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.

Potential involvement of DSCAML1 mutations in neurodevelopmental disorders

“…Given that DSCAML1 is also involved in various steps in the nervous system development, we suspected that mutations in DSCAML1 may be related not only to epilepsy but also other NDDs. However, there has been no evidence showing the contribution of this gene to neuropsychiatric diseases except for our report on epilepsy (Hayase et al., 2020).…”

“…Similar to DSCAML1 C729R protein, DSCAML1 A2105T protein was barely presented on the cell surface because of its disorganized conformation. Interestingly, not only homozygotes but also heterozygotes for Dscaml1 A2105T exhibited morphological abnormalities which were also observed in IER homozygotes but not in heterozygotes (Hayase et al., 2020). This suggests that DSCAML1 A2105T may act as a dominant negative form of wild‐type DSCAML1 protein and contribute to the pathophysiology, although direct evidence for this is still lacking.…”

“…We previously identified a heterozygous DSCAML1 A2105T mutation in a limbic epilepsy patient and generated a knock‐in mice that carried the corresponding mutation (Hayase et al., 2020). Similar to DSCAML1 C729R protein, DSCAML1 A2105T protein was barely presented on the cell surface because of its disorganized conformation.…”

“…Recently, we identified Down syndrome cell adhesion molecule like 1 ( Dscaml1 ), as the responsible gene for IER (Hayase et al., 2020). DSCAML1 protein and its paralogue Down syndrome cell adhesion molecule (DSCAM) belong to the one‐transmembrane immunoglobulin (Ig) superfamily.…”

“…After screening for DSCAML1 genomic mutations in the “Depository of the patients with epilepsy and intellectual disability” of our institute (Takano et al., 2008; Takeshita et al., 2012), we identified a single nucleotide substitution that would result in a one amino acid change from alanine to threonine at the C‐terminal region of DSCAML1 ( DSCAML1 A2105T mutation) (Hayase et al., 2020). The mutant DSCAML1 A2105T protein is not presented on the cell surface, therefore resulting in its loss of function.…”