title: Glutamate transporter splice variant expression in an enriched pyramidal cell population in schizophrenia.
abstract: Dysregulation of the glutamate transporters EAAT1 and EAAT2 and their isoforms have been implicated in schizophrenia. EAAT1 and EAAT2 expression has been studied in different brain regions but the prevalence of astrocytic glutamate transporter expression masks the more subtle changes in excitatory amino acid transporters (EAATs) isoforms in neurons in the cortex. Using laser capture microdissection, pyramidal neurons were cut from the anterior cingulate cortex of postmortem schizophrenia (n = 20) and control (n = 20) subjects. The messenger RNA (mRNA) levels of EAAT1, EAAT2 and the splice variants EAAT1 exon9skipping, EAAT2 exon9skipping and EAAT2b were analyzed by real time PCR (RT-PCR) in an enriched population of neurons. Region-level expression of these transcripts was measured in postmortem schizophrenia (n = 25) and controls (n = 25). The relationship between selected EAAT polymorphisms and EAAT splice variant expression was also explored. Anterior cingulate cortex pyramidal cell expression of EAAT2b mRNA was increased (P < 0.001; 67%) in schizophrenia subjects compared with controls. There was no significant change in other EAAT variants. EAAT2 exon9skipping mRNA was increased (P < 0.05; 38%) at region level in the anterior cingulate cortex with no significant change in other EAAT variants at region level. EAAT2 single-nucleotide polymorphisms were significantly associated with changes in EAAT2 isoform expression. Haloperidol decanoate-treated animals, acting as controls for possible antipsychotic effects, did not have significantly altered neuronal EAAT2b mRNA levels. The novel finding that EAAT2b levels are increased in populations of anterior cingulate cortex pyramidal cells further demonstrates a role for neuronal glutamate transporter splice variant expression in schizophrenia.
authors.affiliation: Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: O'Donovan
authors.affiliation: Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: K
authors.initials: K
authors.lastname: Hasselfeld
authors.affiliation: Department of Neuroscience, Wellesley College, Wellesley, MA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Bauer
authors.affiliation: Department of Psychiatry, University of Alabama, Birmingham, AL, USA.
authors.forename: M
authors.initials: M
authors.lastname: Simmons
authors.affiliation: 1] Department of Psychiatry, Department of Genetics and Genomic Sciences, and Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA [2] James J. Peters VA Medical Center, Mental Illness Research Education and Clinical Center, Bronx, NY, USA.
authors.forename: P
authors.initials: P
authors.lastname: Roussos
authors.affiliation: Department of Psychiatry and Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: V
authors.initials: V
authors.lastname: Haroutunian
authors.affiliation: Department of Psychiatry, University of Alabama, Birmingham, AL, USA.
authors.forename: J H
authors.initials: JH
authors.lastname: Meador-Woodruff
authors.affiliation: 1] Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, OH, USA [2] Department of Neuroscience, Wellesley College, Wellesley, MA, USA [3] Department of Psychiatry, University of Alabama, Birmingham, AL, USA.
authors.forename: R E
authors.initials: RE
authors.lastname: McCullumsmith
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D016022:Case-Control Studies; D027341:Excitatory Amino Acid Transporter 1 / Q000235:genetics* / Q000378:metabolism; D027342:Excitatory Amino Acid Transporter 2 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D005260:Female; D050491:Glutamate Plasma Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D006179:Gyrus Cinguli / Q000187:drug effects / Q000378:metabolism*; D006220:Haloperidol / Q000494:pharmacology; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D020033:Protein Isoforms / Q000235:genetics* / Q000378:metabolism; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D012559:Schizophrenia / Q000235:genetics* / Q000378:metabolism
chemical_list: D014150:Antipsychotic Agents; D027341:Excitatory Amino Acid Transporter 1; D027342:Excitatory Amino Acid Transporter 2; D050491:Glutamate Plasma Membrane Transport Proteins; D020033:Protein Isoforms; D012333:RNA, Messenger; C493397:SLC1A2 protein, human; C493394:SLC1A3 protein, human; C493395:Slc1a2 protein, rat; D006220:Haloperidol