title: Neuregulin directly decreases voltage-gated sodium current in hippocampal ErbB4-expressing interneurons.
abstract: The Neuregulin 1 (NRG1)/ErbB4 signaling pathway has been genetically and functionally implicated in the etiology underlying schizophrenia, and in the regulation of glutamatergic pyramidal neuron function and plasticity. However, ErbB4 receptors are expressed in subpopulations of GABAergic interneurons, but not in hippocampal or cortical pyramidal neurons, indicating that NRG1 effects on principal neurons are indirect. Consistent with these findings, NRG1 effects on hippocampal long-term potentiation at CA1 pyramidal neuron synapses in slices are mediated indirectly by dopamine. Here we studied whether NRG/ErbB signaling directly regulates interneuron intrinsic excitability by pharmacologically isolating ErbB4-expressing neurons in rat dissociated hippocampal cultures, which lack dopaminergic innervation. We found that NRG1 acutely attenuates ErbB4-expressing interneuron excitability by depolarizing the firing threshold; neurons treated with the pan-ErbB inhibitor PD158780 or negative for ErbB4 were unaffected. These effects of NRG1 are primarily attributable to decreased voltage-gated sodium channel activity, as current density was attenuated by ∼60%. In stark contrast, NRG1 had minor effects on whole-cell potassium currents. Our data reveal the direct actions of NRG1 signaling in ErbB4-expressing interneurons, and offer novel insight into how NRG1/ErbB4 signaling can impact hippocampal activity.
authors.affiliation: Section on Molecular Neurobiology, Program in Developmental Neuroscience, Eunice Shriver Kennedy National Institute of Child Health and Human Development, Bethesda, Maryland 20892, USA.
authors.forename: Megan J
authors.initials: MJ
authors.lastname: Janssen
authors.forename: Elias
authors.initials: E
authors.lastname: Leiva-Salcedo
authors.forename: Andres
authors.initials: A
authors.lastname: Buonanno
mesh_terms: D000200:Action Potentials; D000818:Animals; D002478:Cells, Cultured / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000502:physiology*; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D007395:Interneurons / Q000737:chemistry / Q000378:metabolism*; D017136:Ion Transport / Q000187:drug effects / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology; D020890:Neuregulin-1 / Q000494:pharmacology* / Q000502:physiology; D010446:Peptide Fragments / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D066247:Receptor, ErbB-4; D012964:Sodium / Q000378:metabolism; D061567:Voltage-Gated Sodium Channel Blockers / Q000494:pharmacology*; D061566:Voltage-Gated Sodium Channels / Q000502:physiology
chemical_list: C107875:6-(methylamino)pyrido(3,4-d)pyrimidine; C094131:NRG1 protein, human; D009419:Nerve Tissue Proteins; D020890:Neuregulin-1; C490580:Nrg1 protein, rat; D010446:Peptide Fragments; D011743:Pyrimidines; D061567:Voltage-Gated Sodium Channel Blockers; D061566:Voltage-Gated Sodium Channels; C117467:neuregulin beta; D012964:Sodium; C587689:ERBB4 protein, human; D066246:ErbB Receptors; C587691:Erbb4 protein, rat; D066247:Receptor, ErbB-4