Gene expression profiling in the developing rat brain exposed to ketamine.
Ketamine, a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, is associated with accelerated neuronal apoptosis in the developing rodent brain. In this study, postnatal day (PND) 7 rats were treated with 20 mg/kg ketamine or saline in six successive doses (s.c.) at 2-h intervals. Brain frontal cortical areas were collected 6 h after the last dose and RNA isolated and hybridized to Illumina Rat Ref-12 Expression BeadChips containing 22,226 probes. Many of the differentially expressed genes were associated with cell death or differentiation and receptor activity. Ingenuity Pathway Analysis software identified perturbations in NMDA-type glutamate, GABA and dopamine receptor signaling. Quantitative polymerase chain reaction (Q-PCR) confirmed that NMDA receptor subunits were significantly up-regulated. Up-regulation of NMDA receptor mRNA signaling was further confirmed by in situ hybridization. These observations support our working hypothesis that prolonged ketamine exposure produces up-regulation of NMDA receptors and subsequent over-stimulation of the glutamatergic system by endogenous glutamate, triggering enhanced apoptosis in developing neurons.
Shi
Q
Q
Division of Systems Toxicology, National Center for Toxicological Research, US Food and Drug Administration, 3900 NCTR Road, Jefferson, AR 72079, USA.
Guo
L
L
Patterson
T A
TA
Dial
S
S
Li
Q
Q
Sadovova
N
N
Zhang
X
X
Hanig
J P
JP
Paule
M G
MG
Slikker
W
W
Wang
C
C
D018681:Anesthetics, General / Q000633:toxicity*; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D020869:Gene Expression Profiling; D017403:In Situ Hybridization; D007649:Ketamine / Q000633:toxicity*; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000096:biosynthesis; D015398:Signal Transduction; D009626:Terminology as Topic; D015854:Up-Regulation
D018681:Anesthetics, General; D016194:Receptors, N-Methyl-D-Aspartate; D007649:Ketamine