Initiation of epileptiform activity in a rat model of periventricular nodular heterotopia

Abstract

Summary Purpose Periventricular nodular heterotopia (PNH) are, in humans, often associated with difficult-to-control epilepsy. However, there is considerable controversy about the role of the PNH in seizure generation and spread. To study this issue, we have used a rat model in which injection of methylazoxymethanol (MAM) into pregnant rat dams produces offspring with nodular heterotopia-like brain abnormalities. Methods Electrophysiological methods were used to examine the activity of the MAM-induced PNH relative to activity in the neighboring hippocampus and overlying neocortex. Recordings were obtained simultaneously from these three structures in slice preparations from MAM-exposed rats and in intact animals. Bath application or systemic injection of bicuculline was used to induce epileptiform activity. Key findings In the in vitro slice, epileptiform discharge was generally initiated in hippocampus. In some cases, independent PNH discharge occurred, but the PNH never “led” discharges in hippocampus or neocortex. Intracellular recordings from PNH neurons confirmed that these cells received synaptic drive from both hippocampus and neocortex, and sent axonal projections to these structures – consistent with anatomical observations on biocytin-injected PNH cells. In intact animal preparations, bicuculline injection resulted in epileptiform discharge in all experiments, with a period of ictal-like electrographic activity typically initiated within 2-3 minutes after drug injection. In almost all animals, the onset of ictus was seen synchronously across PNH, hippocampal, and neocortical electrodes; in a few cases, the PNH electrode (histologically confirmed) did not participate, but in no case was activity initiated in the PNH electrode. Interictal discharge was also synchronized across all three electrodes; again, the PNH never “led” the other two electrodes, and typically followed (onset several milliseconds after hippocampal/neocortical discharge onset). Significance These results do not support the hypothesis that the PNH lesion is the primary epileptogenic site since it does not initiate or lead epileptiform activity that subsequently propagates to other brain regions.

Periventricular nodular heterotopia functionally couples with the overlying hippocampus

“…This speculation seems reasonable when considering a previous study using brain slices from model rats with PVNH. In that study, spontaneous discharges induced by bicuculline were time‐locked between the HN and the hippocampus, and the discharges were always initiated in the hippocampus, and not in the HN (Tschuluun et al., 2011).…”

Novel Animal Models of Pediatric Epilepsy

“…Abnormal connectivity between heterotopia clusters and the cortical and hippocampal regions has been shown using tract-tracing methods [74]. The focal abnormalities induced in this model are more than anatomical abnormalities; the surrounding tissue is also abnormal [75], and it has been suggested that this tissue is the initiator/driver of the epileptiform discharge [76].…”

Partial disconnection procedure in a patient with bilateral lesions (case report)

“…In some cases, heterotopic nodules can generate normal activity and may not be epileptogenic [9]. Furthermore, experimental data do not support the concept that NH lesions are the primary epileptogenic but rather point to the overlying cortex, which has been shown in a rat model [10]. Perhaps, the epileptogenicity of the dysplastic cortex is the main condition for generating epileptic activity in the cortex-NH functional complexes.…”