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The role of glutamate transporters in the pathophysiology of neuropsychiatric disorders.

ABSTRACT: Altered glutamate transporter expression is a common feature of many neuropsychiatric conditions, including schizophrenia. Excitatory amino acid transporters (EAATs) are responsible for the reuptake of glutamate, preventing non-physiological spillover from the synapse. Postmortem studies have revealed significant dysregulation of EAAT expression in various brain regions at the cellular and subcellular level. Recent animal studies have also demonstrated a role for glutamate spillover as a mechanism of disease. In this review, we describe current evidence for the role of glutamate transporters in regulating synaptic plasticity and transmission. In neuropsychiatric conditions, EAAT splice variant expression is altered. There are changes in the localization of the transporters and disruption of the metabolic and structural protein network that supports EAAT activity. This results in aberrant neuroplasticity and excitatory signaling, contributing to the symptoms associated with neuropsychiatric disease. Understanding the complex functions of glutamate transporters will clarify the relevance of their role in the pathophysiology of neuropsychiatric disorders.

SUBMITTER: O'Donovan SM

PROVIDER: S-EPMC5608761 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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The role of glutamate transporters in the pathophysiology of neuropsychiatric disorders.

O'Donovan Sinead M SM Sullivan Courtney R CR McCullumsmith Robert E RE

NPJ schizophrenia 20170921 1

Altered glutamate transporter expression is a common feature of many neuropsychiatric conditions, including schizophrenia. Excitatory amino acid transporters (EAATs) are responsible for the reuptake of glutamate, preventing non-physiological spillover from the synapse. Postmortem studies have revealed significant dysregulation of EAAT expression in various brain regions at the cellular and subcellular level. Recent animal studies have also demonstrated a role for glutamate spillover as a mechani ...[more]

PMID: 28935880

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Project description:Glutamate is the primary excitatory neurotransmitter in the central nervous system (CNS) which initiates rapid signal transmission in the synapse before its re-uptake into the surrounding glia, specifically astrocytes. The astrocytic glutamate transporters glutamate-aspartate transporter (GLAST) and glutamate transporter-1 (GLT-1) and their human homologs excitatory amino acid transporter 1 (EAAT1) and 2 (EAAT2), respectively, are the major transporters which take up synaptic glutamate to maintain optimal extracellular glutamic levels, thus preventing accumulation in the synaptic cleft and ensuing excitotoxicity. Growing evidence has shown that excitotoxicity is associated with various neurological disorders, including amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), manganism, ischemia, schizophrenia, epilepsy, and autism. While the mechanisms of neurological disorders are not well understood, the dysregulation of GLAST/GLT-1 may play a significant role in excitotoxicity and associated neuropathogenesis. The expression and function of GLAST/GLT-1 may be dysregulated at the genetic, epigenetic, transcriptional or translational levels, leading to high levels of extracellular glutamate and excitotoxicity. Consequently, understanding the regulatory mechanisms of GLAST/GLT-1 has been an area of interest in developing therapeutics for the treatment of neurological disorders. Pharmacological agents including β-lactam antibiotics, estrogen/selective estrogen receptor modulators (SERMs), growth factors, histone deacetylase inhibitors (HDACi), and translational activators have shown significant efficacy in enhancing the expression and function of GLAST/GLT-1 and glutamate uptake both in vitro and in vivo. This comprehensive review will discuss the regulatory mechanisms of GLAST/GLT-1, their association with neurological disorders, and the pharmacological agents which mediate their expression and function. This article is part of the issue entitled 'Special Issue on Neurotransmitter Transporters'.

Dataset Information

The role of glutamate transporters in the pathophysiology of neuropsychiatric disorders.

Publications

The role of glutamate transporters in the pathophysiology of neuropsychiatric disorders.

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