Differential expression of T-type calcium channels in P/Q-type calcium channel mutant mice with ataxia and absence epilepsy

Abstract

Mutations in P/Q-type calcium channels generate common phenotypes in mice and humans, which are characterized by ataxia, paroxysmal dyskinesia, and absence seizures. Subsequent functional changes of T-type calcium channels in thalamus are observed in P/Q-type calcium channel mutant mice and these changes play important roles in generation of absence seizures. However, the changes in T-type calcium channel function and/or expression in the cerebellum, which may be related to movement disorders, are still unknown. The leaner mouse exhibits severe ataxia, paroxysmal dyskinesia, and absence epilepsy due to a P/Q-type calcium channel mutation. We investigated changes in T-type calcium channel expression in the leaner mouse thalamus and cerebellum using quantitative real-time polymerase chain reaction (qRT-PCR) and quantitative in situ hybridization histochemistry (ISHH). qRT-PCR analysis showed no change in T-type calcium channel alpha 1G subunit (Cav3.1) expression in the leaner thalamus, but a significant decrease in alpha 1G expression in the whole leaner mouse cerebellum. Interestingly, quantitative ISHH revealed differential changes in alpha 1G expression in the leaner cerebellum, where the granule cell layer showed decreased alpha 1G expression while Purkinje cells showed increased alpha 1G expression. To confirm these observations, the granule cell layer and the Purkinje cell layer were laser capture microdissected separately, then analyzed with qRT-PCR. Similar to the observation obtained by ISHH, the leaner granule cell layer showed decreased alpha 1G expression and the leaner Purkinje cell layer showed increased alpha 1G expression. These results suggest that differential expression of T-type calcium channels in the leaner cerebellum may be involved in the observed movement disorders.

Targeted Deletion of a SingleSca8Ataxia Locus Allele in Mice Causes Abnormal Gait, Progressive Loss of Motor Coordination, and Purkinje Cell Dendritic Deficits

“…Alternatively, KLHL1 could be involved in anchoring other associated proteins essential for postsynaptic functions, such as ion channels, to the actin network of the spine (Shirao and Sekino, 2001). Because disruptions of ion channel activity are known causes of Purkinje cell dysfunction and ataxia (Nahm et al, 2005;Walter et al, 2006), we find this latter possibility particularly intriguing.…”

Normal motor learning during pharmacological prevention of Purkinje cell long-term depression

“…It is now well recognized that embryonic gene deletion or mutation can lead to unintended increases in the expression of untargeted proteins that may be compensatory to mask a phenotype (20,21,22) or secondary changes that may produce phenotypes not directly related to the targeted or mutant protein (23,24,25). Acute administration and rapid clearance of T-588 in the normal brain allows LTD to be transiently prevented without the consequences of an embryonic mutation.…”

The Cav2.3 voltage-gated calcium channel in epileptogenesis—Shedding new light on an enigmatic channel

“…However, in some mouse models, e.g. Ca v 2.1 leaner, Ca v 3.1 is down regulated in the cerebellar granule cells while expression in Purkinje cells is increased and might therefore be involved in complex movement disorders such as ataxia and paroxysmal dyskinesia (Nahm et al, 2005;Pietrobon 2005). Thus, increased T-type Ca 2+ currents in various structural components of the thalamocortical circuitry seem to be a common feature in absence epileptogenesis though it is not an absolute must (Song et al, 2004).…”