic memory processing among first-degree relatives of schizophrenia subjects. Neuroimage 63:1154-61

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