Abstracts

Rationale: Malformations of cortical development (MCD) are a common cause of epilepsy and cognitive impairment. Here we investigated the potential effect of environmental enrichment on the cognitive impairments associated with MCD in developing rats. Hippocampal electrophysiology and spatial learning and memory were studied in the methylazoxymethanol (MAM) rat model of cortical dysplasia. Additionally, the resulting malformations were histologically assessed Methods: Two pregnant female rats were injected with 20mg/kg methylazoxymethanol (MAM), a methylating agent, either at embryonic day (E) 15 or 17 to vary the severity of the cerebral malformations. Immediately after birth, half of the pups from each litter were randomly allocated to the other dam. At weaning, one set of pups (comprising rats from both E17 and E15 group) was maintained in normal laboratory caging and the other set was exposed to an enriched environment for a minimum of 8 hours a day. This environment contained a running wheel and various tubes and toys. At P22-25 rats from all groups (enriched E15, enriched E17, non-enriched E15, non-enriched E17) were implanted with custom single unit electrodes in the dorsal hippocampus and place cells (hippocampal neurons that fire in a location specific manner) were recorded during environmental exploration. Non-implanted rats from all groups underwent testing in the Morris water maze to test for spatial memory. At the completion of the experiment, the rat brains were sliced and stained with Thionine, and the number of heterotopias in E15 and E17 rats were quantified. Results: The extent of hippocampal malformation was greater in E15 than in E17 rats. We observed two types of dysplasia: 1) a diffuse disruption of neuronal organization and b) spheres of neocortical grey matter in the vicinity of or interrupting CA1. 73% of E15 rats had spheres of neocortical grey matter, averaging an area of 3.36mm² compared to 50% in E17 averaging 1mm². Place cells were found in all animals. In the water maze task, the performance of the enriched animals, measured by the escape latency to the hidden platform, was improved as compared to non-enriched counterparts. Conclusions: Place cells were observed in both E15 and E17 rats, which suggests that this system can be functional even in the presence of MCD. While more data is needed to determine the effect of environmental enrichment in place cell physiology and MCD, we found that environmental enrichment significantly improved spatial memory performance in the water maze. These results suggest that environmental enrichment may be a powerful adjunct to therapy for children with brain malformations and epilepsy. This work was supported by NIH Grants R01NS044295 and R01NS056170.