Abstracts

Rationale: Focal Cortical Dysplasias (FCDs) are frequent causes of medically intractable epilepsy. Although the age at seizure onset is variable, the first seizure is usually the result of a brain insult known as the "second hit", such as a minor head trauma, brain infection, or cerebral ischemia. Following a latent period, seizures become medically-intractable. Neurotrophins acting via various Trk receptors have been implicated in promoting epileptogenesis in both human and animal models of epilepsy. We investigated the expression of Pan-Trk receptor proteins in an adult rat model of irradiation-induced FCD and upregulation of Pan-Trk proteins by a single subconvulsive dose of Pentylenetetrazol (PTZ) as a "2nd hit". Methods: Timed pregnant rats were irradiated (XRT) on E17 with 145 cGy, which is the standard protocol for inducing focal cortical dysplasias in our lab. Adult rats (PND 70) that received in utero irradiation (XRT) and control rats were injected with a single dose of PTZ (40 mg/kg, i.p.). The rats were sacrificed at 2 days (2d) and 15 days (15d) following the PTZ injection for Pan-Trk immunohistochemistry (IHC) and histological staining. All XRT rats had acquired FCD, as evidenced by histopathological examinations. The 53 rats were divided into 6 groups: 1) -XRT/-PTZ (n=10); 2) +XRT/-PTZ (n=8); 3) -XRT/+PTZ -2d (n=9); 4) +XRT/+PTZ-2d (n=8); 5) -XRT/+PTZ-15d (n=10); 5) +XRT/PTZ-15d (n=8). Results: Pan-Trk IHC immunoreactivates (IRs) in the cortex were qualitatively graded based on the extent of staining (percentage of stained neurons) and intensity of cellular staining. The student unpaired t- test was used for statistical analysis. A. Compared to normal rats, Pan-Trk receptor protein IRs were significantly higher in XRT rats (group 2 vs group1; group 4 vs group 3; group 6 vs group 5). B. Among non-XRT rats (group 1, group 3 and group 5), Pan-Trk IRs were significantly higher in rats of group 3 compared to rats of group 1. No significant difference was found between rats in group 5 vs rats in group 1 or rats in group 5 vs rats in group 3. C: Among XRT rats (group 2, group 4 and group 6), Pan-Trk IRs were significantly higher in rats of group 6 compared to rats in group 2. No significant difference was found between rats in group 2 vs rats in group 4; rats in group 4 and rats in group 6. Conclusions: The Pan-Trk proteins were increased in the FCD cortex compared to normal rat cortex. Furthermore, the 2nd hit (single PTZ injection) upregulated Pan-Trk receptor proteins in both FCD and normal rat cortices, but significantly higher in FCD groups. Moreover, the upregulated Pan-Trk receptor proteins induced by PTZ injection was temporary in normal rats but more sustained in FCD rats. It is known that neurotrophins upregulate NDMA receptors and excitatory synaptic activities. Our findings suggest that neurotrophins may have a critical role in formation and development of epileptogenicity in FCD.