title: Calcineurin signaling mediates activity-dependent relocation of the axon initial segment.
abstract: The axon initial segment (AIS) is a specialized neuronal subcompartment located at the beginning of the axon that is crucially involved in both the generation of action potentials and the regulation of neuronal polarity. We recently showed that prolonged neuronal depolarization produces a distal shift of the entire AIS structure away from the cell body, a change associated with a decrease in neuronal excitability. Here, we used dissociated rat hippocampal cultures, with a major focus on the dentate granule cell (DGC) population, to explore the signaling pathways underlying activity-dependent relocation of the AIS. First, a pharmacological screen of voltage-gated calcium channels (VGCCs) showed that AIS relocation is triggered by activation of L-type Cav1 VGCCs with negligible contribution from any other VGCC subtypes. Additional pharmacological analysis revealed that downstream signaling events are mediated by the calcium-sensitive phosphatase calcineurin; inhibition of calcineurin with either FK506 or cyclosporin A totally abolished both depolarization- and optogenetically-induced activity-dependent AIS relocation. Furthermore, calcineurin activation is sufficient for AIS plasticity, because expression of a constitutively active form of the phosphatase resulted in relocation of the AIS of DGCs without a depolarizing stimulus. Finally, we assessed the role of calcineurin in other forms of depolarization-induced plasticity. Neither membrane resistance changes nor spine density changes were affected by FK506 treatment, suggesting that calcineurin acts via a separate pathway to modulate AIS plasticity. Together, these results emphasize calcineurin as a vital player in the regulation of intrinsic plasticity as governed by the AIS.
authors.affiliation: Medical Research Council Centre for Developmental Neurobiology, King's College London, London SE1 1UL, United Kingdom.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Evans
authors.forename: Rosanna P
authors.initials: RP
authors.lastname: Sammons
authors.forename: Sabrina
authors.initials: S
authors.lastname: Lebron
authors.forename: Adna S
authors.initials: AS
authors.lastname: Dumitrescu
authors.forename: Thomas B K
authors.initials: TB
authors.lastname: Watkins
authors.forename: Victor N
authors.initials: VN
authors.lastname: Uebele
authors.forename: John J
authors.initials: JJ
authors.lastname: Renger
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Grubb
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001369:Axons / Q000378:metabolism*; D001549:Benzamides / Q000494:pharmacology; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D002478:Cells, Cultured; D000075402:Channelrhodopsins; D049229:Dendritic Spines / Q000378:metabolism; D004622:Embryo, Mammalian; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology; D018398:Homeodomain Proteins / Q000378:metabolism; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000166:cytology; D010775:Photic Stimulation; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D000098551:Prospero-Related Homeobox 1 Protein
chemical_list: C570743:3,5-dichloro-N-(1-(2,2-dimethyltetrahydropyran-4-ylmethyl)-4-fluoropiperidin-4-ylmethyl)benzamide; D001549:Benzamides; D002121:Calcium Channel Blockers; D000075402:Channelrhodopsins; D018691:Excitatory Amino Acid Antagonists; D018398:Homeodomain Proteins; D008164:Luminescent Proteins; D050778:NFATC Transcription Factors; D010880:Piperidines; D025521:Tumor Suppressor Proteins; D000098551:Prospero-Related Homeobox 1 Protein; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D019703:Calcineurin; D002118:Calcium