title: Developmental delay in motor skill acquisition in Niemann-Pick C1 mice reveals abnormal cerebellar morphogenesis.
abstract: Niemann-Pick type C1 (NPC1) disease is a lysosomal storage disorder caused by defective intracellular trafficking of exogenous cholesterol. Purkinje cell (PC) degeneration is the main sign of cerebellar dysfunction in both NPC1 patients and animal models. It has been recently shown that a significant decrease in Sonic hedgehog (Shh) expression reduces the proliferative potential of granule neuron precursors in the developing cerebellum of Npc1 (-/-) mice. Pursuing the hypothesis that this developmental defect translates into functional impairments, we have assayed Npc1-deficient pups belonging to the milder mutant mouse strain Npc1 (nmf164) for sensorimotor development from postnatal day (PN) 3 to PN21. Npc1 (nmf164) / Npc1 (nmf164) pups displayed a 2.5-day delay in the acquisition of complex motor abilities compared to wild-type (wt) littermates, in agreement with the significant disorganization of cerebellar cortex cytoarchitecture observed between PN11 and PN15. Compared to wt, Npc1 (nmf164) homozygous mice exhibited a poorer morphological differentiation of Bergmann glia (BG), as indicated by thicker radial shafts and less elaborate reticular pattern of lateral processes. Also BG functional development was defective, as indicated by the significant reduction in GLAST and Glutamine synthetase expression. A reduced VGluT2 and GAD65 expression also indicated an overall derangement of the glutamatergic/GABAergic stimulation that PCs receive by climbing/parallel fibers and basket/stellate cells, respectively. Lastly, Npc1-deficiency also affected oligodendrocyte differentiation as indicated by the strong reduction of myelin basic protein. Two sequential 2-hydroxypropyl-β-cyclodextrin administrations at PN4 and PN7 counteract these defects, partially preventing functional impairment of BG and fully restoring the normal patterns of glutamatergic/GABAergic stimulation to PCs.These findings indicate that in Npc1 (nmf164) homozygous mice the derangement of synaptic connectivity and dysmyelination during cerebellar morphogenesis largely anticipate motor deficits that are typically observed during adulthood.
authors: Department of Psychology, Section of Neuroscience and "Daniel Bovet" Neurobiology Research Center, Sapienza University of Rome, Via dei Sardi 70, 00185, Rome, Italy.
authors: Paola
authors: P
authors: Caporali
authors: Department of Psychology, Section of Neuroscience and "Daniel Bovet" Neurobiology Research Center, Sapienza University of Rome, Via dei Sardi 70, 00185, Rome, Italy.
authors: Francesco
authors: F
authors: Bruno
authors: Department of Psychology, Section of Neuroscience and "Daniel Bovet" Neurobiology Research Center, Sapienza University of Rome, Via dei Sardi 70, 00185, Rome, Italy.
authors: Giampiero
authors: G
authors: Palladino
authors: Department of Psychology, Section of Neuroscience and "Daniel Bovet" Neurobiology Research Center, Sapienza University of Rome, Via dei Sardi 70, 00185, Rome, Italy.
authors: Jessica
authors: J
authors: Dragotto
authors: Department of Psychology, Section of Neuroscience and "Daniel Bovet" Neurobiology Research Center, Sapienza University of Rome, Via dei Sardi 70, 00185, Rome, Italy.|IRCCS Fondazione Santa Lucia, Via del Fosso di Fiorano 64, 00179, Rome, Italy.
authors: Laura
authors: L
authors: Petrosini
authors: Department of Psychology, Section of Neuroscience and "Daniel Bovet" Neurobiology Research Center, Sapienza University of Rome, Via dei Sardi 70, 00185, Rome, Italy.
authors: Franco
authors: F
authors: Mangia
authors: Department of Pediatrics, University of Arizona, 1501 N Campbell Ave, Tucson, AZ, 85724-5073, USA.
authors: Robert P
authors: RP
authors: Erickson
authors: Department of Psychology, Section of Neuroscience and "Daniel Bovet" Neurobiology Research Center, Sapienza University of Rome, Via dei Sardi 70, 00185, Rome, Italy.
authors: Sonia
authors: S
authors: Canterini
authors: Department of Psychology, Section of Neuroscience and "Daniel Bovet" Neurobiology Research Center, Sapienza University of Rome, Via dei Sardi 70, 00185, Rome, Italy. mariateresa.fiorenza@uniroma1.it.
authors: Maria Teresa
authors: MT
authors: Fiorenza
mesh_terms: D000375:Aging / Q000473:pathology / Q000502:physiology; D000818:Animals; D000831:Animals, Newborn; D002531:Cerebellum / Q000254:growth & development* / Q000378:metabolism / Q000473:pathology*; D015331:Cohort Studies; D002658:Developmental Disabilities / Q000473:pathology* / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009048:Motor Skills; D009186:Myelin Sheath / Q000378:metabolism / Q000473:pathology; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology; D000077296:Niemann-Pick C1 Protein; D052556:Niemann-Pick Disease, Type C / Q000473:pathology* / Q000503:physiopathology; D004856:Postural Balance; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D012720:Severity of Illness Index; D013569:Synapses / Q000378:metabolism / Q000473:pathology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D011506:Proteins; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid
keywords: 2-hydroxypropyl-β-cyclodextrin; Cerebellar cortex development; Cholesterol; Dysmyelination; Lysosomal storage disorders; Motor behavior