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- Title
H-channels as a Therapeutic Target in Epilepsy.
- Authors
Poolos, N.P.; Migliore, M.; Johnston, D.; Coulter, Douglas A.
- Abstract
Pharmacological Upregulation of H-channels Reduces the Excitability of Pyramidal Neuron Dendrites The dendrites of pyramidal neurons have markedly different electrical properties from those of the soma, owing to the nonuniform distribution of voltage-gated ion channels in dendrites. It is thus possible that drugs acting on ion channels might preferentially alter dendritic, but not somatic, excitability. By using dendritic and somatic whole-cell and cell-attached recordings in rat hippocampal slices, we found that the anticonvulsant lamotrigine selectively reduced action-potential firing from dendritic depolarization, while minimally affecting firing at the soma. This regional and input-specific effect resulted from an increase in the hyperpolarization-activated cation current (I[sub h] ), a voltage-gated current present predominantly in dendrites. These results demonstrate that neuronal excitability can be altered by drugs acting selectively on dendrites, and suggest an important role for I[sub h] in controlling dendritic excitability and epileptogenesis. Gabapentin Increases the Hyperpolarization-activated Cation Current I[sub h ] in rat CA1 pyramidal cells. PURPOSE: Gabapentin (GBP) is a commonly used drug in the treatment of partial seizures, but its mode of action is still unclear. The genesis of seizures in temporal lobe epilepsy is thought to be crucially influenced by intrinsic membrane properties. Because the I[sub h] substantially contributes to the intrinsic membrane properties of neurons, the effects of GBP on the I[sub h] were investigated in CA1 pyramidal cells of rat hippocampus. METHODS: CA1 pyramidal cells in hippocampal slices were examined by using the whole-cell patch-clamp technique. RESULTS: GBP increased the I[sub h] amplitude in a concentration-dependent manner mainly by increasing the conductance, without significant changes in the activation properties or in the time course of I[sub h] . The effects ranged from 20% at 50 μM , 25% at 75 μM , to 35% at 100 μM GBP (at -110 mV). In the presence of intracellular cyclic adenosine monophosphate (cAMP), the effects of GBP on I[sub h] were similar to those obtained in the absence of cAMP. CONCLUSIONS: These results suggest that GBP increases the I[sub h] through a cAMP-independent mechanism. Because the applied GBP concentrations were in a clinically relevant range, the observed effect may contribute to the anticonvulsant action of GBP in partial seizures and may represent a new concept of how this anticonvulsant drug works.
- Subjects
DENDRITES; NEURONS; EPILEPSY; BRAIN diseases
- Publication
Epilepsy Currents, 2003, Vol 3, Issue 5, p164
- ISSN
1535-7597
- Publication type
Article
- DOI
10.1046/j.1535-7597.2003.03505.x