Behavioral deficits, early gliosis, dysmyelination and synaptic dysfunction in a mouse model of mucolipidosis IV
Year: 2014
Type: article
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.
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,790
Funders: Hearst Foundations, Harvard NeuroDiscovery Center, Batten Disease Support and Research Association, Harvard University, Harvard Catalyst, Mucolipidosis IV Foundation, Batten Disease Family Association, National Institutes of Health, National Institute on Aging, National Institute of Neurological Disorders and Stroke, National Institute of Biomedical Imaging and Bioengineering, National Center for Research Resources, National Center for Advancing Translational Sciences
Awards: Molecular Analysis of Mucolipidosis IV, G1735140896, Multiphoton microscopy for in vivo neural imaging, A replacement multiphoton microscope for in vivo imaging in rodent models of neur, G5887770846, Massachusetts Alzheimer's Disease Research Center, Harvard Clinical and Translational Science Center (UL1), G8923804000, G96181942
OpenAlex ID: W2154697281