Adenosine triphosphate depletion reverses sodium-dependent, neuronal uptake of glutamate in rat hippocampal slices

Madl, James E.; Burgesser, Kent M.

doi:10.1523/jneurosci.13-10-04429.1993

Cited by 147 publications

(70 citation statements)

References 47 publications

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“…The expression of GLT1a in axon terminals has potentially important implications for the physiology of excitatory synaptic transmission in regulating synaptic glutamate, maintaining glutamate stores in the presynaptic terminal, interacting with glutamate receptors, contributing a glutamate regulated anionic conductance to the plasma membrane of the presynaptic bouton, and controlling cross-talk between excitatory synapses. This finding is also of potential importance in understanding the pathogenesis of excitotoxic injury, because the presynaptic excitatory terminal has been thought to be a major source of the glutamate that accumulates to pathological levels in the setting of energy failure, and reversal of glutamate transporters has been hypothesized to be an important mechanism for this accumulation (Szatkowski et al, 1990;Ottersen et al, 1992;Storm-Mathisen et al, 1992;Madl and Burgesser, 1993;Rossi et al, 2000;Mitani and Tanaka, 2003). If GLT1 is the principal glutamate transporter associated with excitatory axon terminals, then GLT1 is specifically implicated in multiple important physiological and pathological processes.…”

Section: Significance Of Expression Of Glt1 In Axon Terminalsmentioning

confidence: 98%

The Glutamate Transporter GLT1a Is Expressed in Excitatory Axon Terminals of Mature Hippocampal Neurons

Chen¹,

Mahadomrongkul²,

Berger³

et al. 2004

J. Neurosci.

248

250

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GLT1 is the major glutamate transporter of the brain and has been thought to be expressed exclusively in astrocytes. Although excitatory axon terminals take up glutamate, the transporter responsible has not been identified. GLT1 is expressed in at least two forms varying in the C termini, GLT1a and GLT1b. GLT1 mRNA has been demonstrated in neurons, without associated protein. Recently, evidence has been presented, using specific C terminus-directed antibodies, that GLT1b protein is expressed in neurons in vivo. These data suggested that the GLT1 mRNA detected in neurons encodes GLT1b and also that GLT1b might be the elusive presynaptic transporter. To test these hypotheses, we used variant-specific probes directed to the 3Ј-untranslated regions for GLT1a and GLT1b to perform in situ hybridization in the hippocampus. Contrary to expectation, GLT1a mRNA was the more abundant form. To investigate further the expression of GLT1 in neurons in the hippocampus, antibodies raised against the C terminus of GLT1a and against the N terminus of GLT1, found to be specific by testing in GLT1 knock-out mice, were used for light microscopic and EM-ICC. GLT1a protein was detected in neurons, in 14 -29% of axons in the hippocampus, depending on the region. Many of the labeled axons formed axo-spinous, asymmetric, and, thus, excitatory synapses. Labeling also occurred in some spines and dendrites. The antibody against the N terminus of GLT1 also produced labeling of neuronal processes. Thus, the originally cloned form of GLT1, GLT1a, is expressed as protein in neurons in the mature hippocampus and may contribute significantly to glutamate uptake into excitatory terminals.

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Section: Significance Of Expression Of Glt1 In Axon Terminalsmentioning

confidence: 98%

The Glutamate Transporter GLT1a Is Expressed in Excitatory Axon Terminals of Mature Hippocampal Neurons

Chen¹,

Mahadomrongkul²,

Berger³

et al. 2004

J. Neurosci.

248

250

View full text Add to dashboard Cite

show abstract

“…This decrease is slow at first, but after a few minutes, an abrupt increase in [K ϩ ] o to ϳ60 mM depolarizes neurons to Ϫ20 mV, an event called anoxic depolarization (AD) (Hansen, 1985;Erecinska and Silver, 1994). The AD is associated with a large release of glutamate, resulting from the decrease in ion gradients reversing glutamate transporters (Szatkowski et al, 1990;Madl and Burgesser, 1993;Roettger and Lipton, 1996;Rossi et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

A Preferential Role for Glycolysis in Preventing the Anoxic Depolarization of Rat Hippocampal Area CA1 Pyramidal Cells

