ENT1 Regulates Ethanol‐Sensitive EAAT2 Expression and Function in Astrocytes

Wu, Jing; Lee, Moonnoh R.; Choi, Sun Hee; Kim, Tae Hyun; Choi, Doo Sup

doi:10.1111/j.1530-0277.2010.01187.x

Cited by 45 publications

(65 citation statements)

References 44 publications

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“…21 Ethanol, which acutely alleviates ET in many patients significantly increases SLC1A2 expression and glutamate uptake activity. 22 Furthermore, elevated glutamate concentrations are present in the CSF and serum of patients with ET. 23 For further progress in the genetics of sporadic ET, 2 prerequisites have to be met.…”

Section: Resultsmentioning

confidence: 99%

Polymorphisms in the glial glutamate transporter SLC1A2 are associated with essential tremor

Thier¹,

Lorenz²,

Nothnagel³

et al. 2012

Neurology

106

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Objective: Sporadic, genetically complex essential tremor (ET) is one of the most common movement disorders and may lead to severe impairment of the quality of life. Despite high heritability, the genetic determinants of ET are largely unknown. We performed the second genome-wide association study (GWAS) for ET to elucidate genetic risk factors of ET. Methods:Using the Affymetrix Genome-Wide SNP Array 6.0 (1000K) we conducted a two-stage GWAS in a total of 990 subjects and 1,537 control subjects from Europe to identify genetic variants associated with ET. Results:We discovered association of an intronic variant of the main glial glutamate transporter (SLC1A2) gene with ET in the first-stage sample (rs3794087, p ϭ 6.95 ϫ 10 Ϫ5 , odds ratio [OR] ϭ 1.46). We verified the association of rs3794087 with ET in a second-stage sample (p ϭ 1.25 ϫ 10 Ϫ3 , OR ϭ 1.38). In the subgroup analysis of patients classified as definite ET, rs3794087obtained genome-wide significance (p ϭ 3.44 ϫ 10 Ϫ10 , OR ϭ 1.59) in the combined first-and second-stage sample. Genetic fine mapping using nonsynonymous single nucleotide polymorphisms (SNPs) and SNPs in high linkage disequilibrium with rs3794087 did not reveal any SNP with a stronger association with ET than rs3794087. Conclusions:We identified SLC1A2 encoding the major glial high-affinity glutamate reuptake transporter in the brain as a potential ET susceptibility gene. Acute and chronic glutamatergic overexcitation is implied in the pathogenesis of ET. SLC1A2 is therefore a good functional candidate gene for ET. Neurology Sporadic, genetically complex essential tremor (ET) is one of the most frequent neurologic disorders with a prevalence between 0.9% and 4.6% in the population older than 65 years. 1The clinical hallmark of the disease is a postural or kinetic tremor of the upper extremities. Severe ET not only causes permanent disability but often also social stigmatization. In a large proportion of patients, ET can be acutely alleviated by moderate doses of ethanol. 2,3 The diagnosis of ET is based on the clinical examination because no biomarker or specific diagnostic test exists. The most stringent research diagnostic criteria for ET are the consensus criteria proposed by the Tremor Investigation Group (TRIG).1 Family history studies and twin studies demonstrated high heritability with concordance rates of up to 95% in monozygotic vs 29% in

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Section: Resultsmentioning

confidence: 99%

Polymorphisms in the glial glutamate transporter SLC1A2 are associated with essential tremor

Thier¹,

Lorenz²,

Nothnagel³

et al. 2012

Neurology

106

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“…Pharmacological experiments have shown that blockade of adenosine A 2A receptors in the NAc can increase locomotor sensitivity to cocaine (Filip et al, 2006), as well as cocaine seeking (O'Neill et al, 2014;Wu et al, 2010). Adenosine A 2A receptors exert tonic inhibitory control over D 2 receptor signaling within the striatum where A 2A receptor stimulation decreases DA binding at D 2 receptors (Ferre et al, 1991).…”

