Gabaa Receptor-Mediated Activation Of L-Type Calcium Channels Induces Neuronal Excitation In Surgically Resected Human Hypothalamic Hamartomas
Purpose: The human hypothalamic hamartoma (HH) is a rare, intrinsically epileptogenic lesion associated with gelastic seizures, but the underlying mechanisms remain unclear. Here, we examined the role of GABAA receptors in surgically resected HH tissue. Methods: HH tissue slices (350 Î¼m) were studied using cellular electrophysiological, calcium imaging, and immunocytochemical techniques. Results: Two neuronal cell types were seen: small (10-16 Î¼m) spontaneously firing GABAergic neurons and large (20-28 Î¼m) quiescent neurons. In gramicidin-perforated patch recordings, muscimol (30 Î¼M) induced membrane depolarization in 70% of large (but not small) neurons and a concomitant rise in intracellular calcium. These responses were blocked by bicuculline methiodide (50 Î¼M). Depolarizing neurons also exhibited more positive reversal potentials (Emuscimol) and significantly higher intracellular chloride concentrations compared to those that hyperpolarized. The cation chloride co-transporters NKCC1 and KCC2 were coexpressed in the majority of large neurons, but fluorometric measurements revealed that 84% of large HH neurons expressed solely or relatively more NKCC1. Bumetanide (20 Î¼M), a NKCC1 antagonist, partially suppressed muscimol-induced excitation in large neurons. Concordant with robust expression of CaV1.2 and CaV1.3 subunits in HH neurons, the L-type calcium channel blocker nifedipine (100 Î¼M) prevented muscimol-induced neuronal excitation. Conclusions: GABAA receptor-mediated excitation, due in part to differential expression of NKCC1 and KCC2 and subsequent activation of L-type calcium channels, may contribute to seizure genesis in HH tissue. Given the ready availability of L-type calcium channel blockers, our results have clinical ramifications for the treatment of seizures associated with HH lesions. Â© 2008 International League Against Epilepsy.
Digital Object Identifier (DOI)
Kim, Do Young; Fenoglio, Kristina A.; Simeone, Timothy A.; Coons, Stephen W.; Wu, Jie; Chang, Yongchang; Kerrigan, John F.; and Rho, Jong M., "Gabaa Receptor-Mediated Activation Of L-Type Calcium Channels Induces Neuronal Excitation In Surgically Resected Human Hypothalamic Hamartomas" (2008). Neurobiology. 54.