Reduced plasma membrane surface expression of GLAST mediates decreased glutamate regulation in the aged striatum

Nickell, Justin R.; Salvatore, Michael F.; Pomerleau, François; Apparsundaram, Subbu; Gerhardt, Greg A.

doi:10.1016/j.neurobiolaging.2006.07.015

Cited by 40 publications

(42 citation statements)

References 71 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previous research in our lab found that changes in clearance parameters were correlated with changes in the surface expression of Glu transporters (Nickell et al, 2007). Previous studies for DA in the Str, and NAc of F344 rats demonstrated that signal amplitudes of the applied neurotransmitter normalized for the amount applied, was correlated with B max -values for DA transporters (as assessed by radioligand binding and uptake studies; Hebert and Gerhardt, 1999).…”

Section: Discussionmentioning

confidence: 68%

Decreased Dopamine D4 Receptor Expression Increases Extracellular Glutamate and Alters Its Regulation in Mouse Striatum

Thomas

Grandy

Gerhardt

et al. 2008

Neuropsychopharmacol

View full text Add to dashboard Cite

To better understand the effect of the dopamine D4 receptor (DRD4) on glutamate (Glu) neurotransmission in the brain, we utilized transgenic mice with partial or complete removal of functional DRD4 plasma membrane expression (DRD4 + /À and DRD4À/À, respectively). We measured resting extracellular Glu levels, Glu clearance kinetics, and KCl-evoked release of Glu in the striatum and nucleus accumbens core of these mice using in vivo amperometry coupled to a novel microelectrode array configured for sub-second detection of Glu. Recordings from DRD4À/À and DRD4 + /À mice were compared with their wild-type littermates (DRD4 + / + ). Resting extracellular levels of Glu were increased in the striatum of DRD4À/À mice (po0.01). Glu clearance kinetics were significantly decreased in the dorsal striatum of DRD4À/À mice (po0.05). KCl-evoked overflow of Glu was reliably measured but unchanged in the striatum of the three groups. By contrast, no changes in resting Glu, Glu uptake kinetics, or KCl-evoked release of Glu were observed in the nucleus accumbens core among the three genotypes. These data indicate that the DRD4 receptor is involved in modulation of Glu neurotransmission, primarily in the striatum. A better understanding of Glu control by the DRD4 may improve our understanding of the physiological role of the DRD4 in disorders such as attention-deficit/hyperactivity disorder and schizophrenia.

show abstract

Section: Discussionmentioning

confidence: 68%

Decreased Dopamine D4 Receptor Expression Increases Extracellular Glutamate and Alters Its Regulation in Mouse Striatum

Thomas

Grandy

Gerhardt

et al. 2008

Neuropsychopharmacol

View full text Add to dashboard Cite

show abstract

“…A few previous studies have addressed the status of glutamate uptake during aging, and most have reported a lowered uptake and a loss of glutamate transporter sites in the glutamatergic terminals of aged rodents (Wheeler & Ondo, 1986;Najlerahim et al, 1990;Saransaari & Oja, 1995;Vatassery et al, 1998). More recently, in vivo voltammetric recordings have demonstrated that the loss of plasma membrane GLAST transporters in the striatum of aged Fisher 344 rats is correlated with an increased clearance time ⁄ slower clearance of glutamate (Nickell et al, 2007). The fact that the bulk of functional glutamate transport is undertaken by GLT-1 and GLAST (Rothstein et al, 1996) underlines the importance of their alteration in aged animals.…”

