The overall goal of this Mentored Research Career Award (K08) application is to provide training in innovative techniques that will permit the applicant to ask and answer the largest possible questions in translational mental health research. This research training plan has two overall objectives. The first is to train the applicant in new cutting-edge techniques to study gene expression in postmortem tissue. The second is for the applicant to learn how to perform and evaluate inducible gene deletion or overexpression in the rodent brain. To achieve these objectives, the applicant has planned a series of complementary educational and research training experiences, including formal coursework in biostatistics, bioinformatics, clinical epidemiology, genetics and signal transduction, as well as extended laboratory experiences with consultants to learn electrophysiology, laser capture microscopy (LCM), quantitative PCR, and gene manipulation techniques with viral vectors. In concert with this application's overall objectives, we have designed a research project that maximizes the applicant's exposure to innovative research methodologies and builds on his previous findings of glutamate transporter transcript abnormalities in schizophrenia. These data suggest abnormalities of glutamate transporter expression in corticothalamic circuits in schizophrenia. Accordingly, we hypothesize that expression and regulation of excitatory amino acid transporters (EAATs) is altered in corticothalamic circuits in schizophrenia, contributing to psychopathology in this illness. To evaluate this hypothesis we will measure EAAT mRNA expression in populations of microdissected cells and examine post-translational modification of EAAT proteins in subjects with schizophrenia and a control group. Guided by these human studies, we will then characterize the electrophysiological and neurochemical consequences associated with corticothalamic alterations of transporter gene expression generated using viral mediated gene transfer and/or the cre-loxP recombinase system. These studies will link identified changes in gene expression in schizophrenia with circuit specific alterations in glutamate synapse composition and function. At the conclusion of this set of experiments, the applicant will have learned innovative, state-of-the-art techniques for investigating abnormalities of gene expression and regulation in severe psychiatric illness, providing the tools needed to develop an independent research program. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08MH074016-02
Application #
7291607
Study Section
Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
Program Officer
Chavez, Mark
Project Start
2006-09-28
Project End
2011-08-31
Budget Start
2007-09-01
Budget End
2008-08-31
Support Year
2
Fiscal Year
2007
Total Cost
$174,446
Indirect Cost
Name
University of Alabama Birmingham
Department
Psychiatry
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
O'Donovan, Sinead M; Franco-Villanueva, Ana; Ghisays, Valentina et al. (2018) Sex differences in DEK expression in the anterior cingulate cortex and its association with dementia severity in schizophrenia. Schizophr Res 202:188-194
O'Donovan, Sinead Marie; Sullivan, Courtney; Koene, Rachael et al. (2018) Cell-subtype-specific changes in adenosine pathways in schizophrenia. Neuropsychopharmacology 43:1667-1674
Sullivan, Courtney R; O'Donovan, Sinead M; McCullumsmith, Robert E et al. (2018) Defects in Bioenergetic Coupling in Schizophrenia. Biol Psychiatry 83:739-750
O'Donovan, Sinead M; Sullivan, Courtney R; McCullumsmith, Robert E (2017) The role of glutamate transporters in the pathophysiology of neuropsychiatric disorders. NPJ Schizophr 3:32
McGuire, Jennifer L; Depasquale, Erica A; Funk, Adam J et al. (2017) Abnormalities of signal transduction networks in chronic schizophrenia. NPJ Schizophr 3:30
McCullumsmith, R E; O'Donovan, S M; Drummond, J B et al. (2016) Cell-specific abnormalities of glutamate transporters in schizophrenia: sick astrocytes and compensating relay neurons? Mol Psychiatry 21:823-30
McCullumsmith, Robert E; Hammond, John H; Shan, Dan et al. (2015) Postmortem brain: an underutilized substrate for studying severe mental illness. Neuropsychopharmacology 40:1307
Sullivan, Courtney R; Funk, Adam J; Shan, Dan et al. (2015) Decreased chloride channel expression in the dorsolateral prefrontal cortex in schizophrenia. PLoS One 10:e0123158
O'Donovan, S M; Hasselfeld, K; Bauer, D et al. (2015) Glutamate transporter splice variant expression in an enriched pyramidal cell population in schizophrenia. Transl Psychiatry 5:e579
Roberts, R C; Roche, J K; McCullumsmith, R E (2014) Localization of excitatory amino acid transporters EAAT1 and EAAT2 in human postmortem cortex: a light and electron microscopic study. Neuroscience 277:522-40

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