Abstracts

Rationale:
Childhood absence epilepsy (CAE) is the most common type of pediatric epilepsy. Children with CAE have poor academic performance associated with deficits in multiple cognitive domains, including attention and executive function. Our poor understanding of the disease is underscored by the fact that first-line anti-seizure medications are not effective in nearly 50% of CAE patients, and do not alleviate attention deficits, one core feature of CAE. While many single gene mouse models are available, familial monogenic CAE is uncommon. Polygenic variants likely explain the majority of sporadic CAE patients. However, this complex genetic etiology has not been systematically explored in mouse models. Many sporadic CAE patients carry mutations in CACNA1H, the gene that encodes the Cav3.2 T-type calcium channel α1H, and CACNA1H polymorphisms are more common in pharmacoresistant CAE patients. However, Cacna1h knockout mice do not develop a CAE phenotype. Interestingly, our recent study demonstrates that loss of Cacna1h promotes absence seizure generation in P/Q-type calcium channel knockout mice (Miao et al, Brain, 2020). To explore whether the pathogenic role of Cacna1h in CAE is dependent upon the presence of other related genetic defects, we tested whether removal of a single copy of Cacna1h could interact with Cacna1a, the P/Q-type calcium channel gene underlying CAE in both mice and humans.
Method:
We crossed heterozygous α1A (α1A+/-) mice with α1H knockout (α1H-/-) mice, which lacking a spike-wave seizure phenotype (Figure 1), to create compound double heterozygous (α1A+/-;α1H+/-) mice. EEG recordings are performed on these mice and control α1A+/- and α1H+/- mice.
Results:
Surprisingly, α1A+/-;α1H+/- mice (n = 7) display robust absence epilepsy (Figure 2), but control α1A+/- and α1H+/- mice do not. These results reveal the epileptogenic contribution of a single Cacna1h mutant allele. Future studies using this digenic CAE model, will determine whether α1A+/-;α1H+/- mice develop attention deficits, and explore the region specific role of a second T-type calcium channel, α1G, known to be essential for thalamocortical spike-wave seizures in mice.
Conclusion:
The α1A+/-;α1H+/- mouse described here is the first digenic mouse model for CAE and reveals a complex pathogenic role for the mutation of CACNA1H, the most common gene linked with human CAE.
Funding:
:NINDS NS29709