Abstracts

RATIONALE: Fragile X syndrome is a common inherited cause of mental retardation in children. A high prevalence of complex partial epileptic disorders is seen in these patients (20-30% of the cases). Here, we used brain slices obtained from wild type (WT) and Fragile X knockout (KO) mice to identify the cellular and pharmacological mechanisms underlying the epileptiform activity induced by the cholinergic agent carbachol (CCh) in the subiculum. This limbic structure is involved in seizures recorded in patients presenting with partial seizures.
METHODS: We used field potential recordings from slices of the subiculum of WT and KO mice, during bath application of CCh.
RESULTS: Epileptiform discharges in WT animals were elicited only when concentrations of CCh larger than 70[mu]M were used. These epileptiform events were characterized by series of oscillations at 5-15Hz that rode a DC negative shift (1[ndash]4 mV in amplitude), occurred at intervals of 2-2.5s, and lasted 0.2-8 s (n=4). By contrast, similar epileptiform activity were induced in KO slices with CCh concentrations as low as 25[mu]M (n=8). Next, we investigated which muscarinic receptor subtypes contribute to the generation of CCh-induced epileptiform activity. Similar antagonistic effects were induced on CCh-induced epileptiform discharges in both WT an KO slices with methoctramine (1[mu]M, n=3; an M2 antagonist), 4DAMP (1[mu]M; n=3; an M3 antagonist). In contrast, pirenzepine (1[mu]M; n=3; an M1 antagonist) made epileptiform activity disappear in WT slices only.
CONCLUSIONS: Our findings demonstrate that subicular networks in Fragile X mice have an increased susceptibility to generate CCh-induced epileptiform discharges. These differences in muscarinic receptor mechanisms may underlie both learning and memory deficits and epileptic disorders in Fragile X patients.
[Supported by: Fragile X Research Foundation of Canada and Canadian Institutes of Health Research (CIHR).]