The role of glutamate transporters in neurodegenerative diseases and potential opportunities for intervention

Abstract

Extracellular concentrations of the predominant excitatory neurotransmitter, glutamate, and related excitatory amino acids are maintained at relatively low levels to ensure an appropriate signal-to-noise ratio and to prevent excessive activation of glutamate receptors that can result in cell death. The latter phenomenon is known as 'excitotoxicity' and has been associated with a wide range of acute and chronic neurodegenerative disorders, as well as disorders that result in the loss of non-neural cells such as oligodendroglia in multiple sclerosis. Unfortunately clinical trials with glutamate receptor antagonists that would logically seem to prevent the effects of excessive receptor activation have been associated with untoward side effects or little clinical benefit. In the mammalian CNS, the extracellular concentrations of glutamate are controlled by two types of transporters; these include a family of Na(+)-dependent transporters and a cystine-glutamate exchange process, referred to as system X(c)(-). In this review, we will focus primarily on the Na(+)-dependent transporters. A brief introduction to glutamate as a neurotransmitter will be followed by an overview of the properties of these transporters, including a summary of the presumed physiologic mechanisms that regulate these transporters. Many studies have provided compelling evidence that impairing the function of these transporters can increase the sensitivity of tissue to deleterious effects of aberrant activation of glutamate receptors. Over the last decade, it has become clear that many neurodegenerative disorders are associated with a change in localization and/or expression of some of the subtypes of these transporters. This would suggest that therapies directed toward enhancing transporter expression might be beneficial. However, there is also evidence that glutamate transporters might increase the susceptibility of tissue to the consequences of insults that result in a collapse of the electrochemical gradients required for normal function such as stroke. In spite of the potential adverse effects of upregulation of glutamate transporters, there is recent evidence that upregulation of one of the glutamate transporters, GLT-1 (also called EAAT2), with beta-lactam antibiotics attenuates the damage observed in models of both acute and chronic neurodegenerative disorders. While it seems somewhat unlikely that antibiotics specifically target GLT-1 expression, these studies identify a potential strategy to limit excitotoxicity. If successful, this type of approach could have widespread utility given the large number of neurodegenerative diseases associated with decreases in transporter expression and excitotoxicity. However, given the massive effort directed at developing glutamate receptor agents during the 1990s and the relatively modest advances to date, one wonders if we will maintain the patience needed to carefully understand the glutamatergic system so that it will be successfully targeted in the future.

The mGluR2/3 Agonist LY379268 Blocks the Effects of GLT-1 Upregulation on Prepulse Inhibition of the Startle Reflex in Adult Rats

“…For its fundamental role in regulating Glu levels, GLT-1 is involved in the pathophysiology of several neuropsychiatric diseases (Beart and O'Shea, 2007;Lauriat and McInnes, 2007;Sheldon and Robinson, 2007). Some evidence suggests a role for GLT-1 in the pathophysiology of schizophrenia as follows: (1) a susceptibility locus for schizophrenia is probably located within or near the GLT-1 gene (Deng et al, 2004), and this gene is reportedly dysregulated in patients with schizophrenia (Shao and Vawter, 2008); (2) GLT-1 immunoreactivity is increased in the thalamus, striatum, and prefrontal cortex of schizophrenia patients McCullumsmith and Meador-Woodruff, 2002;Smith et al, 2001); (3) the antipsychotic clozapine specifically downregulates GLT-1 expression and function both in vivo and in vitro (Melone et al, 2001(Melone et al, , 2003VallejoIllarramendi et al, 2005); (4) the psychotomimetics PCP specifically upregulates GLT-1 expression and function (Fattorini et al, 2008); and (5) pharmacologically induced GLT-1 upregulation is associated with an impairment of the prepulse inhibition (PPI) of the startle reflex, a neurophysiological parameter altered in schizophrenia patients and in animal models of schizophrenia, in a dihydrokainate (DHK)-reversible manner, and worsens PCP-induced PPI alterations Melone et al, 2009b).…”

Reactive astrocytosis and glial glutamate transporter clustering are early changes in a spinocerebellar ataxia type 1 transgenic mouse model

“…The role of neuron-glia interactions is also being investigated in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (Sheldon and Robinson, 2007). Moreover, glial dysfunction is likely to contribute to the pathogenesis of cerebellar ataxia in a mouse model of spinocerebellar ataxia type 7 (SCA7) (Custer et al, 2006).…”

Nanofiber mat spinal cord dressing-released glutamate impairs blood-spinal cord barrier

“…Its physiological content in the nervous tissue corresponds with the metabolic demand of the cells, and the BBB and BSCB protect CNS parenchyma from an influx of excessive extra-CNS glutamate amounts [26]. It is common knowledge that CNS glutamate concentration is greatly elevated in many CNS pathologies [23,35,43,48]. It has been demonstrated as well that the considerable ischemia-related elevation of intracerebral glutamate results in BBB damage and brain edema [41].…”