Epigenetic mechanisms expressed in basal ganglia GABAergic neurons differentiate schizophrenia from bipolar disorder

Schizophr Res. 2007 Mar;91(1-3):51-61. doi: 10.1016/j.schres.2006.11.029. Epub 2007 Jan 31.

Abstract

In the cerebral prefrontal cortex (PFC), DNA-methyltransferase 1 (DNMT1), the enzyme that catalyzes the methylation of cytosine at carbon atoms in position 5 in CpG dinucleotides, is expressed selectively in GABAergic neurons and is upregulated in layers I and II of schizophrenia (SZ) and bipolar disorder patients with psychosis (BDP). To replicate these earlier findings and to verify whether overexpression of DNMT1 and the consequent epigenetic decrease of reelin and glutamic acid decarboxylase (GAD) 67 mRNA expression also occur in GABAergic medium spiny neurons of the caudate nucleus (CN) and putamen (PT) of SZ and BDP, we studied the entire McLean 66 Cohort (Harvard Brain Tissue Resource Center, McLean Hospital, Belmont, MA) including SZ and BDP, which were matched with nonpsychiatric subjects. The data demonstrate that in GABAergic medium spiny neurons of CN and PT, unlike in GABAergic neurons of layer I and II PFC, the increased expression of DNMT1 and the decrease of reelin and GAD67 occur in SZ but not in BDP. This suggests that different epigenetic mechanisms must exist in the pathogenesis underlying SZ and BDP and implies that these disorders might involve two separate entities that are characterized by a well-defined neuropathology.

Publication types

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

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Basal Ganglia / metabolism*
  • Basal Ganglia / pathology*
  • Bipolar Disorder / metabolism*
  • Bipolar Disorder / pathology*
  • Caudate Nucleus / metabolism
  • Caudate Nucleus / pathology
  • Cell Adhesion Molecules, Neuronal / genetics
  • Cohort Studies
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNA (Cytosine-5-)-Methyltransferases / genetics
  • DNA-Cytosine Methylases / genetics
  • Epigenesis, Genetic / genetics*
  • Extracellular Matrix Proteins / genetics
  • Female
  • Fluorescence
  • Humans
  • Immunohistochemistry
  • In Situ Hybridization
  • Male
  • Methylation
  • Microscopy, Confocal
  • Middle Aged
  • Nerve Tissue Proteins / genetics
  • Neurons / metabolism*
  • Neurons / pathology*
  • Prefrontal Cortex / metabolism
  • Prefrontal Cortex / pathology
  • Putamen / metabolism
  • Putamen / pathology
  • RNA, Messenger / genetics
  • Reelin Protein
  • Schizophrenia* / genetics
  • Schizophrenia* / metabolism
  • Schizophrenia* / pathology
  • Serine Endopeptidases / genetics
  • gamma-Aminobutyric Acid / metabolism*

Substances

  • Cell Adhesion Molecules, Neuronal
  • Extracellular Matrix Proteins
  • Nerve Tissue Proteins
  • RNA, Messenger
  • Reelin Protein
  • gamma-Aminobutyric Acid
  • DNA modification methylase SssI
  • DNA-Cytosine Methylases
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNA (Cytosine-5-)-Methyltransferases
  • DNMT1 protein, human
  • RELN protein, human
  • Serine Endopeptidases