title: Synaptic destabilization by neuronal Nogo-A.
abstract: Formation and maintenance of a neuronal network is based on a balance between plasticity and stability of synaptic connections. Several molecules have been found to regulate the maintenance of excitatory synapses but nothing is known about the molecular mechanisms involved in synaptic stabilization versus disassembly at inhibitory synapses. Here, we demonstrate that Nogo-A, which is well known to be present in myelin and inhibit growth in the adult CNS, is present in inhibitory presynaptic terminals in cerebellar Purkinje cells at the time of Purkinje cell-Deep Cerebellar Nuclei (DCN) inhibitory synapse formation and is then downregulated during synapse maturation. We addressed the role of neuronal Nogo-A in synapse maturation by generating several mouse lines overexpressing Nogo-A, starting at postnatal ages and throughout adult life, specifically in cerebellar Purkinje cells and their terminals. The overexpression of Nogo-A induced a progressive disassembly, retraction and loss of the inhibitory Purkinje cell terminals. This led to deficits in motor learning and coordination in the transgenic mice. Prior to synapse disassembly, the overexpression of neuronal Nogo-A led to the downregulation of the synaptic scaffold proteins spectrin, spectrin-E and beta-catenin in the postsynaptic neurons. Our data suggest that neuronal Nogo-A might play a role in the maintenance of inhibitory synapses by modulating the expression of synaptic anchoring molecules.
authors.affiliation: Brain Research Institute, University of Zurich and Department of Biology, Swiss Federal Institute of Technology (ETH), Zurich, Winterthurerstrasse 190, Zurich, CH-8057, Switzerland. aloy@hifo.unizh.ch
authors.forename: Elisabeth M
authors.initials: EM
authors.lastname: Aloy
authors.forename: Oliver
authors.initials: O
authors.lastname: Weinmann
authors.forename: Caroline
authors.initials: C
authors.lastname: Pot
authors.forename: Hansjörg
authors.initials: H
authors.lastname: Kasper
authors.forename: Dana A
authors.initials: DA
authors.lastname: Dodd
authors.forename: Thomas
authors.initials: T
authors.lastname: Rülicke
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Rossi
authors.forename: Martin E
authors.initials: ME
authors.lastname: Schwab
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation / Q000502:physiology*; D002529:Cerebellar Nuclei / Q000254:growth & development / Q000378:metabolism / Q000648:ultrastructure; D002531:Cerebellum / Q000254:growth & development / Q000378:metabolism* / Q000648:ultrastructure; D015536:Down-Regulation / Q000502:physiology; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016253:Microscopy, Immunoelectron; D009069:Movement Disorders / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D009185:Myelin Proteins / Q000235:genetics / Q000378:metabolism*; D009433:Neural Inhibition / Q000502:physiology; D009434:Neural Pathways / Q000254:growth & development / Q000378:metabolism* / Q000648:ultrastructure; D000070798:Nogo Proteins; D017729:Presynaptic Terminals / Q000378:metabolism* / Q000648:ultrastructure; D011689:Purkinje Cells / Q000378:metabolism* / Q000648:ultrastructure; D051381:Rats; D013049:Spectrin / Q000378:metabolism; D013570:Synaptic Membranes / Q000378:metabolism / Q000648:ultrastructure; D009435:Synaptic Transmission / Q000502:physiology; D051176:beta Catenin / Q000378:metabolism
chemical_list: D009185:Myelin Proteins; D000070798:Nogo Proteins; C000603201:Rtn4 protein, mouse; C000603197:Rtn4 protein, rat; D051176:beta Catenin; D013049:Spectrin