Changes in gene expression after phencyclidine administration in developing rats: a potential animal model for schizophrenia.
Repeated administration of phencyclidine (PCP), an N-methyl-d-aspartate (NMDA) receptor antagonist, during development, may result in neuronal damage that leads to behavioral deficits in adulthood. The present study examined the potential neurotoxic effects of PCP exposure (10mg/kg) in rats on postnatal days (PNDs) 7, 9 and 11 and the possible underlying mechanism(s) for neurotoxicity. Brain tissue was harvested for RNA extraction and morphological assessments. RNA was collected from the frontal cortex for DNA microarray analysis and quantitative RT-PCR. Gene expression profiling was determined using Illumina Rat Ref-12 Expression BeadChips containing 22,226 probes. Based on criteria of a fold-change greater than 1.4 and a P-value less than 0.05, 19 genes including NMDAR1 (N-methyl-d-aspartate receptor) and four pro-apoptotic genes were up-regulated, and 25 genes including four anti-apoptotic genes were down-regulated, in the PCP-treated group. In addition, the schizophrenia-relevant genes, Bdnf (Brain-derived neurotrophic factor) and Bhlhb2 (basic helix-loop-helix domain containing, class B, 2), were significantly different between the PCP and the control groups. Quantitative RT-PCR confirmed the microarray results. Elevated neuronal cell death was further confirmed using Fluoro-Jade C staining. These findings support the hypothesis that neurodegeneration caused by PCP occurs, at least in part, through the up-regulation of NMDA receptors, which makes neurons possessing these receptors more vulnerable to endogenous glutamate. The changes in schizophrenia-relevant genes after repeated PCP exposure during development may provide important information concerning the validation of an animal model for this disorder.
Liu
F
F
Division of Neurotoxicology, National Center for Toxicological Research/U.S. Food & Drug Administration, 3900 NCTR Road, Jefferson, AR 72079-9502, USA.
Zou
X
X
Sadovova
N
N
Zhang
X
X
Shi
L
L
Guo
L
L
Qian
F
F
Wen
Z
Z
Patterson
T A
TA
Hanig
J P
JP
Paule
M G
MG
Slikker
W
W
Wang
C
C
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D016000:Cluster Analysis; D004195:Disease Models, Animal; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005452:Fluoresceins / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D046228:Microarray Analysis; D008969:Molecular Sequence Data; D009410:Nerve Degeneration / Q000139:chemically induced / Q000473:pathology; D010622:Phencyclidine / Q000494:pharmacology*; D025341:Principal Component Analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012559:Schizophrenia / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*
D018691:Excitatory Amino Acid Antagonists; D005452:Fluoresceins; C534582:fluoro-jade C; D010622:Phencyclidine