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A Simple Composite Phenotype Scoring System for Evaluating Mouse Models of Cerebellar Ataxia
Published on: May 21, 2010
Phenotypical, genotypical and pathological characterization of the moonwalker mouse, a model of ataxia
Gabriella Sekerková1, Sumeyra Kilic1, Yen-Hsin Cheng1
1Department of Neuroscience, Northwestern University, Feinberg School of Medicine, 300 E. Superior, Chicago, IL 60611, USA.
Abstract:
We performed a comprehensive study of the morphological, functional, and genetic features of moonwalker (MWK) mice, a mouse model of spinocerebellar ataxia caused by a gain of function of the TRPC3 channel. These mice show numerous behavioral symptoms including tremor, altered gait, circling behavior, impaired motor coordination, impaired motor learning and decreased limb strength. Cerebellar pathology is characterized by early and almost complete loss of unipolar brush cells as well as slowly progressive, moderate loss of Purkinje cell (PCs). Structural damage also includes loss of synaptic contacts from parallel fibers, swollen ER structures, and degenerating axons. Interestingly, no obvious correlation was observed between PC loss and severity of the symptoms, as the phenotype stabilizes around 2 months of age, while the cerebellar pathology is progressive. This is probably due to the fact that PC function is severely impaired much earlier than the appearance of PC loss. Indeed, PC firing is already impaired in 3 weeks old mice. An interesting feature of the MWK pathology that still remains to be explained consists in a strong lobule selectivity of the PC loss, which is puzzling considering that TRPC is expressed in every PC. Intriguingly, genetic analysis of MWK cerebella shows, among other alterations, changes in the expression of both apoptosis inducing and resistance factors possibly suggesting that damaged PCs initiate specific cellular pathways that protect them from overt cell loss.
Insights
Moonwalker mice with TRPC3 channel gain-of-function mutation exhibit spinocerebellar ataxia symptoms. Cerebellar pathology includes cell loss and impaired neuron function, but the exact relationship between cell loss and symptom severity remains unclear.
Area of Science:
- Neuroscience
- Genetics
- Cell Biology
Background:
- Spinocerebellar ataxias (SCAs) are a group of neurodegenerative disorders.
- Gain-of-function mutations in the TRPC3 channel are implicated in certain neurological conditions.
- Moonwalker (MWK) mice serve as a model for studying SCA.
Purpose of the Study:
- To comprehensively investigate the morphological, functional, and genetic characteristics of MWK mice.
- To understand the pathogenesis of spinocerebellar ataxia in the context of TRPC3 channel dysfunction.
- To explore the relationship between cerebellar pathology and behavioral symptoms in MWK mice.
Main Methods:
- Behavioral analysis of MWK mice to assess motor deficits.
- Histopathological examination of cerebellar tissue to evaluate cell loss and structural damage.
- Electrophysiological recordings to assess Purkinje cell (PC) function.
- Genetic analysis of cerebellar tissue to identify molecular alterations.
Main Results:
- MWK mice display significant motor impairments, including tremor, ataxia, and reduced limb strength.
- Cerebellar pathology is marked by early loss of unipolar brush cells and progressive Purkinje cell (PC) loss, alongside synaptic and axonal damage.
- PC function is impaired early (3 weeks), preceding overt cell loss, and the phenotype stabilizes by 2 months, despite ongoing pathology.
- PC loss exhibits lobule selectivity, and genetic analysis reveals altered expression of apoptosis-related factors in MWK cerebella.
Conclusions:
- TRPC3 gain-of-function in MWK mice leads to spinocerebellar ataxia with distinct cerebellar pathology.
- Impaired PC function precedes cell loss, and the stabilization of symptoms despite progressive pathology suggests compensatory mechanisms.
- The lobule-selective PC loss and altered apoptosis factor expression indicate complex cellular responses to TRPC3 dysfunction in the cerebellum.
