1. Behavioral deficits, early gliosis, dysmyelination and synaptic dysfunction in a mouse model of mucolipidosis IV.
- Author
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Grishchuk Y, Sri S, Rudinskiy N, Ma W, Stember KG, Cottle MW, Sapp E, Difiglia M, Muzikansky A, Betensky RA, Wong AM, Bacskai BJ, Hyman BT, Kelleher RJ 3rd, Cooper JD, and Slaugenhaupt SA
- Subjects
- Animals, Astrocytes pathology, Disease Models, Animal, Exploratory Behavior physiology, Gliosis, Male, Mice, Mice, Knockout, Microglia pathology, Motor Activity physiology, Myelin Sheath pathology, Neuronal Plasticity, Neurons physiology, Transient Receptor Potential Channels genetics, Brain pathology, Brain physiopathology, Mucolipidoses pathology, Mucolipidoses physiopathology
- 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.
- Published
- 2014
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