title: Deficient Wnt signalling triggers striatal synaptic degeneration and impaired motor behaviour in adult mice.
abstract: Synapse degeneration is an early and invariant feature of neurodegenerative diseases. Indeed, synapse loss occurs prior to neuronal degeneration and correlates with the symptom severity of these diseases. However, the molecular mechanisms that trigger synaptic loss remain poorly understood. Here we demonstrate that deficient Wnt signalling elicits synaptic degeneration in the adult striatum. Inducible expression of the secreted Wnt antagonist Dickkopf1 (Dkk1) in adult mice (iDkk1) decreases the number of cortico-striatal glutamatergic synapses and of D1 and D2 dopamine receptor clusters. Synapse loss occurs in the absence of axon retraction or cell death. The remaining excitatory terminals contain fewer synaptic vesicles and have a reduced probability of evoked transmitter release. IDkk1 mice show impaired motor coordination and are irresponsive to amphetamine. These studies identify Wnts as key endogenous regulators of synaptic maintenance and suggest that dysfunction in Wnt signalling contributes to synaptic degeneration at early stages in neurodegenerative diseases.
authors.affiliation: Department of Cell and Developmental Biology, University College London, London WC1E 6BT, UK.
authors.forename: Soledad
authors.initials: S
authors.lastname: Galli
authors.affiliation: Department of Cell and Developmental Biology, University College London, London WC1E 6BT, UK.
authors.forename: Douglas M
authors.initials: DM
authors.lastname: Lopes
authors.affiliation: Department of Neuroscience, Physiology and Pharmacology, University College London, London WC1E 6BT, UK.
authors.forename: Rachida
authors.initials: R
authors.lastname: Ammari
authors.affiliation: Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, Helsinki 00014, Finland.
authors.forename: Jaakko
authors.initials: J
authors.lastname: Kopra
authors.affiliation: Department of Dermatology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Millar
authors.affiliation: Department of Neuroscience, Physiology and Pharmacology, University College London, London WC1E 6BT, UK.
authors.forename: Alasdair
authors.initials: A
authors.lastname: Gibb
authors.affiliation: Department of Cell and Developmental Biology, University College London, London WC1E 6BT, UK.
authors.forename: Patricia C
authors.initials: PC
authors.lastname: Salinas
mesh_terms: D000662:Amphetamines / Q000737:chemistry; D000818:Animals; D001369:Axons / Q000378:metabolism; D016923:Cell Death; D003342:Corpus Striatum / Q000473:pathology; D004298:Dopamine / Q000378:metabolism; D004318:Doxycycline / Q000737:chemistry; D005260:Female; D006579:Heterozygote; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D009048:Motor Skills; D019636:Neurodegenerative Diseases / Q000378:metabolism / Q000503:physiopathology*; D009474:Neurons / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D015398:Signal Transduction; D013569:Synapses / Q000473:pathology*; D051153:Wnt Proteins / Q000378:metabolism*
chemical_list: D000662:Amphetamines; C501127:Dkk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D051153:Wnt Proteins; D004318:Doxycycline; D004298:Dopamine