Section: Discussionmentioning

confidence: 99%

Reduction in glutamate uptake is associated with extrasynaptic NMDA and metabotropic glutamate receptor activation at the hippocampal CA1 synapse of aged rats

et al. 2010

View full text Add to dashboard Cite

SummaryThis study aims to determine whether the regulation of extracellular glutamate is altered during aging and its possible consequences on synaptic transmission and plasticity. A decrease in the expression of the glial glutamate transporters GLAST and GLT-1 and reduced glutamate uptake occur in the aged (24-27 months) SpragueDawley rat hippocampus. Glutamatergic excitatory postsynaptic potentials recorded extracellularly in ex vivo hippocampal slices from adult (3-5 months) and aged rats are depressed by DL-TBOA, an inhibitor of glutamate transporter activity, in an N-Methyl-D-Aspartate (NMDA)-receptor-dependent manner. In aged but not in young rats, part of the depressing effect of DL-TBOA also involves metabotropic glutamate receptor (mGluRs) activation as it is significantly reduced by the specific mGluR antagonist d-methyl-4-carboxy-phenylglycine (MCPG). The paired-pulse facilitation ratio, a functional index of glutamate release, is reduced by MCPG in aged slices to a level comparable to that in young rats both under control conditions and after being enhanced by DL-TBOA. These results suggest that the age-associated glutamate uptake deficiency favors presynaptic mGluR activation that lowers glutamate release. In parallel, 2 Hz-induced long-term depression is significantly decreased in aged animals and is fully restored by MCPG. All these data indicate a facilitated activation of extrasynaptic NMDAR and mGluRs in aged rats, possibly because of an altered distribution of glutamate in the extrasynaptic space. This in turn affects synaptic transmission and plasticity within the aged hippocampal CA1 network.

show abstract

“…A better understanding of the role of glutamate in the trans-synaptic spread of pathology could facilitate our understanding of risk factors for AD. For example, aging, the greatest known risk factor for AD, is associated with a decline in glutamate transporters and uptake [173,174], leading to higher levels of extracellular glutamate [175]. This age-related increase in extracellular glutamate results in greater activation of extrasynaptic NMDARs [176,177] and could potentially be permissive for the spread of Aβ and tau pathology through vulnerable networks.…”

Section: Future Directionsmentioning

confidence: 99%

The Role of the Tripartite Glutamatergic Synapse in the Pathophysiology of Alzheimer’s Disease

Rudy¹,

Hunsberger²,

Weitzner³

et al. 2015

Aging and disease

133

106

View full text Add to dashboard Cite

Alzheimer's disease (AD) is the most common form of dementia in individuals over 65 years of age and is characterized by accumulation of beta-amyloid (Aβ) and tau. Both Aβ and tau alter synaptic plasticity, leading to synapse loss, neural network dysfunction, and eventually neuron loss. However, the exact mechanism by which these proteins cause neurodegeneration is still not clear. A growing body of evidence suggests perturbations in the glutamatergic tripartite synapse, comprised of a presynaptic terminal, a postsynaptic spine, and an astrocytic process, may underlie the pathogenic mechanisms of AD. Glutamate is the primary excitatory neurotransmitter in the brain and plays an important role in learning and memory, but alterations in glutamatergic signaling can lead to excitotoxicity. This review discusses the ways in which both beta-amyloid (Aβ) and tau act alone and in concert to perturb synaptic functioning of the tripartite synapse, including alterations in glutamate release, astrocytic uptake, and receptor signaling. Particular emphasis is given to the role of N-methyl-D-aspartate (NMDA) as a possible convergence point for Aβ and tau toxicity.

show abstract

Reduced plasma membrane surface expression of GLAST mediates decreased glutamate regulation in the aged striatum

Cited by 40 publications

References 71 publications

Decreased Dopamine D4 Receptor Expression Increases Extracellular Glutamate and Alters Its Regulation in Mouse Striatum

Decreased Dopamine D4 Receptor Expression Increases Extracellular Glutamate and Alters Its Regulation in Mouse Striatum

Reduction in glutamate uptake is associated with extrasynaptic NMDA and metabotropic glutamate receptor activation at the hippocampal CA1 synapse of aged rats

The Role of the Tripartite Glutamatergic Synapse in the Pathophysiology of Alzheimer’s Disease

Contact Info

Product

Resources

About