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Evidence of Glutamatergic Dysfunction in the Pathophysiology of Schizophrenia

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Synaptic Stress and Pathogenesis of Neuropsychiatric Disorders

Abstract

Abnormalities of the glutamate system are widely recognized to be involved in the pathophysiology of schizophrenia, though the exact mechanism is still unclear. Accumulating evidence from postmortem studies has implicated alterations in several components of glutamatergic synapses, including abnormalities of glutamate receptors and transporters. These data support the hypothesis that expression, trafficking, and downstream signaling pathways of N-methyl-D-aspartate (NMDA) receptors are altered in this illness. Changes in glutamate transporter expression suggest there may be chronic glutamate spillover from the synaptic cleft, leading to increased activation of extrasynaptic glutamate receptors. We propose that changes in NMDA-subtype glutamate receptor function and glutamate transporter expression are components of a common pathophysiological pathway leading to the schizophrenia phenotype.

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Abbreviations

NMDA:

N-methyl-D-aspartate

CRH:

Corticotropin-releasing hormone

AMPAR:

α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor

GluA:

Glutamate receptor AMPA-subtype

EAAT:

Excitatory amino acid transporter

CSF:

Cerebrospinal fluid

PCP:

Phencyclidine

LTP:

Long-term potentiation

LTD:

Long-term depression

GluN:

Glutamate receptor NMDA-subtype

EEA1:

Early endosome Antigen

VGLUT:

Vesicular glutamate transporter

xCT:

Cystine-glutamate antiporter

PSD95:

Postsynaptic density 95

SynGAP:

Synaptic GTPase activating protein

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Authors and Affiliations

  1. Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, USA

    J.C. Hammond, D. Shan & J.H. Meador-Woodruff

  2. Department of Psychiatry and Behavioral Neuroscience, University of Cincinnat, Room E688B, 231 Albert Sabin Way, ML0583, PO Box 670583, 45267-0583, Cincinnati, OH, USA

    R.E. McCullumsmith

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  1. J.C. Hammond
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  2. D. Shan
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  3. J.H. Meador-Woodruff
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  4. R.E. McCullumsmith
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  1. Department of Pharmacological and Biomolecular Sciences, University of Milano, Milano, Italy

    Maurizio Popoli

  2. Department of Psychology, University of South Florida, Tampa, Florida, USA

    David Diamond

  3. Psychiatry Depression Research Program, Yale School of Medicine, New Haven, Connecticut, USA

    Gerard Sanacora

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Hammond, J., Shan, D., Meador-Woodruff, J., McCullumsmith, R. (2014). Evidence of Glutamatergic Dysfunction in the Pathophysiology of Schizophrenia. In: Popoli, M., Diamond, D., Sanacora, G. (eds) Synaptic Stress and Pathogenesis of Neuropsychiatric Disorders. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-1056-4_15

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