title: A mouse model for creatine transporter deficiency reveals early onset cognitive impairment and neuropathology associated with brain aging.
abstract: Mutations in the creatine (Cr) transporter (CrT) gene lead to cerebral creatine deficiency syndrome-1 (CCDS1), an X-linked metabolic disorder characterized by cerebral Cr deficiency causing intellectual disability, seizures, movement and autistic-like behavioural disturbances, language and speech impairment. Since no data are available about the neural and molecular underpinnings of this disease, we performed a longitudinal analysis of behavioural and pathological alterations associated with CrT deficiency in a CCDS1 mouse model. We found precocious cognitive and autistic-like defects, mimicking the early key features of human CCDS1. Moreover, mutant mice displayed a progressive impairment of short and long-term declarative memory denoting an early brain aging. Pathological examination showed a prominent loss of GABAergic synapses, marked activation of microglia, reduction of hippocampal neurogenesis and the accumulation of autofluorescent lipofuscin. Our data suggest that brain Cr depletion causes both early intellectual disability and late progressive cognitive decline, and identify novel targets to design intervention strategies aimed at overcoming brain CCDS1 alterations.
authors.affiliation: Institute of Neuroscience, National Research Council (CNR), Pisa, Italy baroncelli@in.cnr.it.
authors.forename: Laura
authors.initials: L
authors.lastname: Baroncelli
authors.affiliation: Institute of Neuroscience, National Research Council (CNR), Pisa, Italy.|Department of Neuroscience, Psychology, Drug Research and Child Health NEUROFARBA, University of Florence, Florence, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Molinaro
authors.affiliation: BioSNS laboratory, Scuola Normale Superiore di Pisa, Pisa, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Cacciante
authors.affiliation: Department of Developmental Neuroscience, IRCCS Stella Maris Scientific Institute, IRCCS Stella Maris Foundation, Pisa, Italy.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Alessandrì
authors.affiliation: BioSNS laboratory, Scuola Normale Superiore di Pisa, Pisa, Italy.
authors.forename: Debora
authors.initials: D
authors.lastname: Napoli
authors.affiliation: Institute of Neuroscience, National Research Council (CNR), Pisa, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Putignano
authors.affiliation: Institute of Neuroscience, National Research Council (CNR), Pisa, Italy.
authors.forename: Jonida
authors.initials: J
authors.lastname: Tola
authors.affiliation: Department of Paediatrics, Child Neurology and Psychiatry, Sapienza University of Rome, Rome, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Leuzzi
authors.affiliation: Department of Developmental Neuroscience, IRCCS Stella Maris Scientific Institute, IRCCS Stella Maris Foundation, Pisa, Italy.|Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Cioni
authors.affiliation: Institute of Neuroscience, National Research Council (CNR), Pisa, Italy.|Department of Neuroscience, Psychology, Drug Research and Child Health NEUROFARBA, University of Florence, Florence, Italy.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Pizzorusso
mesh_terms: D000375:Aging / Q000235:genetics / Q000473:pathology; D000818:Animals; D001921:Brain / Q000503:physiopathology; D020739:Brain Diseases, Metabolic, Inborn / Q000235:genetics* / Q000503:physiopathology; D060825:Cognitive Dysfunction / Q000235:genetics* / Q000503:physiopathology; D003401:Creatine / Q000172:deficiency* / Q000235:genetics; D004195:Disease Models, Animal; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000503:physiopathology; D026901:Membrane Transport Proteins / Q000235:genetics*; D038901:X-Linked Intellectual Disability / Q000235:genetics* / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D050480:Plasma Membrane Neurotransmitter Transport Proteins / Q000172:deficiency* / Q000235:genetics
chemical_list: D026901:Membrane Transport Proteins; D050480:Plasma Membrane Neurotransmitter Transport Proteins; C080679:creatine transporter; D003401:Creatine