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.
Highlights
Excitatory amino acid transporters (EAATs) mediate clearance of glutamate levels in the central nervous system preventing pathological accumulation of glutamate in the synapse.[1]
Cell-level analysis of EAAT messenger RNA (mRNA) expression in a population of anterior cingulate cortex (ACC) pyramidal cells found a significant increase (P o 0.001, 67% increase on control levels) in neuronal EAAT2b mRNA in schizophrenia subjects compared with controls
Of particular interest is our finding that EAAT2b mRNA levels are increased in an enriched population of pyramidal cells in the ACC
Summary
Excitatory amino acid transporters (EAATs) mediate clearance of glutamate levels in the central nervous system preventing pathological accumulation of glutamate in the synapse.[1]. Expression of EAAT1 and EAAT2 and their interacting proteins are altered in both the thalamus and cortex.[8,9,10] EAAT1 and EAAT2 expression is generally found in glial cells.[11] recent microscopy studies have expanded our understanding of the cellular localization of EAAT1 and EAAT2 in human brain. We hypothesize that cell-level changes in expression of glutamate transporters occur in pyramidal neurons in schizophrenia These subtle alterations in neuronal EAAT expression, in the splice variants, may have a little understood role in the pathophysiology of this disorder
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