title: Early Disruption of Extracellular Pleiotrophin Distribution Alters Cerebellar Neuronal Circuit Development and Function.
abstract: The cerebellum is a structure of the central nervous system involved in balance, motor coordination, and voluntary movements. The elementary circuit implicated in the control of locomotion involves Purkinje cells, which receive excitatory inputs from parallel and climbing fibers, and are regulated by cerebellar interneurons. In mice as in human, the cerebellar cortex completes its development mainly after birth with the migration, differentiation, and synaptogenesis of granule cells. These cellular events are under the control of numerous extracellular matrix molecules including pleiotrophin (PTN). This cytokine has been shown to regulate the morphogenesis of Purkinje cells ex vivo and in vivo via its receptor PTPζ. Since Purkinje cells are the unique output of the cerebellar cortex, we explored the consequences of their PTN-induced atrophy on the function of the cerebellar neuronal circuit in mice. Behavioral experiments revealed that, despite a normal overall development, PTN-treated mice present a delay in the maturation of their flexion reflex. Moreover, patch clamp recording of Purkinje cells revealed a significant increase in the frequency of spontaneous excitatory postsynaptic currents in PTN-treated mice, associated with a decrease of climbing fiber innervations and an abnormal perisomatic localization of the parallel fiber contacts. At adulthood, PTN-treated mice exhibit coordination impairment on the rotarod test associated with an alteration of the synchronization gait. Altogether these histological, electrophysiological, and behavior data reveal that an early ECM disruption of PTN composition induces short- and long-term defaults in the establishment of proper functional cerebellar circuit.
authors.affiliation: INSERM U982, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, University of Rouen, 76821, Mont-Saint-Aignan cedex, France.|Institute for Research and Innovation in Biomedicine (IRIB), Normandie University, Mont-Saint-Aignan, France.
authors.forename: M M
authors.initials: MM
authors.lastname: Hamza
authors.affiliation: CNRS-UMR 8118, Laboratory of Cerebral Physiology, University Paris Descartes, 75006, Paris, France.
authors.forename: S A
authors.initials: SA
authors.lastname: Rey
authors.affiliation: EA 4700, Laboratory of Psychology and Neuroscience of Cognition, University of Rouen, 76821-cedex, Mont-Saint-Aignan, France.
authors.forename: P
authors.initials: P
authors.lastname: Hilber
authors.affiliation: UFR sciences et techniques, University of Rouen, 76821-cedex, Mont-Saint-Aignan, France.
authors.forename: A
authors.initials: A
authors.lastname: Arabo
authors.affiliation: CNRS-UMR 8118, Laboratory of Cerebral Physiology, University Paris Descartes, 75006, Paris, France.
authors.forename: T
authors.initials: T
authors.lastname: Collin
authors.affiliation: INSERM U982, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, University of Rouen, 76821, Mont-Saint-Aignan cedex, France.|Institute for Research and Innovation in Biomedicine (IRIB), Normandie University, Mont-Saint-Aignan, France.
authors.forename: D
authors.initials: D
authors.lastname: Vaudry
authors.affiliation: INSERM U982, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, University of Rouen, 76821, Mont-Saint-Aignan cedex, France. delphine.burel@univ-rouen.fr.|Institute for Research and Innovation in Biomedicine (IRIB), Normandie University, Mont-Saint-Aignan, France. delphine.burel@univ-rouen.fr.
authors.forename: D
authors.initials: D
authors.lastname: Burel
mesh_terms: D000375:Aging / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000008:administration & dosage / Q000494:pharmacology*; D048430:Cell Shape / Q000187:drug effects; D002531:Cerebellum / Q000254:growth & development*; D016207:Cytokines / Q000008:administration & dosage / Q000494:pharmacology*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005110:Extracellular Space / Q000737:chemistry*; D005260:Female; D005684:Gait / Q000187:drug effects; D006801:Humans; D008124:Locomotion / Q000187:drug effects; D008297:Male; D051379:Mice; D009415:Nerve Net / Q000254:growth & development*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D016207:Cytokines; C066845:pleiotrophin
keywords: Cerebellum; Locomotor behavior; Neurodevelopment; Pleiotrophin; Purkinje cells