Abstracts

Rationale: The 6 Hz, low frequency electroshock model of experimental epilepsy induces partial or “psychomotor” seizures.  Unlike conventional high frequency electroshock whereby seizure severity progresses from “minimal” to “maximal” behavioral endpoints with increasing stimulus amplitude, the seizure endpoint in the 6 Hz model does not escalate.  Anticonvulsant and antiepileptic drugs are also known to have significantly different efficacies between the two electroconvulsive models, and the 6 Hz test in particular is considered to be useful for studying pharmacoresistant epilepsy (e.g. Barker-Haliski et al. 2017, Neurochem Res., Mar 16), although to date it has not been widely used in genetic models.   We included the 6 Hz test in our assessments of seizure susceptibility in several newly developed mouse models of intractable genetic epilepsy. Methods: Electroconvulsive thresholds were determined by sequential daily testing of individual mice using transcorneal electrodes on a modified Ugo Basile Electroconvulsive Device, using either high frequency (299 or 280 Hz, 1.6 ms pulse width, 0.2 s duration), or low frequency stimulus (6 Hz, 0.2 ms pulse width, 3.0 s duration).  Mean thresholds of each genotype/sex were determined from at least 8 individuals, and were rank- and normal-quantile transformed prior to statistical analysis. Results: We observed at least three mouse mutants that have unusually elevated thresholds to the 6 Hz test – Cdkl5-/Y, Iqsec2-/Y or -/+,and Grin2aS644G/+.– between 3 mA and 7 mA higher than that of respective controls, highly significant at p < 0.0001 but essentially a binary effect.  This robust resistance was independent of the respective spontaneous seizure or high frequency electroshock susceptibility conferred by these genotypes.  Other new mutants examined, including Arfgef1-/+ and Gnb1K78R/+, have low threshold to conventional electroshock but do not have abnormally elevated 6 Hz threshold. Conclusions: We are proceeding with the hypothesis that this 6 Hz resistance phenomenon is a proxy for constitutional neurodevelopmental defects that are shared by several intractable genetic epilepsies, the pathogenic mechanism(s) of which are currently under investigation. Funding: NIH R37 NS031348NIH U54 OD020351