Sodium channel beta4 subunit: down-regulation and possible involvement in neuritic degeneration in Huntington's disease transgenic mice.

Sodium channel beta4 is a very recently identified auxiliary subunit of the voltage-gated sodium channels. To find the primarily affected gene in Huntington's disease (HD) pathogenesis, we profiled HD transgenic mice using a high-density oligonucleotide array and identified beta4 as an expressed sequence tag (EST) that was significantly down-regulated in the striatum of HD model mice and patients. Reduction in beta4 started at a presymptomatic stage in HD mice, whereas other voltage-gated ion channel subunits were decreased later. In contrast, spinal cord neurons, which generate only negligible levels of expanded polyglutamine aggregates, maintained normal levels of beta4 expression even at the symptomatic stage. Overexpression of beta4 induced neurite outgrowth in Neuro2a cells, and caused a thickening of dendrites and increased density of dendritic spines in hippocampal primary neurons, indicating that beta4 modulates neurite outgrowth activities. These results suggest that down-regulation of beta4 may lead to abnormalities of sodium channel and neurite degeneration in the striatum of HD transgenic mice and patients with HD.

Transcriptional profiling of a mouse model for Lafora disease reveals dysregulation of genes involved in the expression and modification of proteins.

Lafora's progressive myoclonus epilepsy (Lafora disease: LD) is caused by mutations in the EPM2A or NHLRC1 gene, but cellular mechanisms of the pathogenesis remain unclear. In an attempt to understand and elucidate the disease pathway, we have investigated the global gene expression profile in a mouse model for LD that developed a phenotype similar to that observed in human patients, including presence of Lafora bodies, neurodegeneration and profound neurological disturbances. We found 62 differentially expressed genes in the Epm2a knockout mice brains. These genes encode factors involved in protein catabolism, phosphatase, transcription factors, and molecules involved in protein translation, and homeostasis. The two largest functional groups of mRNAs that showed altered expression were predicted to be involved in post-translational modification of proteins and transcriptional regulation, suggesting that defects in protein activity and/or turnover may be the key trigger in the pathophysiology of LD. Furthermore we show that changes in gene expression are not limited to brain and are seen in other organs that develop Lafora bodies. Our study may provide valuable insights into the pathophysiology of LD and may aid in developing potential therapeutic targets.

Decreased expression of hypothalamic neuropeptides in Huntington disease transgenic mice with expanded polyglutamine-EGFP fluorescent aggregates.

Huntington disease is caused by polyglutamine (polyQ) expansion in huntingtin. Selective and progressive neuronal loss is observed in the striatum and cerebral cortex in Huntington disease. We have addressed whether expanded polyQ aggregates appear in regions of the brain apart from the striatum and cortex and whether there is a correlation between expanded polyQ aggregate formation and dysregulated transcription. We generated transgenic mouse lines expressing mutant truncated N-terminal huntingtin (expanded polyQ) fused with enhanced green fluorescent protein (EGFP) and carried out a high-density oligonucleotide array analysis using mRNA extracted from the cerebrum, followed by TaqMan RT-PCR and in situ hybridization. The transgenic mice formed expanded polyQ-EGFP fluorescent aggregates and this system allowed us to directly visualize expanded polyQ aggregates in various regions of the brain without performing immunohistochemical studies. We show here that polyQ-EGFP aggregates were intense in the hypothalamus, where the expression of six hypothalamic neuropeptide mRNAs, such as oxytocin, vasopressin and cocaine-amphetamine-regulated transcript, was down-regulated in the transgenic mouse brain without observing a significant loss of hypothalamic neurons. These results indicate that the hypothalamus is susceptible to aggregate formation in these mice and this may result in the down-regulation of specific genes in this region of the brain.

Modulation of monoamine transporter expression and function by repetitive transcranial magnetic stimulation.

Repetitive transcranial magnetic stimulation (rTMS) is a new tool for the treatment of neuropsychiatric disorders. However, the mechanisms underlying the effects of rTMS are still unclear. In this study, we analyzed mRNA expression changes of monoamine transporter (MAT) genes, which are targets for antidepressants and psychostimulants. Following a 20-day rTMS treatment, these genes were found to be differentially expressed in the mouse brain. Down-regulation of serotonin transporter (SERT) mRNA levels and the subsequent decrease in serotonin uptake and binding were observed after chronic rTMS. In contrast to the SERT changes, increased mRNA levels of dopamine transporter (DAT) and norepinephrine transporter (NET) were observed. For NET, but not DAT, there were accompanying changes in uptake and binding. Similar effect on NET was observed in PC12 cells stimulated by rTMS for 15 days. These results indicate that modulation of MATs by chronic rTMS may be one therapeutic mechanism for the treatment of neuropsychiatric disorders.

Dosage-dependent over-expression of genes in the trisomic region of Ts1Cje mouse model for Down syndrome.

Down syndrome (DS) is the most common chromosomally caused form of mental retardation and is caused by trisomy of chromosome 21. The over-expression of genes located on the trisomic region has been assumed to be responsible for the phenotypic abnormalities of DS, but this hypothesis has not been confirmed fully and the very existence of gene dosage effects has been called into question. We have therefore investigated global gene expression profiles in Ts1Cje, a mouse model for DS that displays learning deficits and has a segmental trisomy of chromosome 16 orthologous to a segment of human chromosome 21 spanning from Sod1 to Znf295. DNA microarray analyses of six Ts1Cje and six normal littermate (2N) mouse brains at postnatal day 0 with probe sets representing approximately 11,300 genes revealed that the number of expressed genes and their identities in Ts1Cje mice were almost same in 2N mice. Notably, the expression levels of most genes in the trisomic region were increased approximately 1.5-fold, and the top 24 most consistently over-expressed genes in the Ts1Cje mice were all located in the trisomic region. In contrast, the expression levels of genes on other chromosomes or the euploid region of chromosome 16 were largely the same (1.0-fold) in Ts1Cje and 2N mice. These results indicate that the genes in the trisomic region of Ts1Cje are over-expressed in a dosage-dependent manner and are implicated in the molecular pathogenesis of DS.