Abstracts

To identify new genes involved in temporal lobe epilepsy (TLE) using quantitative trait locus (QTL) mapping, initial studies were conducted to compare the pilocarpine model of TLE in A/J vs. DBA/2J mouse strains, two strains that are fully sequenced. The incidence and latency to status epilepticus were compared using pilocarpine doses that spanned the dose-response curve. Animals that had status were also compared after recurrent, spontaneous seizures developed, to examine structural changes that often accompany chronic seizures: hippocampal neuronal loss, mossy fiber sprouting, mossy fiber neuropeptide Y (NPY) expression, and hilar ectopic granule cells (EGCs)., Male mice (10 wks old) were administered atropine methylbromide (5mg/kg, s.c.) 30[apos] before pilocarpine hydrochloride (200, 220, 250, or 300mg/kg, i.p.), and 1 hr after the onset of status, diazepam was administered (5mg/kg, i.p.). Mice were transcardially-perfused [gt] 4 wks after status, and immunocytochemistry was conducted using antibodies to NeuN, a neuronal marker (1:5,000, Chemicon), NPY (1:30,000, Peninsula), or PROX1 to label granule cells (1:60,000, Covance). PROX1-labeled EGCs were quantified using stereology (StereoInvestigator software)., A/J mice had a higher incidence of status, if animals which died after a tonic-clonic seizure, prior to clear signs of status, were excluded. However, the incidence of these tonic-clonic seizures was higher for A/J mice than DBA mice, and the tonic-clonic event could have been the start of status, so an incidence comparison is complex. When status occurred, the mean ([plusmn]sem) latency to status was longer for A/J mice at all doses (A/J: 132.6[plusmn]6.5min, n=26; DBA: 30.4[plusmn]1.7min, n=24; p[lt]0.05). Recordings in A/J mice confirmed that the onset of behavioral status reflected the onset of electrographic status (n=4). All DBA mice demonstrated neuronal loss in CA3 (n=6/6), but all A/J mice did not (n=3/6). Neuronal loss was detected in area CA1 in DBA (n=3/6) but not A/J mice (n=0/6). Both strains demonstrated NPY expression in mossy fibers (A/J: n=5/6; DBA: n=4/5). There were more EGCs in DBA mice (A/J: 3029.9[plusmn]1053.4 cells/hippocampus, n=4; DBA: 9590.2[plusmn]1979.2, n=6; p[lt]0.05)., A/J and DBA/2J mice show differences in acute behavioral and long-term anatomical changes with the pilocarpine model. Differences suggest that use of one variable to define susceptibility can be misleading. The results suggest guidelines for future studies of strain-dependent seizure susceptibility, and characterize an infrequently-studied strain for QTL mapping of seizure susceptibility., (Supported by NINDS R01 41490, K02 NS050429, K23 NS02211.)