Section: Discussionmentioning

confidence: 99%

Effects of Adolescent Caffeine Consumption on Cocaine Sensitivity

O’Neill

Levis

Schreiner

et al. 2014

Neuropsychopharmacol

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Caffeine is the most commonly used psychoactive substance, and consumption by adolescents has risen markedly in recent years. We identified the effects of adolescent caffeine consumption on cocaine sensitivity and determined neurobiological changes within the nucleus accumbens (NAc) that may underlie caffeine-induced hypersensitivity to cocaine. Male Sprague-Dawley rats consumed caffeine (0.3 g/l) or water for 28 days during adolescence (postnatal day 28-55; P28-P55) or adulthood (P67-P94). Testing occurred in the absence of caffeine during adulthood (P62-82 or P101-121). Cocaine-induced and quinpirole (D 2 receptor agonist)-induced locomotion was enhanced in rats that consumed caffeine during adolescence. Adolescent consumption of caffeine also enhanced the development of a conditioned place preference at a sub-threshold dose of cocaine (7.5 mg/kg, i.p.). These behavioral changes were not observed in adults consuming caffeine for an equivalent period of time. Sucrose preferences were not altered in rats that consumed caffeine during adolescence, suggesting there are no differences in natural reward. Caffeine consumption during adolescence reduced basal dopamine levels and augmented dopamine release in the NAc in response to cocaine (5 mg/kg, i.p.). Caffeine consumption during adolescence also increased the expression of the dopamine D 2 receptor, dopamine transporter, and adenosine A 1 receptor and decreased adenosine A 2A receptor expression in the NAc. Consumption of caffeine during adulthood increased adenosine A 1 receptor expression in the NAc, but no other protein expression changes were observed. Together these findings suggest that caffeine consumption during adolescence produced changes in the NAc that are evident in adulthood and may contribute to increases in cocaine-mediated behaviors.

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“…As we described previously (Wu et al, 2010), cells were maintained in Dulbecco's modified Eagle medium containing glucose (Invitrogen, Carlsbad, CA), 10% heat-inactivated fetal bovine serum (ATCC, American Type Culture Collection, VA), 1% L-glutamine (Gibco, Auckland, New Zealand), and 1% Antibiotic-Antimycotic (Invitrogen). Monolayers were cultured at 37 1C in the presence of 5% CO 2 /95% O 2 (normoxia) in a fully humidified atmosphere with medium replacement every 2-3 days.…”

Section: Astrocyte Culture and Reagentsmentioning

confidence: 99%

“…One of the main contributing factors for these behaviors is increased glutamatergic signaling in the nucleus accumbens (NAc) (Nam et al, 2011). Interestingly, our recent findings suggest that ENT1 regulates astrocytic excitatory aminoacid transporter 2 (EAAT2) mRNA expression and glutamate uptake activity function in cultured astrocytes (Wu et al, 2010). As EAAT2 is responsible for the majority (B90%) of glutamate uptake into astrocytes (Tanaka et al, 1997), this reduction of EAAT2 likely contributes to the hyperglutamatergic state in ENT1 null mice (Nam et al, 2011).…”

Section: Introductionmentioning

confidence: 97%

Striatal Adenosine Signaling Regulates EAAT2 and Astrocytic AQP4 Expression and Alcohol Drinking in Mice

Lee

Ruby

Hinton

et al. 2012

Neuropsychopharmacol

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Adenosine signaling is implicated in several neuropsychiatric disorders, including alcoholism. Among its diverse functions in the brain, adenosine regulates glutamate release and has an essential role in ethanol sensitivity and preference. However, the molecular mechanisms underlying adenosine-mediated glutamate signaling in neuroglial interaction remain elusive. We have previously shown that mice lacking the ethanol-sensitive adenosine transporter, type 1 equilibrative nucleoside transporter (ENT1), drink more ethanol compared with wild-type mice and have elevated striatal glutamate levels. In addition, ENT1 inhibition or knockdown reduces glutamate transporter expression in cultured astrocytes. Here, we examined how adenosine signaling in astrocytes contributes to ethanol drinking. Inhibition or deletion of ENT1 reduced the expression of type 2 excitatory amino-acid transporter (EAAT2) and the astrocyte-specific water channel, aquaporin 4 (AQP4). EAAT2 and AQP4 colocalization was also reduced in the striatum of ENT1 null mice. Ceftriaxone, an antibiotic compound known to increase EAAT2 expression and function, elevated not only EAAT2 but also AQP4 expression in the striatum. Furthermore, ceftriaxone reduced ethanol drinking, suggesting that ENT1-mediated downregulation of EAAT2 and AQP4 expression contributes to excessive ethanol consumption in our mouse model. Overall, our findings indicate that adenosine signaling regulates EAAT2 and astrocytic AQP4 expressions, which control ethanol drinking in mice.

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ENT1 Regulates Ethanol‐Sensitive EAAT2 Expression and Function in Astrocytes

Cited by 45 publications

References 44 publications

Polymorphisms in the glial glutamate transporter SLC1A2 are associated with essential tremor

Polymorphisms in the glial glutamate transporter SLC1A2 are associated with essential tremor

Effects of Adolescent Caffeine Consumption on Cocaine Sensitivity

Striatal Adenosine Signaling Regulates EAAT2 and Astrocytic AQP4 Expression and Alcohol Drinking in Mice

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