Differences in white matter structure between seizure prone (FAST) and seizure resistant (SLOW) rat strains

- Increased locomotor activity in FAST compared to SLOW rats
- Decreased fraction anisotropy in corpus callosum of FAST rats
- Negative relationship between corpus callosum fraction anisotropy and behavior
- Increased axon diameter in corpus callosum of FAST rats
- Reduced g-ratio in corpus callosum of FAST rats

Alterations in white matter integrity have been well documented in chronic epilepsy and during epileptogenesis. However, the relationship between white matter integrity and a predisposition towards epileptogenesis has been understudied. The FAST rat strain exhibit heightened susceptibility towards kindling epileptogenesis whereas SLOW rats are highly resistant. FAST rats also display behavioral phenotypes reminiscent of those observed in neurodevelopmental disorders that commonly comorbid with epilepsy. In this study, we aim to identify differences in white matter integrity that may contribute to a predisposition towards epileptogenesis and its associated comorbidities in 6 month old FAST (n = 10) and SLOW (n = 10) male rats. Open field and water consumption tests were conducted to confirm the behavioral phenotype difference between FAST and SLOW rats followed by ex-vivo diffusion-weighted magnetic resonance imaging to identify differences in white matter integrity. Diffusion tensor imaging scalar values namely fractional anisotropy, mean diffusivity, axial diffusivity and radial diffusivity were compared in the anterior commissure, corpus callosum, external capsule, internal capsule, fimbria and optic tract. Electron microscopy was used to evaluate microstructural alterations in myelinated axons. Behavioral phenotyping confirmed higher activity levels (distance moved on days 2-4, p < 0.001; number of rearings on days 2 and 4, p < 0.05 at both days) and polydipsia (p < 0.001) in FAST rats. Comparative analysis of diffusion tensor imaging scalars found a significant decrease in fractional anisotropy in the corpus callosum (p < 0.05) of FAST versus SLOW rats. Using electron microscopy, alterations in myelinated axons including increased axon diameter (p < 0.001) and reduced g-ratio (p < 0.001) in the midline of the corpus callosum in 6 month old FAST (n = 3) versus SLOW (n = 4) male rats. These findings suggest that differences in white matter integrity between FAST and SLOW rats could be a contributing factor to the differential seizure susceptibility and behavioral phenotypes observed in these strains.