Phencyclidine-induced changes in rat cortical gene expression identified by microarray analysis: implications for schizophrenia

Kaiser, Sérgio; Foltz, Lisa; George, Carolyn; Kirkwood, Sandra C.; Bemis, Kerry G.; Lin, Xi; Gelbert, Lawrence M.; Nisenbaum, Laura

doi:10.1016/j.nbd.2004.01.011

Cited by 30 publications

(22 citation statements)

References 144 publications

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“…Kaiser et al [2004] reported statistically significant expression changes induced by acute PCP administration in 477 genes in the rat prefrontal cortex, including 5 of the 12 PCP-responsive genes we identified in the present study (Dusp1, Junb, Cebpb, Plat, Mt1a). In contrast to Kaiser's report, we analyzed gene expression more comprehensively in five brain regions (mPFC, PCC, HIP, NAC, and STR) at multiple time points (1 and 4 hr), in order to select candidate schizophrenia susceptibility genes more extensively.…”

Section: Discussionsupporting

confidence: 60%

“…Amplifications were carried out using the following ramping profile: 1 cycle at 95 C for 10 min, followed by 40 cycles of 95 C for 15 sec, 60 C for 1 min. According to the previous study for PCPresponsive genes [Kaiser et al, 2004], we normalized all reactions using a housekeeping gene, Gapdh (Applied Biosystems). The data analysis was carried out by software ABI PRISM 7000 SDS Software version 1.2.3.…”

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confidence: 99%

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Positive association of Phencyclidine‐responsive genes, PDE4A and PLAT, with schizophrenia

Deng

Takaki

Wang

et al. 2011

American J of Med Genetics Pt B

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As schizophrenia-like symptoms are produced by administration of phencyclidine (PCP), a noncompetitive antagonist of N-methyl-D-aspartate (NMDA) receptors, PCP-responsive genes could be involved in the pathophysiology of schizophrenia. We injected PCP to Wistar rats and isolated five different parts of the brain in 1 and 4 hr after the injection. We analyzed the gene expression induced by the PCP treatment of these tissues using the AGILENT rat cDNA microarray system. We observed changes in expression level in 90 genes and 21 ESTs after the treatment. Out of the 10 genes showing >2-fold expressional change evaluated by qRT-PCR, we selected 7 genes as subjects for the locus-wide association study to identify susceptibility genes for schizophrenia in the Japanese population. In haplotype analysis, significant associations were detected in combinations of two SNPs of BTG2 (P = 1.4 × 10(-6) ), PDE4A (P = 1.4 × 10(-6) ), and PLAT (P = 1 × 10(-3) ), after false discovery rate (FDR) correction. Additionally, we not only successfully replicated the haplotype associations in PDE4A (P = 6.8 × 10(-12) ) and PLAT (P = 0.015), but also detected single-point associations of one SNP in PDE4A (P = 0.0068) and two SNPs in PLAT (P = 0.0260 and 0.0104) in another larger sample set consisting of 2,224 cases and 2,250 controls. These results indicate that PDE4A and PLAT may be susceptibility genes for schizophrenia in the Japanese population.

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Section: Discussionsupporting

confidence: 60%

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confidence: 99%

Positive association of Phencyclidine‐responsive genes, PDE4A and PLAT, with schizophrenia

Deng

Takaki

Wang

et al. 2011

American J of Med Genetics Pt B

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“…All genes listed were within at least 10 cM of the marker for the given chromosomal location. [Kaiser et al, 2004;Ouchi et al, 2005]. While some of this may be technical, that is, whole brain versus microdissected brain regions, cDNA microarrays or older generation oligonucleotide microarrays that did not have probe sets for some of our top findings in the current report, there are genes that are present in both the rat and mouse microarrays used.…”

Section: Limitations and Confoundsmentioning

confidence: 86%

Towards understanding the schizophrenia code: An expanded convergent functional genomics approach

