Prenatal NMDA receptor antagonism impaired proliferation of neuronal progenitor, leading to fewer glutamatergic neurons in the prefrontal cortex

Neuropsychopharmacology. 2012 May;37(6):1387-96. doi: 10.1038/npp.2011.324. Epub 2012 Jan 18.


N-methyl-D-aspartate (NMDA) receptor is a glutamate receptor which has an important role on mammalian brain development. We have reported that prenatal treatment with phencyclidine (PCP), a NMDA receptor antagonist, induces long-lasting behavioral deficits and neurochemical changes. However, the mechanism by which the prenatal antagonism of NMDA receptor affects neurodevelopment, resulting in behavioral deficits, has remained unclear. Here, we report that prenatal NMDA receptor antagonism impaired the proliferation of neuronal progenitors, leading to a decrease in the progenitor pool in the ventricular and the subventricular zone. Furthermore, using a PCR array focused on neurogenesis and neuronal stem cells, we evaluated changes in gene expression causing the impairment of neuronal progenitor proliferation and found aberrant gene expression, such as Notch2 and Ntn1, in prenatal PCP-treated mice. Consequently, the density of glutamatergic neurons in the prefrontal cortex was decreased, probably resulting in glutamatergic hypofunction. Prenatal PCP-treated mice displayed behavioral deficits in cognitive memory and sensorimotor gating until adulthood. These findings suggest that NMDA receptors regulate the proliferation and maturation of progenitor cells for glutamatergic neuron during neurodevelopment, probably via the regulation of gene expression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acoustic Stimulation
  • Age Factors
  • Analysis of Variance
  • Animals
  • Animals, Newborn
  • Behavioral Symptoms / chemically induced
  • Body Weight / drug effects
  • Bromodeoxyuridine / metabolism
  • Cell Proliferation / drug effects*
  • Embryo, Mammalian
  • Excitatory Amino Acid Antagonists / adverse effects*
  • Exploratory Behavior / drug effects
  • Female
  • Gene Expression Regulation, Developmental / drug effects
  • Glutamic Acid / metabolism*
  • Male
  • Mice
  • Mice, Inbred ICR
  • Microdissection
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Neural Inhibition / drug effects
  • Neural Stem Cells / drug effects*
  • Neurons / metabolism
  • Neurons / pathology*
  • Phencyclidine / adverse effects*
  • Prefrontal Cortex / drug effects
  • Prefrontal Cortex / pathology*
  • Pregnancy
  • Prenatal Exposure Delayed Effects / pathology*
  • Prenatal Exposure Delayed Effects / physiopathology
  • Swimming / psychology


  • Excitatory Amino Acid Antagonists
  • Nerve Tissue Proteins
  • Glutamic Acid
  • Bromodeoxyuridine
  • Phencyclidine