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

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.

Open-field behaviors and water-maze learning in the F substrain of Ihara epileptic rats.

PURPOSE: Genetically epileptic model rats, Ihara epileptic rat (IER/F substrain), have neuropathologic abnormalities and develop generalized convulsive seizures when they reach the age of approximately 5 months. Because the neuromorphologic abnormalities are centered in the hippocampus, we expected to observe spatial cognitive deficits. The present study aimed to evaluate emotionality and learning ability of the F substrain of IER. METHODS: To determine whether deficits are caused by inborn neuropathologic abnormalities or by repeated generalized convulsions, we tested nine 6- to 12-week-old IER/F rats that had not yet experienced seizures (experiment 1) and nine 7- to 9-month-old IER/F rats that had repeatedly experienced seizures (experiment 2) with identical tasks: an open-field test and the Morris water-maze place and cue tasks. RESULTS: Both groups of IER/Fs showed behaviors that were different from those of control rats in the open-field test, and extensive learning impairments were seen in both the place task, which requires spatial cognition, and the cue task, which does not require spatial cognition but requires simple association learning. Their impaired performance of the cue task indicates that their deficiency was not limited to spatial cognition. CONCLUSIONS: Because young IER/F rats without seizure experiences also showed severe learning impairments, genetically programmed microdysgenesis in the hippocampus was suspected as a cause of the severe learning deficits of IER/Fs.

Clobazam shows a different antiepileptic action profile from clonazepam and zonisamide in Ihara epileptic rats.

PURPOSE: Clobazam (CLB, 1,5-benzodiazepine, 1,5-BZP) has been reported to show unique antiepileptic action profile distinguishing from standard 1,4-BZPs. To further elucidate the action profile of CLB, its effects on the abnormal circling fits (ACFs) and generalized tonic-clonic convulsions (GTCs) in Ihara epileptic rats (IERs), a genetically epileptic mutant, were examined in comparison with conventional antiepileptic drugs (AEDs), a 1,4-BZP, clonazepam (CZP) and a non-BZP, zonisamide (ZNS). METHODS: The incidence of ACFs or GTCs in IERs was recorded automatically by the computer-assisted behavior monitoring system (COBAS N-IV) before, during and after the drug treatment period for 5 days in each. The drugs were orally administered twice daily. The daily and total incidences of ACFs or GTCs were calculated every each period in each dose group. The incidences of various behaviors such as feeding, gnawing and scratching recorded simultaneously were used for evaluating the behavioral activity (BA). RESULTS: CLB (30 and 60 mg/kg) prevented the appearance of ACFs and GTCs without affecting BAs. CZP (1 and 3 mg/kg) suppressed the occurrence of ACFs but induced no effect on the incidence of GTCs. Furthermore, it inhibited BAs at the same doses. ZNS (15 mg/kg) suppressed GTCs but little ACFs without affecting BA. CONCLUSION: CLB exhibited a different action profile from CZP and ZNS in a novel epileptic mutant, IERs, and was expected to be a useful AED superior to 1,4-BZPs in clinical practice.