Synaptic destabilization by neuronal Nogo-A |
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Authors: | Elisabeth M Aloy Oliver Weinmann Caroline Pot Hansjörg Kasper Dana A Dodd Thomas Rülicke Ferdinando Rossi Martin E Schwab |
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Institution: | (1) Brain Research Institute, University of Zurich and Department of Biology, Swiss Federal Institute of Technology (ETH), Zurich, Winterthurerstrasse 190, Zurich, CH-8057, Switzerland;(2) Institute of Laboratory Animal Science, Central Biological Laboratory, University Hospital Zurich, Sternwartstrasse 6, Zurich, CH-8091, Switzerland;(3) Department of Neuroscience, Section of Physiology, Rita Levi Montalcini Center for Brain Repair, University of Turin, Corso Raffaello 30, Turin, I-10125, Italy;(4) Present address: Department of Neurology, University Hospital, Geneva, CH-1211, Switzerland;(5) Present address: Institut für Labortierkunde, Vienna, A-1210, Austria |
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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 β-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.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. |
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