Developmentally regulated and thalamus-selective induction of leiomodin2 gene by a schizophrenomimetic, phencyclidine, in the rat.
The onset of schizophrenia and the schizophrenomimetic effects of an N-methyl-D-aspartate (NMDA) receptor antagonist, ketamine, rarely occur during infancy and childhood, suggesting that schizophrenia-related neuron circuits and molecules in the brain might show an age-related response to an NMDA receptor antagonist. By using a DNA microarray technique, we have identified the developmentally regulated PCP-inducible gene leiomodin2 (Lmod2) that encodes a tropomyosin-binding actin-capping protein enriched in the cardiac and skeletal muscles. PCP caused an increase in the thalamic amounts of Lmod2 transcripts at postnatal days (PD) 32 and 50 without affecting them at PD 8, 13, 20 and 24, while the NMDA antagonist failed to produce a significant change in the gene expression in the adult heart. In-situ hybridization analysis revealed that the basal and PCP-induced expression of the Lmod2 gene is almost confined to the lateral and anterior nuclei of the thalamus among the brain regions at PD 50. The PCP-induced up-regulation of Lmod2 mRNAs in the adult thalamus was mimicked totally (also up-regulated) by another NMDA antagonist, dizocilpine, and partly by the indirect dopamine agonist, methamphetamine. Moreover, pretreatment with a D(2)-preferring dopamine receptor antagonist, haloperidol, partially antagonizes the increasing effects of PCP on thalamic Lmod2 gene expression. These findings suggest that Lmod2 might be involved in the pathophysiology of the age-dependent onset of drug-induced schizophrenia-like psychosis and schizophrenia and that the limited thalamic nuclei expressing the Lmod2 gene could compose the neuron circuits that are specifically disturbed in these mental disorders.
Takebayashi
Hironao
H
Section of Psychiatry and Behavioral Sciences, Tokyo Medical and Dental University Graduate School, Tokyo, Japan.
Yamamoto
Naoki
N
Umino
Asami
A
Nishikawa
Toru
T
D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal / Q000187:drug effects; D003598:Cytoskeletal Proteins / Q000235:genetics* / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D020869:Gene Expression Profiling / Q000379:methods; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D006213:Hallucinogens / Q000494:pharmacology*; D006220:Haloperidol / Q000494:pharmacology; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D010622:Phencyclidine / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013788:Thalamus / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D013997:Time Factors; D051348:Tropomodulin / Q000235:genetics / Q000378:metabolism
D003598:Cytoskeletal Proteins; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D018691:Excitatory Amino Acid Antagonists; D006213:Hallucinogens; C545284:Lmod2 protein, rat; D008840:Microfilament Proteins; D009124:Muscle Proteins; D012333:RNA, Messenger; C495832:Tmod1 protein, rat; C495835:Tmod2 protein, rat; D051348:Tropomodulin; D016291:Dizocilpine Maleate; D010622:Phencyclidine; D006220:Haloperidol