Journal
EPILEPSIA
Volume 49, Issue 5, Pages 861-871Publisher
WILEY
DOI: 10.1111/j.1528-1167.2007.01455.x
Keywords
hypothalamic hamartoma; GABA(A) receptor; depolarization; L-type calcium channel; cation chloride cotransporters
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Funding
- NINDS NIH HHS [NS 044846] Funding Source: Medline
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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 GABA(A) receptors in surgically resected HH tissue. Methods: HH tissue slices (350 mu m) were studied using cellular electrophysiological, calcium imaging, and immunocytochemical techniques. Results: Two neuronal cell types were seen: small (10-16 mu m) spontaneously firing GABAergic neurons and large (20-28 mu m) quiescent neurons. In gramicidin-perforated patch recordings, muscimol (30 mu M) 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 mu M). Depolarizing neurons also exhibited more positive reversal potentials (E-muscimol) 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 mu M), 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 mu M) prevented muscimol-induced neuronal excitation. Conclusions: GABA(A) 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.
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