title: Noradrenaline acting on astrocytic β₂-adrenoceptors induces neurite outgrowth in primary cortical neurons.
abstract: The neurotransmitter noradrenaline (NA) has anti-inflammatory properties and promotes expression of neurotrophic factors in the central nervous system (CNS) via activation of glial adrenoceptors. Here we examined the ability of conditioned media (CM) from NA-treated glial cells to impact upon neuronal complexity. Primary rat cortical neurons were treated either directly with NA (1-10 μM), or treated with CM from NA-stimulated primary mixed glial cells. Neuronal complexity was assessed using Sholl analysis. Exposure of neurons to CM from NA-stimulated glial cells increased all indices of neuronal complexity, whereas direct exposure of neurons to NA did not. CM from NA-stimulated astrocytes, but not microglia, also increased neuronal complexity indicating a key role for astrocytes. The β-adrenergic subtype was implicated in this response as the increase was blocked by the β-adrenoceptor antagonist propanolol, but not by the α-adrenoceptor antagonist phentolamine. CM from glial cells treated with the β₂-adrenoceptor agonists salmeterol and clenbuterol, but not the β₁-adrenoceptor agonist xamoterol, mimicked the ability of NA to increase neuronal complexity. NA induced expression of a range of growth factors (BDNF, NGF-β, GDNF, FGF-2 and IL-6) in glial cells. In addition to this, the phosphatidylinositol 3-kinase (PI3K), mitogen activated protein kinase (MAPK) and JAK-STAT signalling pathways are implicated in NA CM-induced neuritic growth as inhibition of these pathways attenuated NA CM-induced neuritic growth. In conclusion, this study indicates a novel role for NA acting at glial β₂-adrenoceptors to induce neuritic growth through the expression of soluble factors that elicit a neurotrophic action and increase neuronal complexity.
authors.affiliation: Neuroimmunology Research Group, Department of Physiology, School of Medicine & Trinity College Institute of Neuroscience, Trinity College, Dublin 2, Ireland.
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Day
authors.affiliation: Neuroimmunology Research Group, Department of Physiology, School of Medicine & Trinity College Institute of Neuroscience, Trinity College, Dublin 2, Ireland.
authors.forename: Eimear
authors.initials: E
authors.lastname: O'Neill
authors.affiliation: Neuroimmunology Research Group, Department of Physiology, School of Medicine & Trinity College Institute of Neuroscience, Trinity College, Dublin 2, Ireland.
authors.forename: Caroline
authors.initials: C
authors.lastname: Cawley
authors.affiliation: Neuroimmunology Research Group, Department of Physiology, School of Medicine & Trinity College Institute of Neuroscience, Trinity College, Dublin 2, Ireland.
authors.forename: Nicholas Kruseman
authors.initials: NK
authors.lastname: Aretz
authors.affiliation: Neuroimmunology Research Group, Department of Physiology, School of Medicine & Trinity College Institute of Neuroscience, Trinity College, Dublin 2, Ireland.
authors.forename: Dana
authors.initials: D
authors.lastname: Kilroy
authors.affiliation: Neuroimmunology Research Group, Department of Physiology, School of Medicine & Trinity College Institute of Neuroscience, Trinity College, Dublin 2, Ireland.
authors.forename: Sinead M
authors.initials: SM
authors.lastname: Gibney
authors.affiliation: Neuroimmunology Research Group, Department of Physiology, School of Medicine & Trinity College Institute of Neuroscience, Trinity College, Dublin 2, Ireland. Electronic address: aharkin@tcd.ie.
authors.forename: Andrew
authors.initials: A
authors.lastname: Harkin
authors.affiliation: Neuroimmunology Research Group, Department of Physiology, School of Medicine & Trinity College Institute of Neuroscience, Trinity College, Dublin 2, Ireland.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Connor
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D048430:Cell Shape / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D017077:Culture Media, Conditioned; D016501:Neurites / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009638:Norepinephrine / Q000494:pharmacology*; D010646:Phentolamine / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*
chemical_list: D000317:Adrenergic alpha-Antagonists; D000319:Adrenergic beta-Antagonists; D017077:Culture Media, Conditioned; D018343:Receptors, Adrenergic, beta-2; D011433:Propranolol; D009638:Norepinephrine; D010646:Phentolamine
keywords: Cortical neurons; Glial cells; Neurite growth; Noradrenaline; Trophic factors; β-adrenoceptor