Absence Epilepsy in Tottering Mutant Mice Is Associated with Calcium Channel Defects

Abstract

Mutations at the mouse tottering (tg) locus cause a delayed-onset, recessive neurological disorder resulting in ataxia, motor seizures, and behavioral absence seizures resembling petit mal epilepsy in humans. A more severe allele, leaner (tg(la)), also shows a slow, selective degeneration of cerebellar neurons. By positional cloning, we have identified an alpha1A voltage-sensitive calcium channel gene that is mutated in tg and tg(la) mice. The alpha1A gene is widely expressed in the central nervous system with prominent, uniform expression in the cerebellum. alpha1A expression does not mirror the localized pattern of cerebellar degeneration observed in tg(la) mice, providing evidence for regional differences in biological function of alpha1A channels. These studies define the first mutations in a mammalian central nervous system-specific voltage-sensitive calcium channel and identify the first gene involved in absence epilepsy.

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.…”

Effects of a Cav2.2 inhibitor on spatial and non-spatial short-term memory

“…Given that precise regulation of Ca 2+ signaling is important for neuronal processes, alterations in the Ca 2+ current through different Cav2 channels would affect the functioning of neurons and circuits that lead to memory formation. It has been reported that Cav2.1α1 is strongly expressed in the hippocampus and perirhinal cortex [17]. Our previous study examined whether a subtle disruption of Cav2.1 channel functioning is sufficient to cause deficits in memory formation using the hippocampus-related object location test for spatial memory and perirhinal cortex-related object recognition test for non-spatial memory in aged heterozygous Rolling Nagoya (rol/+) mice carrying a Cav2.1α1 mutation [5].…”

Identification of Epilepsy Genes in Human and Mouse

“…Three mutations in the α subunit gene Cacna1a were identified by positional cloning. The tottering allele substitutes leucine for a highly conserved proline in the S5-S6 linker of domain II (29). The Nagoya mutation is an arginine-to-glycine substitution in the voltage-sensing S4 segment of domain III (49).…”

“…The Nagoya mutation is an arginine-to-glycine substitution in the voltage-sensing S4 segment of domain III (49). Leaner mice have a splice site mutation in the coding region for the C-terminal domain of Cacna1a, which results in truncation of the open reading frame and expression of aberrant C-terminal sequences (29). A significant reduction in calcium current density was recorded from Purkinje cells of tottering mice (28).…”