Abstracts

RATIONALE: The Kcna1-null mouse presents with recurrent spontaneous seizures beginning during the 2nd to 3rd postnatal week, providing a clinically relevant model of developmental epilepsy. In vivo electrophysiological recordings were conducted in the dentate gyrus of Kcna1 wild-type (+/+), heterozygote (+/-), and knockout mice (-/-) to investigate potential genotypic differences in network excitability. We also examined the effects of a ketogenic diet (KD), a treatment for children with intractable epilepsy, on excitability in the Kcna1 -/- mouse.
METHODS: Postnatal day 37-47 animals (-/-, n=14; +/-, n=9; and +/+, n=8) were anesthetized with urethane (1.5g/kg) and electrodes were positioned ipsilaterally into the granule cell layer of the dentate gyrus (recording) and the angular bundle (stimulating). Paired pulses (0.1Hz) were delivered to assess network inhibition/facilitation within the dentate gyrus, using inter-stimulus intervals (ISIs) of 30, 70, and 250ms. In addition, stimulus trains (pulses of 0.3ms duration, 20Hz, 30s train) of increasing intensities were administered until electrographic-seizure (maximal dentate activation-) threshold was determined. Half the mice in each genotypic group were fed either a normal diet (ND) (Rodent Chow, Purina) or a ketogenic diet (Bio-Serv, F-3666) beginning at age P18-21. Diets were maintained for [gt]17 days and fed ad libitum. Plasma beta-hydroxybutyrate (BHB) levels were assessed using a Keto-site reflectance meter.
RESULTS: For ND-fed mice, a greater paired-pulse population spike inhibition (in response to one-half maximal stimulation) was seen at the 30ms ISI in the Kcna1 -/- mice (n=6), compared to the +/+ (n=3, p[lt]0.001) and +/- (n=4, p[lt] 0.025) mice. Kcna1 -/- mice also showed a higher threshold to maximal dentate activation compared to +/+ or +/- ND-fed littermates. Preliminary observations comparing ND- and KD-fed animals indicate that ND-fed Kcna1 -/- mice showed more paired-pulse inhibition compared to KD-fed -/- animals at all intervals tested (30, 70, and 250ms). There were no other diet-induced differences across genotypes.
CONCLUSIONS: These data indicate that the spontaneously-epileptic Kcna1 -/- mice exhibit enhanced early inhibition to paired-pulse stimulation within the dentate gyrus and an elevated threshold to electrographic seizures at 5-6 weeks of age. This finding is consistent with previous work demonstrating augmented inhibition in other chronic seizure models. Preliminary results of ketogenic diet treatment do not indicate that KD further augments this inhibition.
[Supported by: This work was supported by the University of Washington Pediatric Epilepsy Research Center and the NIH-RO1 DC03805 (BLT).]