Abstract
Schizophrenia and similar psychoses induced by NMDA-type glutamate receptor antagonists, such as phencyclidine (PCP) and ketamine, usually develop after adolescence. Moreover, adult-type behavioral disturbance following NMDA receptor antagonist application in rodents is observed after a critical period at around 3 postnatal weeks. These observations suggest that the schizophrenic symptoms caused by and psychotomimetic effects of NMDA antagonists require the maturation of certain brain neuron circuits and molecular networks, which differentially respond to NMDA receptor antagonists across adolescence and the critical period. From this viewpoint, we have identified a novel developmentally regulated phencyclidine-responsive transcript from the rat thalamus, designated as prt6, as a candidate molecule involved in the above schizophrenia-related systems using a DNA microarray technique. The transcript is a non-coding RNA that includes sequences of at least two microRNAs, miR132 and miR212, and is expressed strongly in the brain and testis, with trace or non-detectable levels in the spleen, heart, liver, kidney, lung and skeletal muscle, as revealed by Northern blot analysis. The systemic administration of PCP (7.5 mg/kg, subcutaneously (s.c.)) significantly elevated the expression of prt6 mRNA in the thalamus at postnatal days (PD) 32 and 50, but not at PD 8, 13, 20, or 24 as compared to saline-treated controls. At PD 50, another NMDA receptor antagonist, dizocilpine (0.5 mg/kg, s.c.), and a schizophrenomimetic dopamine agonist, methamphetamine (4.8 mg/kg, s.c.), mimicked a significant increase in the levels of thalamic prt6 mRNAs, while a D2 dopmamine receptor antagonist, haloperidol, partly inhibited the increasing influence of PCP on thalamic prt6 expression without its own effects. These data indicate that prt6 may be involved in the pathophysiology of the onset of drug-induced schizophrenia-like symptoms and schizophrenia through the possible dysregulation of target genes of the long non-coding RNA or microRNAs in the transcript.
Highlights
Schizophrenia is a severe psychiatric disorder that occurs in the early stages of life with a high morbidity rate
These clinical and experimental observations suggest that schizophrenic symptoms and psychotomimetic effects of NMDA receptor antagonists and dopamine agonists may require the maturation of certain brain neuron circuits and molecular networks dysregulated in schizophrenia and their animal homologues
The DNA array screening revealed that candidates for the transcripts differentially regulated by PCP in the thalamus between infant and adult rats include the EST of Affymetrix ID: 1392108_at, which is designated as PCP-responsive transcript 6
Summary
Schizophrenia is a severe psychiatric disorder that occurs in the early stages of life with a high morbidity rate. This common disorder produces various mental disturbances and often results in serious disability due to antipsychotic-resistant symptoms. Adult-type behavioral disturbances following the application of NMDA receptor antagonists or dopamine agonists in rodents, which are recognized as models of schizophrenia, are observed after a critical period at around 3 postnatal weeks [1,2,3]. The molecules composing the above systems should differentially respond to NMDA receptor antagonists or dopamine agonists across adolescence or the critical period
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