Developmentally regulated and thalamus-selective induction of leiomodin2 gene by a schizophrenomimetic, phencyclidine, in the rat

Abstract

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.

Identification of a developmentally-regulated and psychostimulant-inducible novel rat gene mrt3 in the neocortex

“…This view also fits with the previous observation (Takebayashi et al, 2009) that an acute PCP injection significantly elevated the Lmod2 gene mRNA levels Fig. 5 Effects of acute injection of MAP on mrt3 expression in developing rat neocortex.…”

“…Consequently, the postnatal development of the effects of MAP on the mrt3 expression is more likely to be related to that of the interconnections among the neocortical cells and/or of the molecular cascades that can receive increased dopamine signals via the D1 receptor. It is of interest to note that mrt3 shares the developmental features with mrt1 , CCN1 (Ito et al, 2007), SAP97 (Hiraoka et al, 2010) and Lmod2 (Takebayashi et al, 2009) in that the expressional alterations in responses to schizophrenomimetics occur after the critical period based on the pharmacological models of schizophrenia.…”

Identification of Developmentally Regulated PCP-Responsive Non-Coding RNA, prt6, in the Rat Thalamus

“…To obtain an insight into the molecular basis of the onset, we have focused our attention on the fact that both schizophrenia and similar psychoses induced by NMDA-type glutamate receptor antagonists, such as phencyclidine (PCP) and ketamine, or by dopamine agonists, such as amphetamines and cocaine, usually emerge after adolescence. Moreover, 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]–[3]. 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 specifically dysregulated in schizophrenia and their animal homologues.…”

Tropomodulins and tropomyosins: working as a team

“…The presence of Lmod1 was found as a result of steroid induction in human trabecular meshwork cells (Clark et al 2013). It was demonstrated that phencyclidine (a dissociative drug) induction resulted in up-regulation of Lmod2 in the thalamus of rat brain (Takebayashi et al 2009). The authors proposed that the expressional change in the level of thalamic Lmod2 is caused by the drug involvement for regulating psychological and motor function, which eventually causes age-dependent onset of drug-induced schizophrenia.…”

“…Further experiments are necessary to clarify how certain Tmod and Lmod isoforms appear in cells and tissues, where they are normally not expressed (Takebayashi et al 2009; Moyer et al 2010; Clark et al 2013). …”