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. 2010 Mar 31;166(3):852-63.
doi: 10.1016/j.neuroscience.2010.01.007. Epub 2010 Jan 18.

Gene expression profiling in the developing rat brain exposed to ketamine

Q Shi  1 , L Guo, T A Patterson, S Dial, Q Li, N Sadovova, X Zhang, J P Hanig, M G Paule, W Slikker Jr, C Wang
Affiliations

Gene expression profiling in the developing rat brain exposed to ketamine

Q Shi et al. Neuroscience. .

Abstract

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.

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Figures

Fig. 1
Fig. 1
Ketamine-induced neurodegeneration in PND 7 rats assessed by TUNEL labeling. Representative photographs indicate that TUNEL-positive cells are more numerous in layers II and III of the frontal cortex in the ketamine treated rat brain (B). Only a few TUNEL-positive cells were observed in the control (saline treated) rat brain (A). Scale bar=60 µm.
Fig. 2
Fig. 2
Hierarchical Cluster Analysis (HCA) of expression profiles for control and ketamine-treated groups. The log2 intensity of the entire gene set was scaled by Z-score transformation, and then these values were hierarchically clustered using 1-r distance metric and average linkage. Each column represents the results from an individual animal. Each row represents the log2 intensity values of the 20 samples for one particular gene. Samples are labeled according to the convention of Treatment_Animal ID_Gender. Ket, ketamine treatment; CTR, vehicle control; F1-20, animal ID; M, male; F, female.
Fig. 3
Fig. 3
Principal component analysis (PCA) of gene expression profiles for ketamine-treated groups and the concurrent controls. The intensity of entire gene set was used; no specific cut off was applied for the analysis. The autoscaled method was used for the PCA. The circles and triangles indicate controls and ketamine treatments, respectively.
Fig. 4
Fig. 4
NMDA receptor NR1 subunit mRNA abundance in PND 7 rats. In situ hybridization was performed on rat brain sections (coronal) using a 35S-labeled oligonucleotide probe specific for the NMDA receptor NR1 subunit. Panel (I) is a film autoradiography that provides a general view of NMDA receptor NR1 subunit mRNA expression in the frontal cortical areas from both control and ketamine-treated rats. Panel (II) illustrates that the autoradiographic density (labeling) for NR1 subunit mRNA was higher in ketamine-treated (20 mg/kg×6 injections) rat brain frontal cortex (B) compared to control (A). Scale bar=90 µm.
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