While the treatment of schizophrenia with antipsychotic medications revolutionized the clinical management of this illness, approximately one-third of patients with schizophrenia have persistent positive symptoms despite multiple trials of antipsychotic medicines. Recently, new strategies for the treatment of schizophrenia have emerged, including modulation of glutamate receptors, an approach which was developed, in part, based on an accumulating body of evidence of alterations in glutamate transmission from postmortem, imaging, and preclinical studies. While the initial glutamate hypothesis of schizophrenia was focused on NMDA receptor dysfunction, this hypothesis has been extended to include other glutamate receptors, transporters, and enzymes involved in glutamate transmission. Postmortem findings of changes in the expression of glutamatergic molecules in schizophrenia may be conceptualized as functional alterations of remodeled glutamate synapses, secondary to the underlying pathophysiology of chronic severe mental illness and a lifetime of treatment with psychotropic medications. We have found decreased expression of glial glutamate transporters in subjects with schizophrenia, suggesting that glutamate synapses have alterations in glutamate buffering and reuptake capacity. Glutamate transporters facilitate excitatory neurotransmission by limiting glutamate spillover to adjacent synapses, and we postulate that the localization of excitatory amino acid transporters (EAATs) is altered in corticothalamic circuits in schizophrenia, contributing to the psychopathology of this disease. Specifically, we hypothesize that cell-specific localization of EAATs is altered in schizophrenia. We also hypothesize that there are defects of trafficking and subcellular localization of EAATs in this illness. To evaluate these hypotheses, we will assess the localization of EAAT isoforms using immunofluorescence, subcellular fractionization, and Western blot analysis in postmortem tissue from subjects with schizophrenia and a comparison group. Our studies will focus on the dorsomedial nucleus of the thalamus and the anterior cingulate cortex, regions with dense reciprocal innervation that are implicated in the pathophysiology of this illness. We also plan to assess the effects of chronic typical and atypical antipsychotic treatment on localization of glutamate transporters in the rat brain. These rodent studies will provide novel data on the effects of chronic antipsychotic treatment on the composition of excitatory synapses, and compliment the interpretation of our postmortem findings, since most of these subjects were treated with antipsychotics. At the conclusion of this set of experiments, we will have tested the hypothesis that cellular and subcellular localization of glutamate transporters is altered in schizophrenia, suggesting decreased perisynaptic buffering and reuptake of glutamate and increased glutamate spillover. These studies will extend the glutamate hypothesis of schizophrenia beyond the NMDA receptor and provide new substrates for diagnosis and treatment of this often devastating illness.

Public Health Relevance

This project will identify the critical elements of brain function that contribute to the pathophysiology of schizophrenia. Identification of the molecular elements underlying schizophrenia will provide new targets 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 #
5R01MH094445-02
Application #
8298150
Study Section
Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
Program Officer
Meinecke, Douglas L
Project Start
2011-07-06
Project End
2016-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
2
Fiscal Year
2012
Total Cost
$329,625
Indirect Cost
$104,625
Name
University of Alabama Birmingham
Department
Psychiatry
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Funk, Adam J; Mielnik, Catharine A; Koene, Rachael et al. (2017) Postsynaptic Density-95 Isoform Abnormalities in Schizophrenia. Schizophr Bull 43:891-899
Dorsett, Christopher R; McGuire, Jennifer L; DePasquale, Erica A K et al. (2017) Glutamate Neurotransmission in Rodent Models of Traumatic Brain Injury. J Neurotrauma 34:263-272
Dorsett, Christopher R; McGuire, Jennifer L; Niedzielko, Tracy L et al. (2017) Traumatic Brain Injury Induces Alterations in Cortical Glutamate Uptake without a Reduction in Glutamate Transporter-1 Protein Expression. J Neurotrauma 34:220-234
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
Sullivan, Courtney R; O'Donovan, Sinead M; McCullumsmith, Robert E et al. (2017) Defects in Bioenergetic Coupling in Schizophrenia. Biol Psychiatry :
McGuire, Jennifer L; Depasquale, Erica A; Funk, Adam J et al. (2017) Abnormalities of signal transduction networks in chronic schizophrenia. NPJ Schizophr 3:30
LaCrosse, Amber L; O'Donovan, Sinead M; Sepulveda-Orengo, Marian T et al. (2017) Contrasting the Role of xCT and GLT-1 Upregulation in the Ability of Ceftriaxone to Attenuate the Cue-Induced Reinstatement of Cocaine Seeking and Normalize AMPA Receptor Subunit Expression. J Neurosci 37:5809-5821
Pinner, Anita L; Tucholski, Janusz; Haroutunian, Vahram et al. (2016) Decreased protein S-palmitoylation in dorsolateral prefrontal cortex in schizophrenia. Schizophr Res 177:78-87
Heaven, Michael R; Funk, Adam J; Cobbs, Archie L et al. (2016) Systematic evaluation of data-independent acquisition for sensitive and reproducible proteomics-a prototype design for a single injection assay. J Mass Spectrom 51:1-11
McMeekin, Laura J; Lucas, Elizabeth K; Meador-Woodruff, James H et al. (2016) Cortical PGC-1?-Dependent Transcripts Are Reduced in Postmortem Tissue From Patients With Schizophrenia. Schizophr Bull 42:1009-17

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