Transient striatal GLT-1 blockade increases EAAC1 expression, glutamate reuptake, and decreases tyrosine hydroxylase phosphorylation at ser19

Salvatore, Michael F.; Davis, Richard W.; Arnold, Jennifer C.; Chotibut, Tanya

doi:10.1016/j.expneurol.2012.01.012

Cited by 27 publications

(35 citation statements)

References 72 publications

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“…63 Glutamate-induced excitotoxicity has been implicated in neurodegenerative diseases, including PD, 64 and evidence suggests that glutamate-induced excitotoxicity contributes to loss of nigrostriatal DA neurons in PD. 62 Although we did not observe significant differences in striatal glutamate uptake or expression of GLT-1 and GLAST in striatum with this regimen, there may be a functional outcome associated with nigral GLAST expression, 65 which increased in the exercise group but was just beyond the level of significance ( p = 0.050, Figure 8C). …”

Section: Discussionmentioning

confidence: 65%

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Exercise-Mediated Increase in Nigral Tyrosine Hydroxylase Is Accompanied by Increased Nigral GFR-α1 and EAAC1 Expression in Aging Rats

Arnold

Salvatore

2015

ACS Chem. Neurosci.

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Exercise may alleviate locomotor impairment in Parkinson's disease (PD) or aging. Identifying molecular responses immediately engaged by exercise in the nigrostriatal pathway and allied tissue may reveal critical targets associated with its long-term benefits. In aging, there is loss of tyrosine hydroxylase (TH) and the glial cell line-derived neurotrophic factor (GDNF) receptor, GFR-α1, in the substantia nigra (SN). Exercise can increase GDNF expression, but its effect on GFR-α1 expression is unknown. Infusion of GDNF into striatum or GFR-α1 in SN, respectively, can increase locomotor activity and TH function in SN but not striatum in aged rats. GDNF may also increase glutamate transporter expression, which attenuates TH loss in PD models. We utilized a footshock-free treadmill exercise regimen to determine the immediate impact of short-term exercise on GFR-α1 expression, dopamine regulation, glutamate transporter expression, and glutamate uptake in 18 month old male Brown-Norway/Fischer 344 F1 hybrid rats. GFR-α1 and TH expression significantly increased in SN but not striatum. This exercise regimen did not affect glutamate uptake or glutamate transporter expression in striatum. However, EAAC1 expression increased in SN. These results indicate that nigral GFR-α1 and EAAC1 expression increased in conjunction with increased nigral TH expression following short-term exercise.

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Section: Discussionmentioning

confidence: 65%

“…62,65 A total of 30 μ g of synpatosome protein was used in a 200 μ L final volume for glutamate uptake. Prepared synaptosomes were subsequently placed into a water bath at 35 °C for 5 min.…”

Section: Methodsmentioning

confidence: 99%

Exercise-Mediated Increase in Nigral Tyrosine Hydroxylase Is Accompanied by Increased Nigral GFR-α1 and EAAC1 Expression in Aging Rats

Arnold

Salvatore

2015

ACS Chem. Neurosci.

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“…These currents are generated by the co-transport of one negatively charged glutamate with 3 Na+ and 1H+ ions in the cell in exchange for one K+ out of the cell resulting in a net entry of two positive charges across the membrane [40]. Normally, EAAC1/EAAT3 accounts for only 20% of the glutamate reuptake in the striatum [62]. This percentage is likely to increase with morphine-induced inhibition of GLAST and GLT1 leading to an increment of transient depolarizing currents associated with EAAC1/EAAT3 activity.…”

Section: Discussionmentioning

confidence: 99%

GluN2B N-methyl-D-aspartate receptor and excitatory amino acid transporter 3 are upregulated in primary sensory neurons after 7 days of morphine administration in rats

