title: Dopamine denervation of the prefrontal cortex increases expression of the astrocytic glutamate transporter GLT-1.
abstract: Both dopamine and glutamate are critically involved in cognitive processes such as working memory. Astrocytes, which express dopamine receptors, are essential elements in the termination of glutamatergic signaling: the astrocytic glutamate transporter GLT-1 is responsible for > 90% of cortical glutamate uptake. The effect of dopamine depletion on glutamate transporters in the prefrontal cortex (PFC) remains unknown. In an effort to determine if astrocytes are a locus of cortical dopamine-glutamate interactions, we examined the effects of chronic dopamine denervation on PFC protein and mRNA levels of glutamate transporters. PFC dopamine denervation elicited a marked increase in GLT-1 protein levels, but had no effect on levels of other glutamate transporters; high-affinity glutamate transport was positively correlated with the extent of dopamine depletion. GLT-1 gene expression was not altered. Our data suggest that dopamine depletion may lead to post-translational modifications that result in increased expression and activity of GLT-1 in PFC astrocytes. The glutamate transporter GLT-1 is expressed by astrocytes, which also express dopamine receptors. Regulation of prefrontal cortical (PFC) GLT-1 potentially offers a novel treatment approach to the cognitive deficits of schizophrenia. Partial PFC dopamine deafferentation increased membrane expression of GLT-1 protein and glutamate uptake, but did not alter levels of the other two neocortical glutamate transporters, GLAST and EAAC1.
authors.affiliation: Neuroscience Program, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Vollbrecht
authors.forename: Linda D
authors.initials: LD
authors.lastname: Simmler
authors.forename: Randy D
authors.initials: RD
authors.lastname: Blakely
authors.forename: Ariel Y
authors.initials: AY
authors.lastname: Deutch
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D003714:Denervation; D004298:Dopamine / Q000378:metabolism*; D027342:Excitatory Amino Acid Transporter 2 / Q000096:biosynthesis*; D005786:Gene Expression Regulation; D008297:Male; D017397:Prefrontal Cortex / Q000378:metabolism*; D011485:Protein Binding / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D027342:Excitatory Amino Acid Transporter 2; C493395:Slc1a2 protein, rat; D004298:Dopamine
keywords: EAAT2; GLAST; astrocyte; dopamine; prefrontal cortex; schizophrenia