Developmental cuprizone exposure impairs oligodendrocyte lineages differentially in cortical and white matter tissues and suppresses glutamatergic neurogenesis signals and synaptic plasticity in the hippocampal dentate gyrus of rats

Toxicol Appl Pharmacol. 2016 Jan 1:290:10-20. doi: 10.1016/j.taap.2015.11.006. Epub 2015 Nov 11.


Developmental cuprizone (CPZ) exposure impairs rat hippocampal neurogenesis. Here, we captured the developmental neurotoxicity profile of CPZ using a region-specific expression microarray analysis in the hippocampal dentate gyrus, corpus callosum, cerebral cortex and cerebellar vermis of rat offspring exposed to 0, 0.1, or 0.4% CPZ in the maternal diet from gestation day 6 to postnatal day (PND) 21. Transcripts of those genes identified as altered were subjected to immunohistochemical analysis on PNDs 21 and 77. Our results showed that transcripts for myelinogenesis-related genes, including Cnp, were selectively downregulated in the cerebral cortex by CPZ at ≥0.1% or 0.4% on PND 21. CPZ at 0.4% decreased immunostaining intensity for 2',3'-cyclic-nucleotide 3'-phosphodiesterase (CNPase) and CNPase(+) and OLIG2(+) oligodendrocyte densities in the cerebral cortex, whereas CNPase immunostaining intensity alone was decreased in the corpus callosum. By contrast, a striking transcript upregulation for Klotho gene and an increased density of Klotho(+) oligodendrocytes were detected in the corpus callosum at ≥0.1%. In the dentate gyrus, CPZ at ≥0.1% or 0.4% decreased the transcript levels for Gria1, Grin2a and Ptgs2, genes related to the synapse and synaptic transmission, and the number of GRIA1(+) and GRIN2A(+) hilar γ-aminobutyric acid (GABA)-ergic interneurons and cyclooxygenase-2(+) granule cells. All changes were reversed at PND 77. Thus, developmental CPZ exposure reversibly decreased mature oligodendrocytes in both cortical and white matter tissues, and Klotho protected white matter oligodendrocyte growth. CPZ also reversibly targeted glutamatergic signals of GABAergic interneuron to affect dentate gyrus neurogenesis and synaptic plasticity in granule cells.

Keywords: Cuprizone (CPZ); Expression microarray; Glial cell development; Klotho; Myelinogenesis; Neuronal plasticity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Apoptosis / drug effects
  • Cell Lineage / drug effects*
  • Cuprizone / toxicity*
  • Dentate Gyrus / drug effects
  • Dentate Gyrus / metabolism
  • Down-Regulation
  • Female
  • Gene Expression Profiling
  • Glucuronidase / genetics
  • Glucuronidase / metabolism
  • Klotho Proteins
  • Male
  • Neurogenesis / drug effects*
  • Neuronal Plasticity / drug effects*
  • Oligodendroglia / cytology
  • Oligodendroglia / drug effects*
  • Pregnancy
  • Prenatal Exposure Delayed Effects / pathology
  • Rats
  • Rats, Sprague-Dawley
  • Synaptic Transmission
  • White Matter / cytology
  • White Matter / drug effects
  • White Matter / metabolism
  • gamma-Aminobutyric Acid / metabolism


  • gamma-Aminobutyric Acid
  • Cuprizone
  • Glucuronidase
  • Klotho Proteins