title: Enzymatic Depletion of the Polysialic Acid Moiety Associated with the Neural Cell Adhesion Molecule Inhibits Antidepressant Efficacy.
abstract: Antidepressant drugs are too often ineffective, the exact mechanism of efficacy is still ambiguous, and there has been a paucity of novel targets for pharmacotherapy. In an attempt to understand the pathogenesis of depression and subsequently develop more efficacious antidepressant drugs, multiple theories have been proposed, including the modulation of neurotransmission, the upregulation of neurogenesis and neurotrophic factors, normalizing hypothalamic-pituitary-adrenal reactivity, and the reduction of neuroinflammation; all of which have supporting lines of evidence. Therefore, an ideal molecular target for novel pharmaceutical intervention would function at the confluence of these theories. The polysialylated form of the neural cell adhesion molecule (PSA-NCAM) functions broadly, serving to mediate synaptic plasticity, neurogenesis, neurotrophic factor signaling, and inflammatory signaling throughout the brain; all of which are associated with the pathophysiology and treatment of depression. Moreover, the expression of PSA-NCAM is reduced by depression, and conversely enhanced by antidepressant treatment, particularly within the hippocampus. Here we demonstrate that selectively cleaving the polysialic acid moiety, using the bacteriophage-derived enzyme endoneuraminidase N, completely inhibits the antidepressant efficacy of the selective-serotonin reuptake inhibitor fluoxetine (FLX) in a chronic unpredictable stress model of depression. We also observe a corresponding attenuation of FLX-induced hippocampal neuroplasticity, including decreased hippocampal neurogenesis, synaptic density, and neural activation. These data indicate that PSA-NCAM-mediated neuroplasticity is necessary for antidepressant action; therefore PSA-NCAM represents an interesting, and novel, target for pharmacotherapy.
authors.affiliation: Graduate Program in Neuroscience, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Wainwright
authors.affiliation: Department of Psychology, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Cindy K
authors.initials: CK
authors.lastname: Barha
authors.affiliation: Department of Psychology, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Dwayne K
authors.initials: DK
authors.lastname: Hamson
authors.affiliation: Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Epp
authors.affiliation: Department of Psychology, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Carmen
authors.initials: C
authors.lastname: Chow
authors.affiliation: Department of Psychology, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Stephanie E
authors.initials: SE
authors.lastname: Lieblich
authors.affiliation: Department of Cell Biology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Urs
authors.initials: U
authors.lastname: Rutishauser
authors.affiliation: Graduate Program in Neuroscience, University of British Columbia, Vancouver, British Columbia, Canada.|Department of Psychology, University of British Columbia, Vancouver, British Columbia, Canada.|Brain Research Centre, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Liisa Am
authors.initials: LA
authors.lastname: Galea
mesh_terms: D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology*; D003345:Corticosterone / Q000097:blood; D003863:Depression / Q000188:drug therapy; D004195:Disease Models, Animal; D005473:Fluoxetine / Q000494:pharmacology*; D006026:Glycoside Hydrolases / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D039842:Neural Cell Adhesion Molecule L1 / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D009473:Neuronal Plasticity / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012794:Sialic Acids / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D013739:Testosterone / Q000097:blood; D016896:Treatment Outcome
chemical_list: D018687:Antidepressive Agents, Second-Generation; D039842:Neural Cell Adhesion Molecule L1; D012794:Sialic Acids; C103469:polysialyl neural cell adhesion molecule; D005473:Fluoxetine; D013739:Testosterone; D006026:Glycoside Hydrolases; C090534:endo-alpha-sialidase; D003345:Corticosterone