title: Hyperpolarization-activated cyclic nucleotide-gated channels in olfactory sensory neurons regulate axon extension and glomerular formation.
abstract: Mechanisms influencing the development of olfactory bulb glomeruli are poorly understood. While odor receptors (ORs) play an important role in olfactory sensory neuron (OSN) axon targeting/coalescence (Mombaerts et al., 1996; Wang et al., 1998; Feinstein and Mombaerts, 2004), recent work showed that G protein activation alone is sufficient to induce OSN axon coalescence (Imai et al., 2006; Chesler et al., 2007), suggesting an activity-dependent mechanism in glomerular development. Consistent with these data, OSN axon projections and convergence are perturbed in mice deficient for adenylyl cyclase III, which is downstream from the OR and catalyzes the conversion of ATP to cAMP. However, in cyclic nucleotide-gated (CNG) channel knock-out mice OSN axons are only transiently perturbed (Lin et al., 2000), suggesting that the CNG channel may not be the sole target of cAMP. This prompted us to investigate an alternative channel, the hyperpolarization-activated, cyclic nucleotide-gated cation channel (HCN), as a potential developmental target of cAMP in OSNs. Here, we demonstrate that HCN channels are developmentally precocious in OSNs and therefore are plausible candidates for affecting OSN axon development. Inhibition of HCN channels in dissociated OSNs significantly reduced neurite outgrowth. Moreover, in HCN1 knock-out mice the formation of glomeruli was delayed in parallel with perturbations of axon organization in the olfactory nerve. These data support the hypothesis that the outgrowth and coalescence of OSN axons is, at least in part, subject to activity-dependent mechanisms mediated via HCN channels.
authors.affiliation: Department of Neurosurgery and Neurobiology, Interdepartmental Neuroscience Program, Yale University School of Medicine, New Haven, Connecticut 06520-8082, USA.
authors.forename: Arie S
authors.initials: AS
authors.lastname: Mobley
authors.forename: Alexandra M
authors.initials: AM
authors.lastname: Miller
authors.forename: Ricardo C
authors.initials: RC
authors.lastname: Araneda
authors.forename: Lydia R
authors.initials: LR
authors.lastname: Maurer
authors.forename: Frank
authors.initials: F
authors.lastname: Müller
authors.forename: Charles A
authors.initials: CA
authors.lastname: Greer
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000930:Antidiarrheals / Q000494:pharmacology; D001369:Axons / Q000187:drug effects / Q000502:physiology*; D001703:Biophysics / Q000379:methods; D002316:Cardiotonic Agents / Q000494:pharmacology; D002478:Cells, Cultured; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000172:deficiency / Q000502:physiology*; D004558:Electric Stimulation / Q000379:methods; D004622:Embryo, Mammalian; D019922:GAP-43 Protein / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000235:genetics; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism; D008139:Loperamide / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019006:Neural Cell Adhesion Molecules / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology*; D009830:Olfactory Bulb / Q000166:cytology / Q000196:embryology / Q000254:growth & development; D018408:Patch-Clamp Techniques / Q000379:methods; D015221:Potassium Channels / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011743:Pyrimidines / Q000494:pharmacology; D018035:Receptors, Odorant / Q000235:genetics / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000166:cytology* / Q000187:drug effects
chemical_list: D000930:Antidiarrheals; D002316:Cardiotonic Agents; D054815:Cyclic Nucleotide-Gated Cation Channels; D019922:GAP-43 Protein; C513836:HCN4 protein, rat; C578666:Hcn1 protein, mouse; C578667:Hcn1 protein, rat; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007473:Ion Channels; D019006:Neural Cell Adhesion Molecules; C427664:Olfr1507 protein, mouse; D015221:Potassium Channels; D011743:Pyrimidines; D018035:Receptors, Odorant; C082246:ICI D2788; D049452:Green Fluorescent Proteins; D008139:Loperamide