This is an application for a competing continuation of a grant line focused on receptor-based abnormalities in postmortem brain in schizophrenia. While we and others have published findings of abnormal glutamate receptor expression in the brain in schizophrenia, many findings have been subtle and often contradictory. These conflicting studies on the expression of NMDA and AMPA receptors led us in the last period of this grant and project to reconsider the "glutamate hypothesis of schizophrenia" not as "too many" or "too few" receptors, but rather one of alterations in the cell biological processes that manage the total pool of receptors. We hypothesized that there are abnormalities of ionotropic glutamate receptor trafficking, delivery, dendritic localization, recycling, and degradation in schizophrenia. Our overarching hypothesis was that there are changes in NMDA and AMPARs in the brain in schizophrenia that involve abnormalities of specific intracellular processes. The data we have generated from postmortem frontal cortex samples in schizophrenia over the past 5 years support this model, with evidence for accelerated exit from the endoplasmic reticulum (ER) and Golgi apparatus of AMPA and NMDAR complexes including changes in N-linked glycosylation and expression of ER exit and retention signals, abnormal forward trafficking of these receptors, and changes in endosomal content of the AMPA receptors at the dendritic spine. Taken together, these abnormalities are consistent with diminished NMDA and/or AMPAR function even though total cellular levels of these receptors appears to be normal. We hypothesize, based on our prior work, that a fundamental defect in these brains is abnormal handling of the ionotropic receptor complex at the postsynaptic density in the synapse, and the evidence for forward trafficking is homeostatically driven within the cell to overcome this deficiency. We propose in this application, using postmortem brain samples from persons with schizophrenia and a comparison group, to determine the specificity of our findings to the NMDA and AMPARs as well as to the frontal cortex;to determine the extent of abnormality of N-linked and O-linked glycosylation of key proteins associated with glutamatergic neurotransmission;to examine intracellular proteins and posttranslational modifications associated with trafficking and synaptic targeting;and directly examine expression of these receptors in the postsynaptic density and other perisynaptic compartments. These data will permit us to test our model of schizophrenia being associated with abnormality of glutamate receptor dynamics in the dendritic spine.

Public Health Relevance

This project will identify abnormalities of glutamate receptor expression and regulation in the brain in schizophrenia. Identification of the molecular defects underlying schizophrenia will provide new leads for the development of medicines to treat this illness.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH053327-18
Application #
8460936
Study Section
Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
Program Officer
Meinecke, Douglas L
Project Start
1995-07-01
Project End
2016-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
18
Fiscal Year
2013
Total Cost
$405,666
Indirect Cost
$128,761
Name
University of Alabama Birmingham
Department
Psychiatry
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
McCullumsmith, Robert E; Hammond, John H; Shan, Dan et al. (2014) Postmortem brain: an underutilized substrate for studying severe mental illness. Neuropsychopharmacology 39:65-87
McGuire, Jennifer L; Hammond, John H; Yates, Stefani D et al. (2014) Altered serine/threonine kinase activity in schizophrenia. Brain Res 1568:42-54
Tucholski, Janusz; Pinner, Anita L; Simmons, Micah S et al. (2014) Evolutionarily conserved pattern of AMPA receptor subunit glycosylation in Mammalian frontal cortex. PLoS One 9:e94255
Pinner, Anita L; Haroutunian, Vahram; Meador-Woodruff, James H (2014) Alterations of the myristoylated, alanine-rich C kinase substrate (MARCKS) in prefrontal cortex in schizophrenia. Schizophr Res 154:36-41
Mueller, Toni Marie; Haroutunian, Vahram; Meador-Woodruff, James H (2014) N-Glycosylation of GABAA receptor subunits is altered in Schizophrenia. Neuropsychopharmacology 39:528-37
Shan, Dan; Mount, Daniel; Moore, Stephen et al. (2014) Abnormal partitioning of hexokinase 1 suggests disruption of a glutamate transport protein complex in schizophrenia. Schizophr Res 154:1-13
Funk, Adam J; Haroutunian, Vahram; Meador-Woodruff, James H et al. (2014) Increased G protein-coupled receptor kinase (GRK) expression in the anterior cingulate cortex in schizophrenia. Schizophr Res 159:130-5
Rubio, Maria D; Wood, Krista; Haroutunian, Vahram et al. (2013) Dysfunction of the ubiquitin proteasome and ubiquitin-like systems in schizophrenia. Neuropsychopharmacology 38:1910-20
Drummond, Jana B; Tucholski, Janusz; Haroutunian, Vahram et al. (2013) Transmembrane AMPA receptor regulatory protein (TARP) dysregulation in anterior cingulate cortex in schizophrenia. Schizophr Res 147:32-8
Tucholski, Janusz; Simmons, Micah S; Pinner, Anita L et al. (2013) N-linked glycosylation of cortical N-methyl-D-aspartate and kainate receptor subunits in schizophrenia. Neuroreport 24:688-91

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