Mutant mice as a model for cerebellar ataxia

Reduced Sodium Current in Purkinje Neurons from NaV1.1 Mutant Mice: Implications for Ataxia in Severe Myoclonic Epilepsy in Infancy

“…We used our mouse genetic model of SMEI to investigate the relationship between loss of Na V 1.1 channels and ataxia, based on the hypothesis that deletion of the Na V 1.1 channel reduces the excitability of GABAergic Purkinje neurons, which are the output pathway for information on movement, coordination, and balance from the cerebellar cortex. Degeneration of Purkinje neu-rons and abnormal expression of voltage-gated ion channels in them are associated with ataxia (Fletcher et al, 1996;Grusser-Cornehls and Baurle, 2001;Sausbier et al, 2004). Here, we report that both Na V 1.1 KO and heterozygous (HET) mice are ataxic and that the sodium currents and electrical excitability of their Purkinje neurons are sharply reduced, consistent with the conclusion that loss of Purkinje neuron excitability may be sufficient to cause ataxia in these mice and potentially in SMEI patients.…”

“…Moreover, previous studies have linked alterations of ion channel expression or function in Purkinje neurons with ataxia Sausbier et al, 2004;Nahm et al, 2005). Although Na V 1.1 channels are reduced throughout the brain by our gene deletion, it is likely that reduction in Purkinje neurons alone is sufficient to cause ataxia because ataxic symptoms have been previously observed in mutant mice with specific degeneration of cerebellar Purkinje neurons (Grusser-Cornehls and Baurle, 2001) and with cerebellar Purkinje neuron-specific deletion of Na V 1.6 (Levin et al, 2006). Thus, our results suggest that ataxia in Na V 1.1 mutant mice and SMEI patients may be caused by loss of excitability of Purkinje neurons.…”

“…Cerebellar ataxia is characterized by instability of posture and gait, incoordination, atactic reaching and grasp, tremor, dysmetria, muscular hypotonia, and impairment of fine control of movements (Grusser-Cornehls and Baurle, 2001). To evaluate these impairments, WT mice and their mutant littermates (P13-P21) were subjected to a set of behavioral tests.…”

Concise Review: Stem Cells for the Treatment of Cerebellar-Related Disorders

“…Autosomal dominant cerebellar ataxias are an important group of hereditary diseases that includes a variety of SCAs, [1][2][3][4][5][6][7] and a group of episodic ataxias (reviewed in [10,11]). The massive death of PCs is also characteristic of other hereditary and sporadic cerebellar atrophies, including Holmes type of familial cerebello-olivary atrophy, late type of cerebellar atrophy (Marie-Foix-Alajouanine), recessively inherited Fridreich's ataxia, and Ataxia-telangiectasia (A-T) [12].…”

“…It is considered that the wv mutant may be important disease model for GC loss as it is the case in certain types of hereditary degenerative cerebellar atrophy such as the GC hypoplasia in humans [10,55] or olivopontocerebellar atrophy. The pcd mutant represents an animal model related more to PC loss such as cerebello-olivary atrophy [12,28].…”