title: Developmental molecular and functional cerebellar alterations induced by PCP4/PEP19 overexpression: implications for Down syndrome.
abstract: PCP4/PEP19 is a modulator of Ca(2+)-CaM signaling. In the brain, it is expressed in a very specific pattern in postmitotic neurons. In particular, Pcp4 is highly expressed in the Purkinje cell, the sole output neuron of the cerebellum. PCP4, located on human chromosome 21, is present in three copies in individuals with Down syndrome (DS). In a previous study using a transgenic mouse model (TgPCP4) to evaluate the consequences of 3 copies of this gene, we found that PCP4 overexpression induces precocious neuronal differentiation during mouse embryogenesis. Here, we report combined analyses of the cerebellum at postnatal stages (P14 and adult) in which we identified age-related molecular, electrophysiological, and behavioral alterations in the TgPCP4 mouse. While Pcp4 overexpression at P14 induces an earlier neuronal maturation, at adult stage it induces increase in cerebellar CaMK2alpha and in cerebellar LTD, as well as learning impairments. We therefore propose that PCP4 contributes significantly to the development of Down syndrome phenotypes through molecular and functional changes.
authors.affiliation: Univ Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative, EAC4413 CNRS, Paris, France.
authors.forename: François
authors.initials: F
authors.lastname: Mouton-Liger
authors.affiliation: Cellular and Systems Biology, Systems Biology Programme, Center for Genomic Regulation (CRG); Universitat Pompeu Fabra (UPF); Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER): Dr. Aiguader, 88, 08003 Barcelona, Spain.
authors.forename: Ignasi
authors.initials: I
authors.lastname: Sahún
authors.affiliation: CNRS UMR8118, Brain Physiology Laboratory, Universite Paris-Descartes, Centre universitaire des Saints-Pères, 45 Rue des Saints-Pères, 75270 Paris Cedex 06, France.
authors.forename: Thibault
authors.initials: T
authors.lastname: Collin
authors.affiliation: Transgenese et Archivage Animaux Modèles, TAAM, CNRS, UPS44, 3B rue de la Férollerie, 45071 Orléans, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Lopes Pereira
authors.affiliation: Cellular and Systems Biology, Systems Biology Programme, Center for Genomic Regulation (CRG); Universitat Pompeu Fabra (UPF); Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER): Dr. Aiguader, 88, 08003 Barcelona, Spain.
authors.forename: Debora
authors.initials: D
authors.lastname: Masini
authors.affiliation: Univ Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative, EAC4413 CNRS, Paris, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Thomas
authors.affiliation: Univ Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative, EAC4413 CNRS, Paris, France.
authors.forename: Evelyne
authors.initials: E
authors.lastname: Paly
authors.affiliation: Key-Obs SAS, 13 avenue Buffon, 45071 Orléans Cedex 2, France.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Luilier
authors.affiliation: Centre de Biophysique Moléculaire, CNRS UPR 4301, Orléans, France.
authors.forename: Sandra
authors.initials: S
authors.lastname: Même
authors.affiliation: Univ Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative, EAC4413 CNRS, Paris, France.
authors.forename: Quentin
authors.initials: Q
authors.lastname: Jouhault
authors.affiliation: Univ Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative, EAC4413 CNRS, Paris, France.
authors.forename: Soumia
authors.initials: S
authors.lastname: Bennaï
authors.affiliation: Centre de Biophysique Moléculaire, CNRS UPR 4301, Orléans, France.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Beloeil
authors.affiliation: Key-Obs SAS, 13 avenue Buffon, 45071 Orléans Cedex 2, France.
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Bizot
authors.affiliation: Transgenese et Archivage Animaux Modèles, TAAM, CNRS, UPS44, 3B rue de la Férollerie, 45071 Orléans, France; Institut Clinique de la Souris, ICS, 1 rue Laurent Fries, 67404 Illkirch, France; Institut de Génétique Biologie Moléculaire et Cellulaire, Translational medicine and Neuroscience program, IGBMC, CNRS, INSERM, Université de Strasbourg, UMR7104, UMR964, 1 rue Laurent Fries, 67404 Illkirch, France.
authors.forename: Yann
authors.initials: Y
authors.lastname: Hérault
authors.affiliation: Cellular and Systems Biology, Systems Biology Programme, Center for Genomic Regulation (CRG); Universitat Pompeu Fabra (UPF); Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER): Dr. Aiguader, 88, 08003 Barcelona, Spain.
authors.forename: Mara
authors.initials: M
authors.lastname: Dierssen
authors.affiliation: Univ Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative, EAC4413 CNRS, Paris, France. Electronic address: creau@univ-paris-diderot.fr.
authors.forename: Nicole
authors.initials: N
authors.lastname: Créau
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002531:Cerebellum / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D036881:Long-Term Synaptic Depression / Q000187:drug effects / Q000235:genetics; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D011597:Psychomotor Performance / Q000187:drug effects / Q000502:physiology; D011810:Quinoxalines / Q000494:pharmacology; D011930:Reaction Time / Q000187:drug effects / Q000235:genetics; D021641:Recognition, Psychology / Q000187:drug effects / Q000502:physiology; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D018691:Excitatory Amino Acid Antagonists; D009419:Nerve Tissue Proteins; D011810:Quinoxalines; D026941:Sodium Channel Blockers; C050394:PCP4 protein, human; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D013779:Tetrodotoxin; C056639:2-amino-5-phosphopentanoic acid; D014633:Valine
keywords: Cerebellum; Down syndrome; Learning; Pcp4; Transgenic mouse