Phencyclidine-induced changes in rat cortical gene expression identified by microarray analysis: implications for schizophrenia.
Acute phencyclidine induces schizophrenia-like symptoms in healthy humans and psychotic episodes in schizophrenics. Although phencyclidine is known as a N-methyl d-aspartate receptor antagonist (NMDA-R), the molecular events underlying the behavioral symptoms remain largely unknown. Statistical analysis of oligonucleotide microarray data was used to identify phencyclidine-induced alterations in rat cortical gene expression. Acute phencyclidine produced a statistically significant change in 477 genes in rat prefrontal cortex (PFC), a brain area associated with cognitive dysfunction in schizophrenics. Real-time quantitative PCR (RTQ-PCR) confirmed a subset of these changes ranging from -59% to 255% (smallest confirmation: -19%). Subsequent time-course and dose-response studies using RTQ-PCR confirmed and extended the original microarray results. At the molecular level, genes altered by phencyclidine are related to diverse biological processes including stress, inflammatory response, growth and development, neural plasticity and signal transduction. Further analysis, aimed at assessing the relevance of our results to schizophrenia, revealed dysregulation of genes related to: (i) thalamocortical projections, (ii) neurotransmission and neuromodulation, (iii) thyroid hormone activity, (iv) oligodendrocyte linage, (v) brain lipid metabolism, (vi) sleep architecture and (viii) the velocardiofacial syndrome.
Kaiser
Sergio
S
Neuroscience Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285-0438, USA.
Foltz
Lisa A
LA
George
Carolyn A
CA
Kirkwood
Sandra C
SC
Bemis
Kerry G
KG
Lin
Xi
X
Gelbert
Lawrence M
LM
Nisenbaum
Laura K
LK
D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects*; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D010622:Phencyclidine / Q000008:administration & dosage* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012559:Schizophrenia / Q000235:genetics* / Q000378:metabolism
D010622:Phencyclidine