title: Pan-neurexin perturbation results in compromised synapse stability and a reduction in readily releasable synaptic vesicle pool size.
abstract: Neurexins are a diverse family of cell adhesion molecules that localize to presynaptic specializations of CNS neurons. Heterologous expression of neurexins in non-neuronal cells leads to the recruitment of postsynaptic proteins in contacting dendrites of co-cultured neurons, implicating neurexins in synapse formation. However, isoform-specific knockouts of either all α- or all β-neurexins show defects in synaptic transmission but an unaltered density of glutamatergic synapses, a finding that argues against an essential function of neurexins in synaptogenesis. To address the role of neurexin in synapse formation and function, we disrupted the function of all α- and β-neurexins in cultured hippocampal neurons by shRNA knockdown or by overexpressing a neurexin mutant that is unable to bind to postsynaptic neurexin ligands. We show that neurexin perturbation results in an attenuation of neurotransmitter release that is in large part due to a reduction in the number of readily releasable synaptic vesicles. We also find that neurexin perturbation fails to alter the ability of neurons to form synapses, but rather leads to more frequent synapse elimination. These experiments suggest that neurexins are dispensable for the formation of initial synaptic contacts, but play an essential role in the stabilization and functional maturation of synapses.
authors.affiliation: Department of Physiology &Biophysics, Dalhousie University, Halifax Nova Scotia B3H 1X6, Canada.|Department of Neuroscience Institute, Dalhousie University, Halifax Nova Scotia B3H 1X6, Canada.
authors.forename: Dylan P
authors.initials: DP
authors.lastname: Quinn
authors.affiliation: Department of Physiology &Biophysics, Dalhousie University, Halifax Nova Scotia B3H 1X6, Canada.|Department of Neuroscience Institute, Dalhousie University, Halifax Nova Scotia B3H 1X6, Canada.
authors.forename: Annette
authors.initials: A
authors.lastname: Kolar
authors.affiliation: Department of Pharmacology, Dalhousie University, Halifax Nova Scotia B3H 1X6, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Wigerius
authors.affiliation: Department of Psychology and Neuroscience, Dalhousie University, Halifax Nova Scotia B3H 1X6, Canada.
authors.forename: Rachel N
authors.initials: RN
authors.lastname: Gomm-Kolisko
authors.affiliation: Department of Biology, Dalhousie University, Halifax Nova Scotia B3H 1X6, Canada.
authors.forename: Hanine
authors.initials: H
authors.lastname: Atwi
authors.affiliation: Department of Pharmacology, Dalhousie University, Halifax Nova Scotia B3H 1X6, Canada.
authors.forename: James P
authors.initials: JP
authors.lastname: Fawcett
authors.affiliation: Department of Physiology &Biophysics, Dalhousie University, Halifax Nova Scotia B3H 1X6, Canada.|Department of Neuroscience Institute, Dalhousie University, Halifax Nova Scotia B3H 1X6, Canada.
authors.forename: Stefan R
authors.initials: SR
authors.lastname: Krueger
mesh_terms: D000818:Animals; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D018920:Coculture Techniques; D006023:Glycoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019006:Neural Cell Adhesion Molecules / Q000378:metabolism; D009479:Neuropeptides / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013569:Synapses / Q000378:metabolism*; D013572:Synaptic Vesicles / Q000378:metabolism
chemical_list: D006023:Glycoproteins; C561320:LRRTM2 protein, human; C547192:LRRTM2 protein, rat; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D019006:Neural Cell Adhesion Molecules; D009479:Neuropeptides; D018377:Neurotransmitter Agents; D034741:RNA, Small Interfering; C112162:neurexophilin; C086959:neurexin Ibeta