Abstracts

Fragile X syndrome is the most common inherited form of mental retardation, affecting 1 in 1200 males and 1 in 2500 females. The syndrome is characterized primarily by intellectual impairment, ranging from mild learning disability to profound mental retardation. We are interested in studying the cellular electrophysiological factors underlying the pathophysiology of seizure activity in the brain tissue of Fragile X mental retardation protein (FMRP) gene knockout mice (KO)., We have characterized the induction of seizure-like events (SLE) in young adult mouse hippocampal slices exposed to low Mg-ACSF and tetanic stimulation bouts, as with our previous KO mice. All recording were performed on transverse hippocampal slices (400 [micro]m) from mice aged 6-9 weeks, in oxygenated ACSF, at 33[deg]C. SLEs and extracellular field responses were recorded from the CA1 pyramidal layer of the hippocampal slices, in response (were appropriate) to Schaffer collateral stimulation., The KO mice hippocampal slices were more easily induced into SLEs with either low Mg-ACSF, or by repetitive tetanizations. KO slices showed a shorter lag time to SLE of 15.4 min. vs 26.5 min. in wt slices, required fewer tetanic stimuli to produce SLEs. A brief application of the mGluR5 antagonist MPEP (at 1 or 10 [micro]M delayed the onset of low Mg-induced, but not tetanic stimulation-induced SLEs in KO hippocampal slices by more than 3-fold. However, we found that longer application of this same drug leads to diminished (with low Mg-ACSF exposure) or increased susceptibility (with tetanic stimuli) to SLEs in the KO hippocampus.
Also, we have found that inhibitory network that regulates paired-pulse inhibition in CA1 of the hippocampus, is dramatically reduced in the KO hippocampus, leading to a complete lack of PPI that can be elicited in the wt slices. Conversely, we have found that paired-pulse facilitation is significantly enhanced in the KO hippocampus as compared to the wt, and that this may point to alterations in presynaptic calcium handling in these FMRP knockout mice., We have found that hippocampi from FMRP knockout mice are more easily induced into seizure-like events in vitro. We are continuing work to further elucidate the nature of mGluR regulation of SLEs in this model, as well as the influence of inhibitory inputs in the KO hippocampus on seizure susceptibility in these mice., (Supported by the Fragile X Research Foundation of Canada (CJF), The Savoy Foundation (MD), and CIHR (PLC).)