Abstract:

The Ihara epileptic rat (IER) is a mutant model with limbic-like seizures whose pathology and causative gene remain elusive. In this report, via linkage analysis, we identified Down syndrome cell adhesion molecule-like 1(Dscaml1) as the responsible gene for IER. A single base mutation in Dscaml1 causes abnormal splicing, leading to lack of DSCAML1. IERs have enhanced seizure susceptibility and accelerated kindling establishment. Furthermore, GABAergic neurons are severely reduced in the entorhinal cortex (ECx) of these animals.
Voltage-sensitive dye imaging that directly presents the excitation status of brain slices revealed abnormally persistent excitability in IER ECx. This suggests that reduced GABAergic neurons may cause weak sustained entorhinal cortex activations, leading to natural kindling via the perforant path that could cause dentate gyrus hypertrophy and epileptogenesis. Furthermore, we identified a single nucleotide substitution in a human epilepsy that would result in one amino acid change in DSCAML1 (A2105T mutation). The mutant DSCAML1A2105T protein is not presented on the cell surface, losing its homophilic cell adhesion ability. We generated knock-in mice (Dscaml1A2105T) carrying the corresponding mutation and observed reduced GABAergic neurons in the ECx as well as spike-and-wave electrocorticogram. We conclude that DSCAML1 is required for GABAergic neuron placement in the ECx and suppression of seizure susceptibility in rodents. Our findings suggest that mutations in DSCAML1 may affect seizure susceptibility in humans.

日本語要旨:

イハラてんかんラット（IER) の解析から得られた責任候補遺伝子 Down syndrome cell adhesion molecule-like 1(Dscaml1)について、NCNPバイオバンクに登録されている知的障害・てんかん症例30例の検討の結果、2つのバリアントを見いだした。そのうちの一つ A2105Tをヘテロでもつマウスを作製したところ、てんかんを発症した。IERではホモ変異で病態が形成されていたものの、ヒトにおいてはA2105Tがドミナント・ネガティブな効果で病態を形成していると考えられた。以上から、IERの責任原因遺伝子は Dscaml1と結論づけた。