Blockade of N-methyl-D-aspartate receptors by phencyclidine causes the loss of corticostriatal neurons

C. Wang, Noelle Anastasio, Vsevolod Popov, A. Leday, K. M. Johnson

Research output: Contribution to journalArticle

46 Citations (Scopus)

Abstract

Perinatal administration of the N-methyl-D-aspartate (NMDA) receptor antagonist phencyclidine (PCP) has been reported to produce regionally selective apoptotic cell death in the frontal cortex. The development of certain behavioral abnormalities following PCP treatment suggested that extracortical regions such as the striatum also could be affected. In this study, perinatal PCP treatment caused a marked reduction in striatal, but not hippocampal, staining for polysialic acid-neural cell adhesion molecule (PSA-NCAM), an NMDA-regulated molecule important in synaptogenesis. In order to isolate striatal influences to the cortex, this investigation was continued in vitro using corticostriatal slices. For these experiments we cultured coronal corticostriatal slices from postnatal day 7 rats. After 4 days in vitro, PCP was added for 48 h and then washed out for 24 h before harvesting the tissue. Similar to what was observed in vivo, we found that PCP treatment results in a marked reduction in striatal staining for PSA-NCAM. No change was observed in the mature form of NCAM. In striatal synaptoneurosomes, immunoblot analysis confirmed that the levels of PSA-NCAM and synaptophysin, a molecule often used as a marker of synaptogenesis, were substantially down-regulated by PCP. These effects were prevented by M40403, a superoxide dismutase mimetic that also prevented the PCP-induced terminal dUTP nick-end labeling of DNA fragments that was observed selectively in the cortex. These data suggest that PCP causes cell death by apoptosis selectively in the cortex, but not in the striatum, following either in vivo treatment of perinatal rat pups or in vitro treatment of corticostriatal slices. Further, cortical apoptosis induced by PCP negatively impacts striatal synaptogenesis, a process important in normal neural development. This deficit is probably caused by a reduction in corticostriatal neurotransmission. It is possible that the dysregulation of striatal synaptogenesis contributes to the behavioral abnormalities observed following perinatal PCP administration in vivo.

Original languageEnglish (US)
Pages (from-to)473-483
Number of pages11
JournalNeuroscience
Volume125
Issue number2
DOIs
StatePublished - 2004

Fingerprint

Corpus Striatum
Phencyclidine
N-Methyl-D-Aspartate Receptors
Neural Cell Adhesion Molecules
Neurons
Cell Death
Tissue and Organ Harvesting
Apoptosis
Staining and Labeling
Synaptophysin
Frontal Lobe
N-Methylaspartate
Synaptic Transmission
Superoxide Dismutase
Cause of Death
DNA
polysialic acid
In Vitro Techniques

Keywords

  • Analysis of variance
  • ANOVA
  • Apoptosis
  • Bovine serum albumin
  • BSA
  • Days in vitro
  • DIV
  • ELISA
  • Enzyme-linked immunosorbent assay
  • Neurodegeneration
  • NMDA
  • NMDA receptor
  • Polysialic acid neural cell adhesion molecule (PSA-NCAM)
  • Schizophrenia
  • Synaptophysin

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Blockade of N-methyl-D-aspartate receptors by phencyclidine causes the loss of corticostriatal neurons. / Wang, C.; Anastasio, Noelle; Popov, Vsevolod; Leday, A.; Johnson, K. M.

In: Neuroscience, Vol. 125, No. 2, 2004, p. 473-483.

Research output: Contribution to journalArticle

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AU - Johnson, K. M.

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