Mice with Targeted Deletion of the CACNA2D2 Regulatory Calcium Channel Subunit Gene Exhibit EEG Spikes and Reduced Seizure Threshold.
Abstract number :
3.016
Submission category :
Year :
2001
Submission ID :
3102
Source :
www.aesnet.org
Presentation date :
12/1/2001 12:00:00 AM
Published date :
Dec 1, 2001, 06:00 AM
Authors :
M.K. Banks, Ph.D., NINDS, ERB, NES, NIH, Bethesda, MD; S.V. Ivanov, Ph.D., SAIC, NIH, Frederick, MD; L. Tessarollo, Ph.D., NCI-Frederick, NIH, Frederick, MD; D.B. Djurickovic, D.V.S., SAIC, NIH, Frederick, MD; M.I. Lerman, M.D., Ph.D., NCI-Frederick, NIH,
RATIONALE: There has been considerable interest in the role of voltage-gated calcium channels in epilepsy. In mice, naturally occurring mutations in the genes encoding several calcium channel subunits are associated with spike-wave seizures characteristic of absence epilepsy. Moreover, variations in at least one human calcium channel subunit gene have been associated with idiopathic generalized epilepsies (Escayg et al., 2000). Supportive evidence for a role of calcium channel subunits in the pathophysiology of seizures can also be surmised from the discovery of gabapentin binding sites on [alpha]2[delta] calcium channel subunits (Marais et al., 2001).
Recently, Gao et al. cloned a new human calcium channel auxiliary subunit gene, [alpha]2[delta]-2 ([italic]CACNA2D2[/italic]), which shares 56% amino acid identity with the previously known [alpha]2[delta]-1 subunit. The region of the human chromosome 3p21.3 harboring the [italic]CACNA2D2[/italic] gene was found to be syntenic with the believed locus of the mouse neurological mutant [italic]ducky[/italic] on chromosome 9. Knockout of the mouse [italic]CACNA2D2[/italic] gene is associated with neurological abnormalities like those of [italic]ducky[/italic]. Here we sought to determine if these knockout animals have an epileptic phenotype.
METHODS: Mice were implanted with cortical screw electrodes, one over each cerebral hemisphere and a third over the cerebellum as reference. After a recovery period of at least 7 days, animals underwent EEG recording for at least 2 hours. The convulsant threshold was assessed by i.p. injection with 10 to 80 mg/kg of pentylenetetrazol (PTZ).
RESULTS: Homozygous [italic]CACNA2D2[/italic] knockout animals demonstrated frequent high-voltage spike-and-wave events; these spikes were not present in heterozygous or wild type animals. Substantially lower doses of PTZ evoked seizure activity in homozygous knockout mice.
CONCLUSIONS: These converging lines of evidence (EEG and pharmacological) indicate that knockout of [italic]CACNA2D2[/italic] produces an epileptic phenotype, further supporting a role for voltage-activated calcium channels in epilepsy susceptibility. It will be of interest to reexamine the possibility that [italic]ducky[/italic] also exhibits occult epileptiform activity.
Support: National Institutes of Health.