Abstracts

Rationale: Malformations of cortical development (MCD) are a common cause of epilepsy and cognitive impairment. Rats injected with methylazoxymethanol (MAM) exhibit varying degrees of MCDs and impairments of spatial navigation when tested in the Morris Water Maze. It is known that in normal rodents spatial navigation is supported by place cell activity which is modulated by hippocampal EEG, particularly the theta rhythm. MAM administration during gestation affects the migration of parvalbumin interneurons; a cell type known to modulate EEG oscillations. Therefore we hypothesize that animals exposed to MAM during development will have abnormal oscillatory activity in the EEG which will affect place cell function. Methods: Two pregnant Dams were injected with 20mg/kg MAM, a DNA methylating agent, either at embryonic day (E) 15 or 17 to vary the severity of MCDs. At P22-25 rats (n=2) from each litter were implanted with custom microdrives with electrodes aimed at the dorsal hippocampus. After surgery, electrodes were lowered by steps of 20?m every 4 hours until single unit activity was detected. Hippocampal pyramidal cell activity was then recorded each day for two 12min sessions, separated by a 15min interval. Results: Hippocampal EEG spectral analysis of MAM rats (n=2) exhibits identifiable theta and gamma rhythms in the EEG. As in controls, gamma power was modulated by theta power. In the MAM E15 animal 18 cells were recorded; 2 were interneurons and 13 were characterized as place cells. The firing rate of 9 of the place cells was theta modulated. Only 2 place cells were stable between the two sessions. In the MAM E17 animal 14 cells were recorded, including one interneuron. Amongst the 7 identified place cells, 5 were theta modulated and 3 were stable between sessions. Conclusions: Our preliminary data show that the networks subserving spatial navigation are present in animals with extensive MCDs. It is now important to establish whether these networks function normally by comparing animals with MCDs to control animals. Abnormal network function may be an important contributor to cognitive impairment observed in these animals. Thus, modification of network function may represent a novel therapeutic target for improving cognitive outcomes in patients with epilepsy and MCDs.