Abstract
More than half of children with epilepsy outgrow their seizures, yet the underlying mechanism is unknown. GABAergic inhibition increases at puberty in female mice due to expression of extrasynaptic α4βδ GABAA receptors (GABARs). Therefore, we tested the role of these receptors in regulating seizure-like discharges in CA1 hippocampus using a high K+ (8.5 mM) seizure model. Spontaneous field potentials were recorded from hippocampus of pre-pubertal (~28–32 PND) and pubertal (~35–44 PND) female wild-type or α4−/− mice. The coastline length, a measure of burst intensity, was assessed. 8.5 mM K+ induced seizure-like discharges in over 60% of pre-pubertal slices, but only in 7% of pubertal slices, where the coastline length was reduced by 70% (P = 0.04). However, the pubertal decrease in seizure-like discharges was not seen in the α4−/−, implicating α4βδ GABARs as the cause of the decreased seizure-like activity during puberty. Administration of THIP or DS2, to selectively increase α4βδ current, reduced activity in 8.5 mM K+ at puberty, while blockade of α5-GABARs had no effect. GABAergic current was depolarizing but inhibitory in 8.5 mM K+, suggesting a mechanism for the effects of α4βδ and α5-GABARs, which exhibit different polarity-dependent desensitization. These data suggest that α4βδ GABARs are anti-convulsant during adolescence.
Highlights
Epilepsy is a common neurological disorder in childhood
The coastline length was reduced by 70% at puberty compared to pre-pubertal values, suggesting that increases in synaptic activity produced by the high K+ artificial cerebrospinal fluid (aCSF) are reduced at puberty
This study demonstrates that seizure-like activity generated by a high K+ model is significantly decreased during the pubertal period due to the increased inhibition provided by α4βδGABARs which emerge during adolescence in CA1 hippocampus[4,11]
Summary
Epilepsy is a common neurological disorder in childhood. Epilepsy is more than twice as common in children as in adults (about 700 per 100,000 in children under the age of 16 years compared to 330 per 100,000 in adults)[1]. The CA1 hippocampus, which normally exhibits very low levels of expression of this receptor exhibits a dramatic increase in expression during the pubertal period[4,10] Previous studies from this laboratory have shown that expression of α4βδGABARs increases 4 to 8-fold on the dendrites of CA1 hippocampal pyramidal cells at the onset of puberty in female mice from nearly undetectable levels assessed pre-pubertally[4,11]. This increase in tonic inhibition reduces neuronal excitability at puberty[4]. The magnitude of the resultant epileptiform activity was assessed using the coastline length measurement, a measure of individual burst intensity (the summation of burst amplitude, duration and intra-burst frequency)[12], across pubertal stages in wild-type and α4−/−mice
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