Abstracts

Rationale: Human hypothalamic hamartomas (HH) are associated with gelastic seizures and are notoriously refractory to medical therapy. Clinical studies using intracranial electrode recordings found that the HH itself is epileptogenic, however the mechanisms remain unknown. Based on our previous findings that the L-type calcium channel antagonist nifedipine blocked spontaneous action potentials and GABAA-induced depolarization of single cells in HH tissue slices (Kim et al., Epilepsia, 2008), we examined whether nifedipine reduced the spontaneous network activity in HH tissue slices. Methods: Immediately following surgical resection, HH tissue was submerged in oxygenated aCSF (95% O2 / 5% CO2). Tissue specimens were sectioned at 350 microns and kept at room temperature until use. Slices were placed over a 64-microelectrode array and perfused with warmed aCSF. Multi-unit activity (MUA), field potentials and epileptiform activity were examined 1) under normal and pathological (i.e. in the presence of 4-aminopyridine) conditions and 2) after L-type calcium channels were blocked with nifedipine. Results: Neuronal populations within HH tissue were spontaneously active under normal aCSF conditions. A majority of the spontaneous MUA and field potentials were asynchronous. Irregular firing of MUA and MUA bursts occurred throughout the tissue. Field potentials were randomly detectable in most regions of the tissue. Under pathological conditions, the firing rate of MUA and field potentials per electrode increased, epileptiform-like activity was apparent and spontaneous discharges were observed in previously quiescent regions of the tissue. Qualitatively, there was a substantial increase in the synchronicity of these events. Blocking L-type calcium channels with nifedipine significantly reduced the number of spontaneous events and epileptiform-like activity. Conclusions: These data indicate that human HH tissue, known to be intrinsically epileptic, is comprised of neuronal networks that are spontaneously active, i.e. single neurons discharging action potentials and groups of neurons collectively firing field potentials. In addition, the network hyperexcitablity and hypersynchrony induced by 4-AP is attenuated by the currently available FDA-approved calcium channel antagonist, nifedipine. These findings further support our previous studies suggesting L-type calcium channels as a potential target for novel treatments for medically refractory HH. Supported by NIH, CURE Foundation and the Barrow Neurological Foundation, Women’s Board, St. Joseph’s Hospital and Medical Center.