title: COMT val158met polymorphism and molecular alterations in the human dorsolateral prefrontal cortex: Differences in controls and in schizophrenia.
abstract: The single nucleotide val158met polymorphism in catechol o-methyltransferase (COMT) influences prefrontal cortex function. Working memory, dependent on the dorsolateral prefrontal cortex (DLPFC), has been repeatedly shown to be influenced by this COMT polymorphism. The high activity COMT val isoform is associated with lower synaptic dopamine levels. Altered synaptic dopamine levels are expected to lead to molecular adaptations within the synapse and within DLPFC neural circuitry. In this human post mortem study using high quality DLPFC tissue, we first examined the influence of the COMT val158met polymorphism on markers of dopamine neurotransmission, N-methyl-d-aspartate (NMDA) receptor subunits and glutamatic acid decarboxylase 67 (GAD67), all known to be critical to DLPFC circuitry and function. Next, we compared target gene expression profiles in a cohort of control and schizophrenia cases, each characterized by COMT genotype. We find that the COMT val allele in control subjects is associated with significant upregulation of GluN2A and GAD67 mRNA levels compared to met carriers. Comparisons between control and schizophrenia groups reveal that GluN2A, GAD67 and DRD2 are differentially regulated between diagnostic groups in a genotype specific manner. Chronic antipsychotic treatment in rodents did not explain these differences. These data demonstrate an association between COMTval158met genotype and gene expression profile in the DLPFC of controls, possibly adaptations to maintain DLPFC function. In schizophrenia val homozygotes, these adaptations are not seen and could reflect pathophysiologic mechanisms related to the known poorer performance of these subjects on DLPFC-dependent tasks.
authors.affiliation: Department of Psychiatry, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, United States.
authors.forename: Abhay A
authors.initials: AA
authors.lastname: Shukla
authors.affiliation: Department of Psychiatry, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, United States.
authors.forename: Manish
authors.initials: M
authors.lastname: Jha
authors.affiliation: Department of Psychiatry, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, United States.
authors.forename: Thomas
authors.initials: T
authors.lastname: Birchfield
authors.affiliation: Department of Psychiatry, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, United States.
authors.forename: Shibani
authors.initials: S
authors.lastname: Mukherjee
authors.affiliation: Department of Psychiatry, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, United States.
authors.forename: Kelly
authors.initials: K
authors.lastname: Gleason
authors.affiliation: Department of Radiation Oncology/Division of Molecular Radiation Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, United States.
authors.forename: Salim
authors.initials: S
authors.lastname: Abdisalaam
authors.affiliation: Department of Radiation Oncology/Division of Molecular Radiation Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, United States.
authors.forename: Aroumougame
authors.initials: A
authors.lastname: Asaithamby
authors.affiliation: Department of Clinical Sciences, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, United States.
authors.forename: Beverley
authors.initials: B
authors.lastname: Adams-Huet
authors.affiliation: Department of Psychiatry, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, United States.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Tamminga
authors.affiliation: Department of Psychiatry, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, United States. Electronic address: subroto.ghose@utsouthwestern.edu.
authors.forename: Subroto
authors.initials: S
authors.lastname: Ghose
mesh_terms: D000328:Adult; D000368:Aged; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D015331:Cohort Studies; D003933:Diagnosis; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics*; D005838:Genotype; D005968:Glutamate Decarboxylase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D008569:Memory Disorders / Q000209:etiology; D008570:Memory, Short-Term / Q000502:physiology; D008715:Methionine / Q000235:genetics; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D017397:Prefrontal Cortex / Q000378:metabolism*; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism; D012559:Schizophrenia / Q000150:complications / Q000235:genetics* / Q000473:pathology*; D014633:Valine / Q000235:genetics
chemical_list: D002394:Catechol O-Methyltransferase; D005968:Glutamate Decarboxylase; D008715:Methionine; D018091:Receptors, AMPA; D017448:Receptors, Dopamine D2; D016194:Receptors, N-Methyl-D-Aspartate; D014633:Valine; C581293:DRD2 protein, human; C588010:COMT protein, human; C402565:glutamate decarboxylase 1
keywords: DLPFC; Dopamine; GABA; Glutamate; Human; Post mortem brain