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

Do Young Kim, Kristina A. Simeone, Timothy Simeone, Stephen W. Coons, Jie Wu, Yongchang Chang, John F. Kerrigan, Jong M. Rho

Research output: Contribution to journalArticle

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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 μm) were studied using cellular electrophysiological, calcium imaging, and immunocytochemical techniques. Results: Two neuronal cell types were seen: small (10-16 μm) spontaneously firing GABAergic neurons and large (20-28 μm) quiescent neurons. In gramicidin-perforated patch recordings, muscimol (30 μM) 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 μM). 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 μM), 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 μM) 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.

Original languageEnglish
Pages (from-to)861-871
Number of pages11
JournalEpilepsia
Volume49
Issue number5
DOIs
StatePublished - May 2008

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L-Type Calcium Channels
GABA-A Receptors
Neurons
Muscimol
Seizures
Calcium Channel Blockers
Chlorides
Laughter
Calcium
Symporters
Bumetanide
Gramicidin
GABAergic Neurons
Nifedipine
Hypothalamic hamartomas
Cations
Membranes

All Science Journal Classification (ASJC) codes

  • Clinical Neurology
  • Neuroscience(all)

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GABAA receptor-mediated activation of L-type calcium channels induces neuronal excitation in surgically resected human hypothalamic hamartomas. / Kim, Do Young; Simeone, Kristina A.; Simeone, Timothy; Coons, Stephen W.; Wu, Jie; Chang, Yongchang; Kerrigan, John F.; Rho, Jong M.

In: Epilepsia, Vol. 49, No. 5, 05.2008, p. 861-871.

Research output: Contribution to journalArticle

Kim, Do Young ; Simeone, Kristina A. ; Simeone, Timothy ; Coons, Stephen W. ; Wu, Jie ; Chang, Yongchang ; Kerrigan, John F. ; Rho, Jong M. / GABAA receptor-mediated activation of L-type calcium channels induces neuronal excitation in surgically resected human hypothalamic hamartomas. In: Epilepsia. 2008 ; Vol. 49, No. 5. pp. 861-871.
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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 μm) were studied using cellular electrophysiological, calcium imaging, and immunocytochemical techniques. Results: Two neuronal cell types were seen: small (10-16 μm) spontaneously firing GABAergic neurons and large (20-28 μm) quiescent neurons. In gramicidin-perforated patch recordings, muscimol (30 μM) 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 μM). 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 μM), 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 μM) 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.",
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T1 - GABAA receptor-mediated activation of L-type calcium channels induces neuronal excitation in surgically resected human hypothalamic hamartomas

AU - Kim, Do Young

AU - Simeone, Kristina A.

AU - Simeone, Timothy

AU - Coons, Stephen W.

AU - Wu, Jie

AU - Chang, Yongchang

AU - Kerrigan, John F.

AU - Rho, Jong M.

PY - 2008/5

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N2 - 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 μm) were studied using cellular electrophysiological, calcium imaging, and immunocytochemical techniques. Results: Two neuronal cell types were seen: small (10-16 μm) spontaneously firing GABAergic neurons and large (20-28 μm) quiescent neurons. In gramicidin-perforated patch recordings, muscimol (30 μM) 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 μM). 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 μM), 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 μM) 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.

AB - 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 μm) were studied using cellular electrophysiological, calcium imaging, and immunocytochemical techniques. Results: Two neuronal cell types were seen: small (10-16 μm) spontaneously firing GABAergic neurons and large (20-28 μm) quiescent neurons. In gramicidin-perforated patch recordings, muscimol (30 μM) 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 μM). 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 μM), 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 μM) 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.

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