Down syndrome cell adhesion molecule like-1 (DSCAML1) links the GABA system and seizure susceptibility.

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.

• Authors: Yoneko Hayase, Shigeru Amano, Koichi Hashizume, Takashi Tominaga, Hiroyuki Miyamoto, Yukie Kanno, Yukiko Ueno-Inoue, Takayoshi Inoue, Mayumi Yamada, Shigehiro Ogata, Shabeesh Balan, Ken Hayashi, Yoshiki Miura, Kentaro Tokudome, Yukihiro Ohno, Takuma Nishijo, Toshihiko Momiyama, Yuchio Yanagawa, Akiko Takizawa, Tomoji Mashimo, Tadao Serikawa, Akihiro Sekine, Eiji Nakagawa, Eri Takeshita, Takeo Yoshikawa, Chikako Waga, Ken Inoue, Yu-Ichi Goto, Yoichi Nabeshima, Nobuo Ihara, Kazuhiro Yamakawa, Shinichiro Taya, Mikio Hoshino
• Journal: Acta neuropathologica communications (Acta Neuropathol Commun) Vol. 8 Issue 1 Pg. 206 (11 30 2020) ISSN: 2051-5960 [Electronic] England
• PMID: 33256836 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cell Adhesion Molecules
• DSCAML1 protein, mouse

Topics

• Animals
• Cell Adhesion Molecules (genetics)
• Electroencephalography
• Entorhinal Cortex (pathology)
• GABAergic Neurons (pathology)
• Genetic Predisposition to Disease
• Kindling, Neurologic (genetics)
• Mice
• Rats
• Rats, Mutant Strains
• Seizures (genetics)