title: Behavioral deficits, early gliosis, dysmyelination and synaptic dysfunction in a mouse model of mucolipidosis IV.
abstract: Mucolipidosis IV (MLIV) is caused by mutations in the gene MCOLN1. Patients with MLIV have severe neurologic deficits and very little is known about the brain pathology in this lysosomal disease. Using an accurate mouse model of mucolipidosis IV, we observed early behavioral deficits which were accompanied by activation of microglia and astrocytes. The glial activation that persisted during the course of disease was not accompanied by neuronal loss even at the late stage. In vivo [Ca(2+)]-imaging revealed no changes in resting [Ca(2+)] levels in Mcoln1(-/-) cortical neurons, implying their physiological health. Despite the absence of neuron loss, we observed alterations in synaptic plasticity, as indicated by elevated paired-pulse facilitation and enhanced long-term potentiation. Myelination deficits and severely dysmorphic corpus callosum were present early and resembled white matter pathology in mucolipidosis IV patients. These results indicate the early involvement of glia, and challenge the traditional view of mucolipidosis IV as an overtly neurodegenerative condition.
authors.forename: Yulia
authors.initials: Y
authors.lastname: Grishchuk
authors.forename: Sarmi
authors.initials: S
authors.lastname: Sri
authors.forename: Nikita
authors.initials: N
authors.lastname: Rudinskiy
authors.forename: Weiyuan
authors.initials: W
authors.lastname: Ma
authors.forename: Katherine G
authors.initials: KG
authors.lastname: Stember
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Cottle
authors.forename: Ellen
authors.initials: E
authors.lastname: Sapp
authors.forename: Marian
authors.initials: M
authors.lastname: Difiglia
authors.forename: Alona
authors.initials: A
authors.lastname: Muzikansky
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Betensky
authors.forename: Andrew M S
authors.initials: AM
authors.lastname: Wong
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Bacskai
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Hyman
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Kelleher
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Cooper
authors.forename: Susan A
authors.initials: SA
authors.lastname: Slaugenhaupt
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000473:pathology; D001921:Brain / Q000473:pathology* / Q000503:physiopathology*; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000502:physiology; D005911:Gliosis; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000473:pathology; D009043:Motor Activity / Q000502:physiology; D009081:Mucolipidoses / Q000473:pathology* / Q000503:physiopathology*; D009186:Myelin Sheath / Q000473:pathology; D009473:Neuronal Plasticity; D009474:Neurons / Q000502:physiology; D050051:Transient Receptor Potential Channels / Q000235:genetics
chemical_list: C512321:Mcoln1 protein, mouse; D050051:Transient Receptor Potential Channels