Abstracts

Rationale: The neurobiological factors that predispose to developing epilepsy (epileptogenesis) following a brain insult are poorly understood. FAST rats are a strain that have been selectively bred to have enhanced vulnerability to acquired epileptogenesis, while SLOW rats are a strain that have been bred to be resistant to epileptogenesis. FAST rats also exhibit behavioral traits that are reminiscent of those observed in developmental disorders comorbid with epilepsy, including hyperactivity, impulsivity and learning deficits. We hypothesized that white matter structure and development may differ between these strains. Methods: High resolution T2-weighted MRI images were acquired in 6 month old male FAST and SLOW rats (4.7T Bruker small animal MRI). The volumes of corpus callosum, anterior commissure, cerebral hemispheres, cerebellum, cerebellum lobules (anterior and posterior), ventricles (lateral, cerebral aqueduct, third and fourth), brainstem and hippocampus were measured using manual tracing by a single operator blinded to the strain of rat. mRNA expression of the following myelin proteins; Myelin Basic Protein (MBP), Proteolipid Protein (PLP), Myelin Oligodendrocyte Glycoprotein (MOG) and Myelin Associated Glycoprotein (MAG) was examined in post-natal day (PND) 11 and 3 month old male FAST and SLOW rats in the brainstem, cerebellum and cerebral hemisphere using quantitative polymerase chain reaction (qPCR). Neurodevelopment was assessed behaviorally by comparing locomotor activity and eye opening. Results: MRI analysis revealed that adult FAST (n=14) rats had larger volumes compared to SLOW rats (n=9) for the corpus callosum (FAST 87.22 ± 1.65 mm³, SLOW 79.13 ± 1.93 mm³, p<0.01) and for the posterior cerebellar lobules (FAST 55.68 ± 0.98 mm³, SLOW 47.74 ± 0.93 mm³, p<0.05). Compared to SLOW (n=8), FAST rats (n=8) had significantly reduced mRNA expression of two myelin proteins at PND 11 in brainstem (MBP p<0.01; PLP p<0.05), cerebellum (MBP p<0.01; PLP p<0.05) and cerebral hemisphere (MBP p<0.01; PLP p<0.01) indicating slower myelination in FAST rats during postnatal development. However, by 3 months of age there was no significant difference between FAST and SLOW rats in any myelin proteins in any brain region. Relative developmental delay was also observed in the FAST strain (n=11) with only 9% of FAST pups compared to 81% of SLOW pups (n=11) having opened their eyes by PND 13, with less locomotor activity in FAST versus SLOW rats between PND 12-16 (p<0.05). Conclusions: As adults, FAST rats have enlarged volumes of selected white matter structures, and myelination during development appears to be delayed relative to SLOW rats. These changes may be related to the heightened seizure susceptibility and behavioral phenotypes that manifest in the FAST strain.