Gong

Bhargava

Jasmin

2016

Pain

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The contribution of the peripheral nervous system to opiate-induced hyperalgesia (OIH) is not well understood. Here, we determined the changes in excitability of primary sensory neurons after sustained morphine administration for 7 days. Changes in expression of glutamate receptors and glutamate transporters after morphine administration were ascertained in dorsal root ganglions (DRGs). Patch clamp recordings from intact DRGs (ex-vivo preparation) of morphine-treated rats showed increased excitability of small diameter (≤ 30 μm) neurons with respect to rheobase and membrane threshold, whereas the excitability of large diameter (> 30 μm) neurons remained unchanged. Small diameter neurons also displayed increased responses to glutamate, which were mediated mainly by GluN2B containing NMDA receptors (NMDARs), and to a lesser degree by the neuronal excitatory amino acid transporter 3 /excitatory amino acid carrier 1 (EAAT3/EAAC1). Co-administration in vivo of the GluN2B selective antagonist Ro 25-6981 with morphine for 7 days prevented the appearance of OIH and increased morphine-induced analgesia. Administration of morphine for 7 days led to an increased expression of GluN2B and EAAT3/EAAC1, but not of the AMPA, kainate or Group I metabotropic glutamate receptors, or of the vesicular glutamate transporter 2 (VGLUT2). These results suggest that peripheral glutamatergic neurotransmission contributes to OIH and that GluN2B subunit of NMDARs in the periphery may be a target for therapy.

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“…It was recently shown that blockade of GLT1 in the striatum evokes a transient compensatory increase in GLAST activity, resulting in an overall increase in glutamate uptake (55). This response was proposed to provide an endogenous defense mechanism against excitotoxicity to the nigrostriatal pathway (55).…”

Section: Discussionmentioning

confidence: 99%

“…Our findings showing blunted GLT1 activity/expression along with a diminished tonic activation of I NMDA suggests that an alternative glutamate transport mechanism, most likely GLAST, may be compensating in the clearance of extracellular glutamate for the compromised GLT1 activity during HF. It has been recently shown that a diminished GLT1 function/expression can lead to a compensatory response involving an increased function/expression of the alternative major glutamate transporter in the central nervous system, GLAST (55). To determine whether this was the case in HF rats, we measured GLAST immunoreactivity in the SON of sham and HF rats (n ϭ 4 and 3 rats, respectively).…”

Section: Tonic Persistent Activation Of Enmdars By Ambient Glutamate mentioning

confidence: 99%

Altered astrocyte glutamate transporter regulation of hypothalamic neurosecretory neurons in heart failure rats

Potapenko

Biancardi

Zhou

et al. 2012

American Journal of Physiology-Regulatory, Integrative and Comp

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Neurohumoral activation, which includes augmented plasma levels of the neurohormone vasopressin (VP), is a common finding in heart failure (HF) that contributes to morbidity and mortality in this disease. While an increased activation of magnocellular neurosecretory cells (MNCs) and enhanced glutamate function in HF is well documented, the precise underlying mechanisms remain to be elucidated. Here, we combined electrophysiology and protein measurements to determine whether altered glial glutamate transporter function and/or expression occurs in the hypothalamic supraoptic nucleus (SON) during HF. Patch-clamp recordings obtained from MNCs in brain slices show that pharmacological blockade of astrocyte glutamate transporter 1 (GLT1) function [500 μM dihydrokainate (DHK)], resulted in a persistent N-methyl-D-aspartate receptor (NMDAR)-mediated inward current (tonic I(NMDA)) in sham rats, an effect that was significantly smaller in MNCs from HF rats. In addition, we found a diminished GLT1 protein content in plasma membrane (but not cytosolic) fractions of SON punches in HF rats. Conversely, astrocyte GLAST expression was significantly higher in the SON of HF rats, while nonselective blockade of glutamate transport activity (100 μM TBOA) evoked an enhanced tonic I(NMDA) activation in HF rats. Steady-state activation of NMDARs by extracellular glutamate levels was diminished during HF. Taken together, these results support a shift in the relative expression and function of two major glial glutamate transporters (from GLT1 to GLAST predominance) during HF. This shift may act as a compensatory mechanism to preserve an adequate basal glutamate uptake level in the face of an enhanced glutamatergic afferent activity in HF rats.

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Transient striatal GLT-1 blockade increases EAAC1 expression, glutamate reuptake, and decreases tyrosine hydroxylase phosphorylation at ser19

Cited by 27 publications

References 72 publications

Exercise-Mediated Increase in Nigral Tyrosine Hydroxylase Is Accompanied by Increased Nigral GFR-α1 and EAAC1 Expression in Aging Rats

Exercise-Mediated Increase in Nigral Tyrosine Hydroxylase Is Accompanied by Increased Nigral GFR-α1 and EAAC1 Expression in Aging Rats

GluN2B N-methyl-D-aspartate receptor and excitatory amino acid transporter 3 are upregulated in primary sensory neurons after 7 days of morphine administration in rats

Altered astrocyte glutamate transporter regulation of hypothalamic neurosecretory neurons in heart failure rats

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