Plasticity of synapses between Purkinje cell dendritic spines and parallel fiber varicosity in tottering/leaner mice cerebellum

Rhyu, Im Joo; Park, Chang Hyun; Chun, Yong Hyuck; Suh, Young Suk

Abstract

The tottering (tg/tg) is neurologic mutant mouse exhibiting three neurological disorders: ataxia, petit mal-like absence seizures and myoclonic intermittent movement disorder. The tottering mouse carries an autosomal recessive single gene mutation on chromosome 8. The leaner (tgla) and Nagoya rolling (tgrol) are another two alleles of the tottering (tg). The combination of two mutant (tottering and leaner) produces compound heterozygous, tottering/leaner (tg/tgla) mouse. The genetic etilogy of the tottering and leaner was identified to be a mutation in voltage-dependent calcium channel a1A subunit. It made us link these animal model to human neurologic disease such as autosomal dominant cerebellar ataxia (SCA6), familial hemiplegic migraine and episodic ataxia type-2. The different onset and severity of neurological symptom of these three mutants (tg/tg, tg/tgla, tgla/tgla) offer good scale to analysis of pathophysiolgy of the neurologic disorder. Altered synapase between parallel fiber varicosity and dendritic spines of Purkinje cell was observed in adult tottering and leaner mice. Through the electron microscopic observation and anticalbindin-28 kd immunohistochemistry, we anaylzed not only the relationship between neurologic symptoms and synaptic plasticity around the ataxic onset of tottering, leaner and tottering leaner double mutation but also Purkinje cell morphology affected by voltage-sensitive calcium channel a1A subunit mutation in totterring mouse. Purkinje cell dendritic spines from proximal dendrites and axonal swellings of Purkine cell were observed frequently in wild type mice. The first apperance point of altered synapse based on semi-quantitative analysis was postnatal 15 days in leaner, postnatal 18 days in totering/leaner double mutation, and 30 days in tottering. These data suggest that altered synapse is associated with ataxia in tottering and leaner mice. Further study is needed to determine whether altered synapse is primary cause of ataxia.