COMT val158met polymorphism and molecular alterations in the human dorsolateral prefrontal cortex: Differences in controls and in schizophrenia

Schizophr Res. 2016 May;173(1-2):94-100. doi: 10.1016/j.schres.2016.03.019. Epub 2016 Mar 24.

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.

Keywords: DLPFC; Dopamine; GABA; Glutamate; Human; Post mortem brain.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Aged
  • Catechol O-Methyltransferase / genetics*
  • Cohort Studies
  • Diagnosis
  • Female
  • Gene Expression Regulation / genetics*
  • Genotype
  • Glutamate Decarboxylase / genetics
  • Glutamate Decarboxylase / metabolism
  • Humans
  • Male
  • Memory Disorders / etiology
  • Memory, Short-Term / physiology
  • Methionine / genetics
  • Middle Aged
  • Polymorphism, Single Nucleotide / genetics*
  • Prefrontal Cortex / metabolism*
  • Receptors, AMPA / genetics
  • Receptors, AMPA / metabolism
  • Receptors, Dopamine D2 / genetics
  • Receptors, Dopamine D2 / metabolism
  • Receptors, N-Methyl-D-Aspartate / genetics
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Schizophrenia / complications
  • Schizophrenia / genetics*
  • Schizophrenia / pathology*
  • Valine / genetics

Substances

  • DRD2 protein, human
  • Receptors, AMPA
  • Receptors, Dopamine D2
  • Receptors, N-Methyl-D-Aspartate
  • Methionine
  • COMT protein, human
  • Catechol O-Methyltransferase
  • Glutamate Decarboxylase
  • glutamate decarboxylase 1
  • Valine
  • glutamate receptor ionotropic, AMPA 1
  • N-methyl D-aspartate receptor subtype 2A