Abstract
Dysfunction of fast-spiking, parvalbumin-positive (FS-PV) interneurons is implicated in the pathogenesis of epilepsy. ErbB4, a key Neuregulin 1 (NRG1) receptor, is mainly expressed in this type of interneurons, and recent studies suggest that parvalbumin interneurons are a major target of NRG1-ErbB4 signaling in adult brain. Thus, we hypothesized that downregulation of NRG1-ErbB4 signaling in FS-PV interneurons is involved in epilepsy. We found that NRG1, through its receptor ErbB4, increased the intrinsic excitability of FS-PV interneurons. This effect was mediated by increasing the near-threshold responsiveness and decreasing the voltage threshold for action potentials through Kv1.1, a voltage-gated potassium channel. Furthermore, mice with specific deletion of ErbB4 in parvalbumin interneurons were more susceptible to pentylenetetrazole- and pilocarpine-induced models of epilepsy. Exogenous NRG1 delayed the onset of seizures and decreased their incidence and stage. Moreover, expression of ErbB4, but not ErbB2, was downregulated in human epileptogenic tissue. Together, our findings suggest that NRG1-ErbB4 signaling contributes to human epilepsy through regulating the excitability of FS-PV interneurons. ErbB4 may be a new target for anticonvulsant drugs in epilepsy.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Action Potentials / genetics
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Action Potentials / physiology*
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Animals
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Biophysics
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Caveolin 1 / metabolism
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Cell Line, Transformed
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Disease Models, Animal
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Down-Regulation / drug effects
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Down-Regulation / genetics
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Down-Regulation / physiology
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Electric Stimulation
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Epilepsy / chemically induced
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Epilepsy / drug therapy
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Epilepsy / genetics
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Epilepsy / pathology*
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ErbB Receptors / genetics
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ErbB Receptors / metabolism
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Female
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Hippocampus / cytology
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Hippocampus / metabolism
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Hippocampus / pathology
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Humans
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Immunoprecipitation
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In Vitro Techniques
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Kv1.1 Potassium Channel / genetics
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Kv1.1 Potassium Channel / metabolism*
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Male
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Mice
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Mice, Transgenic
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Neuregulin-1 / genetics
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Neuregulin-1 / metabolism*
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Neuregulin-1 / therapeutic use
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Neurons / drug effects
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Neurons / physiology*
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Parvalbumins / metabolism
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Patch-Clamp Techniques
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Pentylenetetrazole / toxicity
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Peptides / pharmacology
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Pilocarpine / toxicity
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Potassium Channel Blockers / pharmacology
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Quinazolines / pharmacology
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Receptor, ErbB-2 / metabolism
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Receptor, ErbB-4
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Signal Transduction / drug effects
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Tyrphostins / pharmacology
Substances
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CAV1 protein, human
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Caveolin 1
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Neuregulin-1
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Nrg1 protein, mouse
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Parvalbumins
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Peptides
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Potassium Channel Blockers
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Quinazolines
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Tyrphostins
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Pilocarpine
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dendrotoxin K
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Kv1.1 Potassium Channel
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RTKI cpd
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ERBB2 protein, human
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ERBB4 protein, human
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ErbB Receptors
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Erbb4 protein, mouse
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Receptor, ErbB-2
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Receptor, ErbB-4
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Pentylenetetrazole