Le-Niculescu

Balaraman

Patel

et al. 2007

American J of Med Genetics Pt B

129

124

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Identifying genes for schizophrenia through classical genetic approaches has proven arduous. Here, we present a comprehensive convergent analysis that translationally integrates brain gene expression data from a relevant pharmacogenomic mouse model (involving treatments with a psychomimetic agent - phencyclidine (PCP), and an anti-psychotic - clozapine), with human genetic linkage data and human postmortem brain data, as a Bayesian strategy of cross validating findings. Topping the list of candidate genes, we have three genes involved in GABA neurotransmission (GABRA1, GABBR1, and GAD2), one gene involved in glutamate neurotransmission (GRIA2), one gene involved in neuropeptide signaling (TAC1), two genes involved in synaptic function (SYN2 and KCNJ4), six genes involved in myelin/glial function (CNP, MAL, MBP, PLP1, MOBP and GFAP), and one gene involved in lipid metabolism (LPL). These data suggest that schizophrenia is primarily a disorder of brain functional and structural connectivity, with GABA neurotransmission playing a prominent role. These findings may explain the EEG gamma band abnormalities detected in schizophrenia. The analysis also revealed other high probability candidates genes (neurotransmitter signaling, other structural proteins, ion channels, signal transduction, regulatory enzymes, neuronal migration/neurite outgrowth, clock genes, transcription factors, RNA regulatory genes), pathways and mechanisms of likely importance in pathophysiology. Some of the pathways identified suggest possible avenues for augmentation pharmacotherapy of schizophrenia with other existing agents, such as benzodiazepines, anticonvulsants and lipid modulating agents. Other pathways are new potential targets for drug development. Lastly, a comparison with our earlier work on bipolar disorder illuminates the significant molecular overlap between schizophrenia and bipolar disorder.

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“…PCP also inhibits other ion channels (including voltage-dependent and the nicotinic channels) and membrane proteins, such as dopamine and serotonin receptors and transporters (Morris et al, 2005) and induces numerous changes in rat cortical gene expression (Kaiser et al, 2004). It has recently been shown that PCP affects the expression of a-amino-3-hydroxy-5-methyl4isoxazole propionate (AMPA; Barbon et al, 2007;Lindahl and Keifer, 2004), kainate (KA) (Barbon et al, 2007; see also Gao and Tamminga, 1996), and metabotropic (mGluR; Abe et al, 2001) Glu receptors as well as that of the synapse-associated protein 90/postsynaptic density-95-associated protein (Kajimoto et al, 2003), thus suggesting that PCP effects on glutamatergic transmission are not limited to NMDARs.…”

Section: Introductionmentioning

confidence: 99%

GLT‐1 expression and Glu uptake in rat cerebral cortex are increased by phencyclidine

Fattorini

Melone

Bragina

et al. 2008

Glia

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Using western blottings, microdialysis, and functional assays we tested the hypothesis that phencyclidine (PCP) modifies the expression and function of glutamate (Glu) transporters in the rat frontal cortex. Western blotting studies revealed that administration of PCP (10 mg/kg/day; 7 days) increased significantly the expression of the astrocytic Glu transporter GLT-1/EAAT2. Functional studies showed that PCP increased significantly Na+-dependent Glu uptake in slices and in neuron/astrocyte co-cultures, and microdialysis studies evidenced that PCP treatment reduced basal Glu output. In our experimental conditions, PCP did not induce toxicity. These studies show that PCP increases the expression of GLT-1 in the cerebral cortex, thereby increasing Glu uptake and reducing extracellular [Glu].

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Phencyclidine-induced changes in rat cortical gene expression identified by microarray analysis: implications for schizophrenia

Cited by 30 publications

References 144 publications

Positive association of Phencyclidine‐responsive genes, PDE4A and PLAT, with schizophrenia

Positive association of Phencyclidine‐responsive genes, PDE4A and PLAT, with schizophrenia

Towards understanding the schizophrenia code: An expanded convergent functional genomics approach

GLT‐1 expression and Glu uptake in rat cerebral cortex are increased by phencyclidine

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