Allen

Káradóttir²,

Attwell³

2005

J. Neurosci.

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During brain anoxia or ischemia, a decrease in the level of ATP leads to a sudden decrease in transmembrane ion gradients [anoxic depolarization (AD)]. This releases glutamate by reversing the operation of glutamate transporters, which triggers neuronal death. By whole-cell clamping CA1 pyramidal cells, we investigated the energy stores that delay the occurrence of the AD in hippocampal slices when O 2 and glucose are removed. With glycolytic and mitochondrial ATP production blocked in P12 slices, the AD occurred in ϳ7 min at 33°C, reflecting the time needed for metabolic activity to consume the existing ATP and phosphocreatine, and for subsequent ion gradient decrease. Allowing glycolysis fueled by glycogen, in the absence of glucose, delayed the AD by 5.5 min, whereas superfused glucose prevented the AD for Ͼ1 h. With glycolysis blocked, the latency to the AD was 6.5 min longer when mitochondria were allowed to function, demonstrating that metabolites downstream of glycolysis (pyruvate, citric acid cycle intermediates, and amino acid oxidation) provide a significant energy store for oxidative phosphorylation. With glycolysis blocked but mitochondria functioning, superfusing lactate did not significantly delay the AD, showing that ATP production from lactate is much less than that from endogenous metabolites. These data demonstrate a preferential role for glycolysis in preventing the AD. They also define a hierarchy of pool sizes for hippocampal energy stores and suggest that brain ATP production from glial lactate may not be significant in conditions of energy deprivation.

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“…Activity of Na þ -dependent glutamate transporters is governed by both thermodynamic and kinetic factors, such as Na þ /K þ gradients, binding affinities (Anderson and Swanson, 2000). Since the driving forces are all supplied by ATP hydrolysis, severe ATP depletion, such as resulting from 6-OHDAinduced CX I inhibition will lead to cessation of glutamate uptake, even reversal of glutamate transporters, which further increases the extracellular accumulation of glutamate (Madl and Burgesser, 1993). Opening of K ATP channels may result in the preservation of intracellular ATP production, hence, subsequently elevate activity of glutamate transporter.…”

Section: Discussionmentioning

confidence: 99%

Effects of Systemic Administration of Iptakalim on Extracellular Neurotransmitter Levels in the Striatum of Unilateral 6-Hydroxydopamine-Lesioned Rats

Wang

Zhang

et al. 2005

Neuropsychopharmacol

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The function of ATP-sensitive potassium (KATP) channels in nigrostriatal pathway in Parkinson's disease (PD) was studied by employing a novel KATP channel opener iptakalim (Ipt). Apomorphine-induced rotation behavior test and microdialysis experiment were carried out in unilateral 6-hydroxydopamine (6-OHDA) lesioned rats. Behavior test showed that systemic administration of Ipt failed to significantly alleviate apomorphine-induced rotation in unilateral 6-OHDA-lesioned PD model rats. However, using in vivo microdialysis in this PD model rats, it was found that Ipt could increase extracellular dopamine levels in the lesioned side of the striatum and decrease dopamine levels in the intact side of the striatum. Meanwhile, Ipt had no influence on glutamate levels in the intact side, but it did decrease glutamate levels in the lesioned side of the striatum of PD rats. Additionally, in primary cultured rat astrocytes, 6-OHDA decreased overall glutamate uptake activity, but this decrease was recovered and glutamate uptake activity was restored by the opening of KATP channels induced by Ipt and pinacidil. The classical KATP channel blocker glibenclamide completely abolished the effects of Ipt and pinacidil. The present study suggests that (i) the function of KATP channels in the lesioned and intact nigrostriatal pathway is different in unilateral 6-OHDA-lesioned PD model rats. (ii) KATP channels regulate extracellular neurotransmitter levels in the striatum of unilateral 6-OHDAlesioned rats and may play neuroprotective roles due to their effects on glutamate transporters. Neuropsychopharmacology (2006) 31, 933-940.

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Adenosine triphosphate depletion reverses sodium-dependent, neuronal uptake of glutamate in rat hippocampal slices

Cited by 147 publications

References 47 publications

The Glutamate Transporter GLT1a Is Expressed in Excitatory Axon Terminals of Mature Hippocampal Neurons

The Glutamate Transporter GLT1a Is Expressed in Excitatory Axon Terminals of Mature Hippocampal Neurons

A Preferential Role for Glycolysis in Preventing the Anoxic Depolarization of Rat Hippocampal Area CA1 Pyramidal Cells

Effects of Systemic Administration of Iptakalim on Extracellular Neurotransmitter Levels in the Striatum of Unilateral 6-Hydroxydopamine-Lesioned Rats

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