GABAA receptor-mediated activation of L-type calcium channels induces neuronal excitation in surgically resected human hypothalamic hamartomas.

Abstract

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 microm) were studied using cellular electrophysiological, calcium imaging, and immunocytochemical techniques.

RESULTS:

Two neuronal cell types were seen: small (10-16 microm) spontaneously firing GABAergic neurons and large (20-28 microm) quiescent neurons. In gramicidin-perforated patch recordings, muscimol (30 microM) 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 microM). 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 microM), 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 microM) 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.

• Authors: Do Young Kim, Kristina A Fenoglio, Timothy A Simeone, Stephen W Coons, Jie Wu, Yongchang Chang, John F Kerrigan, Jong M Rho
• Journal: Epilepsia (Epilepsia) Vol. 49 Issue 5 Pg. 861-71 (May 2008) ISSN: 0013-9580 [Print] United States
• PMID: 18076645 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Calcium Channels, L-Type
• Chloride Channels
• Receptors, GABA-A
• SLC12A2 protein, human
• Sodium-Potassium-Chloride Symporters
• Solute Carrier Family 12, Member 2
• Symporters
• potassium-chloride symporters
• Muscimol
• Nifedipine

Topics

• Action Potentials (drug effects, physiology)
• Adolescent
• Adult
• Calcium Channels, L-Type (drug effects, metabolism, physiology)
• Child, Preschool
• Chloride Channels (metabolism)
• Epilepsies, Partial (metabolism, physiopathology)
• Female
• Hamartoma (metabolism, physiopathology, surgery)
• Humans
• Hypothalamic Diseases (metabolism, physiopathology, surgery)
• Immunohistochemistry
• Infant
• Male
• Membrane Potentials (drug effects, physiology)
• Models, Neurological
• Muscimol (pharmacology)
• Neurons (drug effects, metabolism, physiology)
• Nifedipine (pharmacology)
• Patch-Clamp Techniques
• Receptors, GABA-A (drug effects, metabolism, physiology)
• Sodium-Potassium-Chloride Symporters (metabolism)
• Solute Carrier Family 12, Member 2
• Symporters (drug effects, metabolism)