Abstracts

Rationale: Malformations of cortical development (MCD) are a common cause of epilepsy and cognitive impairment. Methylazoxymethanol (MAM) injection duration gestation in rats causes MCDs and these animals have impaired spatial navigation when tested in the Morris Water maze (Lucas et al 2011). Migration disorders can affect cell properties as well as their networks. In normal rodents spatial navigation is supported by place cell activity which is modulated by hippocampal EEG, particularly the theta rhythm. Therefore we hypothesize that animals exposed to MAM during development will have abnormal place cell function and oscillatory activity in the EEG.Methods: Pregnant Sprague Dawley Dams were injected with either saline or 20mg/kg MAM (a DNA methylating agent which causes dysplasia in the CA1-4 areas of the hippocampus) at embryonic day 17. Rats (N=5) were implanted with custom 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 cell activity was then recorded in three consecutive 15min sessions, with a 5 min break between the first two sessions and 30 min break between the second and third session.Results: Place cell coherence was lower in MAM animals (n=10 cells) than in controls (n=21 cells, p=0.018). In addition place cells in MAM animals had greater number of fields (p=0.003), and the action potential width may be larger in MAM than controls (p=0.071). Hippocampal EEG spectral analysis of MAM rats (N=3) exhibited identifiable theta and gamma rhythms in the EEG. The mean theta frequency was lower in MAM than control (p<0.001) and it seems that the there is a greater theta frequency to speed correlation in controls than MAM, although mean speed is similar in both groups. Interestingly we find that mean theta power is similar but gamma power is lower in MAM animals (p=0.016) when normalized to the entire spectrum.Conclusions: Our data show that networks subserving spatial navigation are abnormal in animals with MCDs, and that further investigation is warranted to understand exactly which components of these networks are essential for normal functioning. Abnormal network function may be an important contributor to cognitive impairment observed in these animals. Future investigations will involve improving place cell characteristics and EEG through environmental enrichment which has been extensively shown to improve cognition in both control rats and humans. Thus, modification of network function may represent a novel therapeutic target for improving cognitive outcomes in patients with epilepsy and MCDs.