Medicine (Austin & Northern Health) - Research Publications
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ItemLow glycaemic index diet reduces seizure susceptibility in a syndrome-specific mouse model of generalized epilepsy(ELSEVIER, 2014-01)PURPOSE: Clinical evidence suggests that low glycaemic index diets are effective at reducing seizure frequency potentially through the stabilization of blood glucose levels. Here we investigate if diets containing carbohydrates with varying glycaemic index (GI) can modulate seizure susceptibility in a mouse model of generalized epilepsy. METHODS: Electrocortical recordings were made from mice harboring the GABAAγ2 (R43Q) epilepsy mutation after three weeks on a low-or high-GI diet. Standard rodent diet was used as a control. Occurrence and durations of spike-wave-discharges (SWDs) were measured. An insulin injection was used to reduce blood glucose to levels known to precipitate SWDs in the GABAAγ2 (R43Q) mouse on the low and high-GI diets. KEY FINDINGS: SWD occurrence was reduced by approximately 35% in mice on the low-GI compared to high-GI diet. SWD occurrence was not different between high-GI diet and a standard diet suggesting that low-GI diet is protective. Weight gain of mice for all diet groups was identical suggesting that they were equally well tolerated. Under low blood glucose conditions SWD occurrence increased in the low and high-GI diets. Importantly, under low glucose conditions the low-GI diet no longer conferred protection against SWDs. SIGNIFICANCE: SWDs were reduced in mice on a low GI-diet suggesting it may be an effective and well tolerated therapy for generalized epilepsy. The lack of effect of low-GI diet when glucose levels are reduced suggests that seizure protection in the GABAAγ2 (R43Q) mouse model may be due to the diets ability to stabilize blood glucose levels.
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ItemPhysiological and genetic analysis of multiple sodium channel variants in a model of genetic absence epilepsy(ACADEMIC PRESS INC ELSEVIER SCIENCE, 2014-07)In excitatory neurons, SCN2A (NaV1.2) and SCN8A (NaV1.6) sodium channels are enriched at the axon initial segment. NaV1.6 is implicated in several mouse models of absence epilepsy, including a missense mutation identified in a chemical mutagenesis screen (Scn8a(V929F)). Here, we confirmed the prior suggestion that Scn8a(V929F) exhibits a striking genetic background-dependent difference in phenotypic severity, observing that spike-wave discharge (SWD) incidence and severity are significantly diminished when Scn8a(V929F) is fully placed onto the C57BL/6J strain compared with C3H. Examination of sequence differences in NaV subunits between these two inbred strains suggested NaV1.2(V752F) as a potential source of this modifier effect. Recognising that the spatial co-localisation of the NaV channels at the axon initial segment (AIS) provides a plausible mechanism for functional interaction, we tested this idea by undertaking biophysical characterisation of the variant NaV channels and by computer modelling. NaV1.2(V752F) functional analysis revealed an overall gain-of-function and for NaV1.6(V929F) revealed an overall loss-of-function. A biophysically realistic computer model was used to test the idea that interaction between these variant channels at the AIS contributes to the strain background effect. Surprisingly this modelling showed that neuronal excitability is dominated by the properties of NaV1.2(V752F) due to "functional silencing" of NaV1.6(V929F) suggesting that these variants do not directly interact. Consequent genetic mapping of the major strain modifier to Chr 7, and not Chr 2 where Scn2a maps, supported this biophysical prediction. While a NaV1.6(V929F) loss of function clearly underlies absence seizures in this mouse model, the strain background effect is apparently not due to an otherwise tempting Scn2a variant, highlighting the value of combining physiology and genetics to inform and direct each other when interrogating genetic complex traits such as absence epilepsy.