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Decreased gene expression of calretinin and ryanodine receptor type 1 in tottering mice
M Cicale1, A Ambesi-Impiombato, V Cimini
1Department of Neuroscience and Behavioral Sciences, Unit of Molecular Psychiatry, Section of Psychiatry, University School of Medicine Federico II, Naples, Italy.
Abstract:
Tottering mice are a spontaneously occurring animal model of human absence epilepsy. They carry a mutation in the P/Q-type calcium channel alpha1A subunit gene which is highly expressed by cerebellar Purkinje cells. In this study, we investigated the role of calretinin and ryanodine receptor type 1 (RyR1) gene expression in the cerebellum of tottering mice. Cerebellar tissue specimens from four experimental groups were processed for in situ hybridization histochemistry (ISHH): (1) wild-type (+/+); (2) heterozygous (tg/+) and two homozygous groups; either (3) without occurrence of an episode of paroxysmal dyskinesia (tg/tg-N); or (4) after an episode of paroxysmal dyskinesia (tg/tg-P) that lasted about 45 min on average. Quantitative analysis showed a statistically significant decrease (p = 0.0001, ANOVA) of calretinin gene expression at the level of the simple lobule of the cerebellum in both homozygous groups compared to the wild-type and heterozygous groups. RyR1 was decreased in the flocculus of the cerebellum in both the tg/tg-N and tg/tg-P groups compared to wild type (p = 0.0174, ANOVA). These results suggest that calretinin gene expression, as well as other genes involved in regulation of calcium homeostasis, such as RyR1, may play a role in the biochemical functional alterations present in tottering mice.
Insights
Tottering mice, an epilepsy model, show decreased calretinin and ryanodine receptor type 1 (RyR1) gene expression in the cerebellum. These findings suggest a role for calcium homeostasis genes in the disorder.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Tottering mice serve as a model for human absence epilepsy.
- They possess a mutation in the P/Q-type calcium channel alpha1A subunit gene.
- This gene is highly expressed in cerebellar Purkinje cells.
Purpose of the Study:
- To investigate calretinin and ryanodine receptor type 1 (RyR1) gene expression in the cerebellum of tottering mice.
- To understand the role of these genes in the biochemical alterations observed in this epilepsy model.
Main Methods:
- Utilized in situ hybridization histochemistry (ISHH) on cerebellar tissue from wild-type, heterozygous, and two homozygous tottering mouse groups (pre- and post-seizure).
- Performed quantitative analysis to assess gene expression levels.
- Employed analysis of variance (ANOVA) for statistical significance.
Main Results:
- A significant decrease in calretinin gene expression was observed in the cerebellar simple lobule of homozygous tottering mice compared to controls (p = 0.0001).
- RyR1 gene expression was reduced in the cerebellum's flocculus in both homozygous groups compared to wild-type mice (p = 0.0174).
Conclusions:
- Calretinin gene expression is significantly downregulated in the cerebellum of tottering mice.
- Ryanodine receptor type 1 (RyR1) gene expression is also decreased, suggesting its involvement.
- These findings highlight the potential role of calcium homeostasis-related genes in the pathophysiology of tottering mice and absence epilepsy.
