title: Activity-Dependent Exocytosis of Lysosomes Regulates the Structural Plasticity of Dendritic Spines.
abstract: Lysosomes have traditionally been viewed as degradative organelles, although a growing body of evidence suggests that they can function as Ca2+stores. Here we examined the function of these stores in hippocampal pyramidal neurons. We found that back-propagating action potentials (bpAPs) could elicit Ca2+release from lysosomes in the dendrites. This Ca2+release triggered the fusion of lysosomes with the plasma membrane, resulting in the release of Cathepsin B. Cathepsin B increased the activity of matrix metalloproteinase 9 (MMP-9), an enzyme involved in extracellular matrix (ECM) remodelling and synaptic plasticity. Inhibition of either lysosomal Ca2+signaling or Cathepsin B release prevented the maintenance of dendritic spine growth induced by Hebbian activity. This impairment could be rescued by exogenous application of active MMP-9. Our findings suggest that activity-dependent exocytosis of Cathepsin B from lysosomes regulates the long-term structural plasticity of dendritic spines by triggering MMP-9 activation and ECM remodelling.
authors.affiliation: Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, OX1 3QT, UK.
authors.forename: Zahid
authors.initials: Z
authors.lastname: Padamsey
authors.affiliation: Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, OX1 3QT, UK.
authors.forename: Lindsay
authors.initials: L
authors.lastname: McGuinness
authors.affiliation: Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, OX1 3QT, UK.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Bardo
authors.affiliation: Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, OX1 3QT, UK.
authors.forename: Marcia
authors.initials: M
authors.lastname: Reinhart
authors.affiliation: Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, OX1 3QT, UK.
authors.forename: Rudi
authors.initials: R
authors.lastname: Tong
authors.affiliation: Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, OX1 3QT, UK.
authors.forename: Anne
authors.initials: A
authors.lastname: Hedegaard
authors.affiliation: Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, OX1 3QT, UK.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Hart
authors.affiliation: Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, OX1 3QT, UK. Electronic address: nigel.emptage@pharm.ox.ac.uk.
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Emptage
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002401:Cathepsin B / Q000378:metabolism*; D003712:Dendrites / Q000378:metabolism; D049229:Dendritic Spines / Q000378:metabolism* / Q000502:physiology; D005089:Exocytosis / Q000502:physiology*; D006624:Hippocampus / Q000166:cytology; D008247:Lysosomes / Q000378:metabolism*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D009473:Neuronal Plasticity / Q000502:physiology*; D018408:Patch-Clamp Techniques; D017966:Pyramidal Cells / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction
chemical_list: D002401:Cathepsin B; C533916:Ctsb protein, rat; D020780:Matrix Metalloproteinase 9; C572337:Mmp9 protein, rat; D002118:Calcium
keywords: MMP-9; TIMP-1; back-propagating action potentials; calcium; dendritic spines; hippocampus; long-term potentiation; lysosome; structural plasticity; synaptic plasticity