Behavioral deficits, early gliosis, dysmyelination and synaptic dysfunction in a mouse model of mucolipidosis IV

Yulia Grishchuk, Sarmi Sri, Nikita Rudinskiy, Weiyuan Ma, Katherine G. Stember, Matthew W. Cottle, Ellen Sapp, Marian Difiglia, Alona Muzikansky, Rebecca A. Betensky, Andrew M.S. Wong, Brian J. Bacskai, Bradley T. Hyman, Raymond J. Kelleher, Jonathan D. Cooper, Susan A. Slaugenhaupt

Research output: Contribution to journalReview articlepeer-review


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 [Ca2+]-imaging revealed no changes in resting [Ca2+] 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.

Original languageEnglish (US)
Article number133
JournalActa Neuropathologica Communications
Issue number1
StatePublished - Jan 27 2014


  • Glia
  • In vivo Ca imaging
  • Lysosomal storage disease
  • Mucolipidosis IV
  • Neuropathology

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience


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