Abstract
Epilepsy is a common and refractory neurological disorder, but the neuronal regulatory mechanisms of epileptogenesis remain largely unclear. Activity-dependent transcription of genes for neurotrophins such as brain-derived neurotrophic factor (BDNF) has been shown to promote epileptogenesis; however, little is known about factors that may act as intrinsic, homeostatic or counterbalancing mechanisms. Using rodent models, here we show that limbic seizure activity upregulated NRG1-ErbB4 signaling and that epileptogenesis was inhibited by infusing NRG1 intracerebrally but exacerbated by neutralizing endogenous NRG1 with soluble ErbB4 extracellular domain, by inhibiting ErbB4 activation or by deleting the Erbb4 gene. Furthermore, specific depletion of ErbB4 in parvalbumin-expressing interneurons abolished NRG1-mediated inhibition of epileptogenesis and promoted kindling progression, resulting in increased spontaneous seizures and exuberant mossy fiber sprouting. In contrast, depleting ErbB4 in CaMKIIα-positive pyramidal neurons had no effect. Thus, NRG1-induced activation of ErbB4 in parvalbumin-expressing inhibitory interneurons may serve as a critical endogenous negative-feedback mechanism to suppress limbic epileptogenesis.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Analysis of Variance
-
Animals
-
Anticonvulsants / therapeutic use
-
Calcium-Calmodulin-Dependent Protein Kinase Type 2 / genetics
-
Diazepam / therapeutic use
-
Disease Models, Animal
-
Electroencephalography / methods
-
Enzyme-Linked Immunosorbent Assay / methods
-
Epilepsy / chemically induced
-
Epilepsy / drug therapy
-
Epilepsy / metabolism
-
Epilepsy / pathology*
-
ErbB Receptors / deficiency
-
ErbB Receptors / genetics
-
ErbB Receptors / metabolism*
-
Estrogen Antagonists / pharmacology
-
Fluoresceins
-
Interneurons / drug effects
-
Interneurons / metabolism*
-
Kindling, Neurologic / drug effects
-
Kindling, Neurologic / physiology
-
Male
-
Mice
-
Mice, Inbred C57BL
-
Mice, Transgenic
-
Muscarinic Agonists / toxicity
-
Muscarinic Antagonists / administration & dosage
-
Neuregulin-1 / genetics
-
Neuregulin-1 / metabolism*
-
Organic Chemicals
-
Parvalbumins / deficiency
-
Parvalbumins / genetics
-
Parvalbumins / metabolism*
-
Pilocarpine / toxicity
-
Pyrimidines / therapeutic use
-
Rats
-
Rats, Sprague-Dawley
-
Receptor, ErbB-4
-
Scopolamine / administration & dosage
-
Tamoxifen / pharmacology
-
Time Factors
-
Up-Regulation / drug effects
-
Up-Regulation / physiology*
Substances
-
6-(methylamino)pyrido(3,4-d)pyrimidine
-
Anticonvulsants
-
Estrogen Antagonists
-
Fluoresceins
-
Muscarinic Agonists
-
Muscarinic Antagonists
-
Neuregulin-1
-
Nrg1 protein, mouse
-
Organic Chemicals
-
Parvalbumins
-
Pyrimidines
-
fluoro jade
-
Pilocarpine
-
Tamoxifen
-
Scopolamine
-
ErbB Receptors
-
Erbb4 protein, mouse
-
Erbb4 protein, rat
-
Receptor, ErbB-4
-
Calcium-Calmodulin-Dependent Protein Kinase Type 2
-
Camk2a protein, mouse
-
Diazepam