Reelin, an extracellular glycoprotein has an important role in the proper migration and positioning of neurons during brain development. Lack of reelin causes not only disorganized lamination of the cerebral and cerebellar cortex but also malpositioning of mesencephalic dopaminergic (mDA) neurons. However, the accurate role of reelin in the migration and positioning of mDA neurons is not fully elucidated. In this study, reelin-deficient reeler mice exhibited a significant loss of mDA neurons in the substantia nigra pars compacta (SNc) and a severe alteration of cell distribution in the retrorubal field (RRF). This abnormality was also found in Dab1-deficinet, yotari mice. Stereological analysis revealed that total number of mDA neurons was not changed compared to wild type, suggesting that the loss of mDA neurons in reeler may not be due to the neurogenesis of mDA neurons. We also found that formation of PSA-NCAM-positive tangential nerve fibers rather than radial glial fibers was greatly reduced in the early developmental stage (E14.5) of reeler. These findings provide direct evidence that the alteration in distribution pattern of mDA neurons in the reeler mesencephalon mainly results from the defect of the lateral migration using tangential fibers as a scaffold.
Animals ; Brain ; Cerebellar Cortex ; Dopaminergic Neurons ; Glycoproteins ; Mesencephalon ; Mice ; Mice, Neurologic Mutants ; Nerve Fibers ; Neurogenesis ; Neurons ; Substantia Nigra

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.
Adult ; Alleles ; Animals ; Ataxia ; Axons ; Calcium Channels ; Cerebellar Ataxia ; Cerebellum* ; Chromosomes, Human, Pair 8 ; Dendrites ; Dendritic Spines* ; Epilepsy, Absence ; Humans ; Immunohistochemistry ; Mice* ; Mice, Neurologic Mutants ; Migraine with Aura ; Models, Animal ; Movement Disorders ; Nervous System Diseases ; Neurologic Manifestations ; Plastics* ; Synapses*