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 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 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 [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
Volume2
Issue number1
DOIs
StatePublished - Jan 27 2014

Fingerprint

Mucolipidoses
Gliosis
Neuroglia
Pathology
Neurons
Neuronal Plasticity
Long-Term Potentiation
Corpus Callosum
Microglia
Neurologic Manifestations
Astrocytes
Mutation
Health
Brain
Genes

Keywords

  • 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

Cite this

Grishchuk, Y., Sri, S., Rudinskiy, N., Ma, W., Stember, K. G., Cottle, M. W., ... Slaugenhaupt, S. A. (2014). Behavioral deficits, early gliosis, dysmyelination and synaptic dysfunction in a mouse model of mucolipidosis IV. Acta neuropathologica communications, 2(1), [133]. https://doi.org/10.1186/s40478-014-0133-7

Behavioral deficits, early gliosis, dysmyelination and synaptic dysfunction in a mouse model of mucolipidosis IV. / Grishchuk, Yulia; Sri, Sarmi; Rudinskiy, Nikita; Ma, Weiyuan; Stember, Katherine G.; Cottle, Matthew W.; Sapp, Ellen; Difiglia, Marian; Muzikansky, Alona; Betensky, Rebecca; Wong, Andrew M.S.; Bacskai, Brian J.; Hyman, Bradley T.; Kelleher, Raymond J.; Cooper, Jonathan D.; Slaugenhaupt, Susan A.

In: Acta neuropathologica communications, Vol. 2, No. 1, 133, 27.01.2014.

Research output: Contribution to journalReview article

Grishchuk, Y, Sri, S, Rudinskiy, N, Ma, W, Stember, KG, Cottle, MW, Sapp, E, Difiglia, M, Muzikansky, A, Betensky, R, Wong, AMS, Bacskai, BJ, Hyman, BT, Kelleher, RJ, Cooper, JD & Slaugenhaupt, SA 2014, 'Behavioral deficits, early gliosis, dysmyelination and synaptic dysfunction in a mouse model of mucolipidosis IV', Acta neuropathologica communications, vol. 2, no. 1, 133. https://doi.org/10.1186/s40478-014-0133-7
Grishchuk, Yulia ; Sri, Sarmi ; Rudinskiy, Nikita ; Ma, Weiyuan ; Stember, Katherine G. ; Cottle, Matthew W. ; Sapp, Ellen ; Difiglia, Marian ; Muzikansky, Alona ; Betensky, Rebecca ; Wong, Andrew M.S. ; Bacskai, Brian J. ; Hyman, Bradley T. ; Kelleher, Raymond J. ; Cooper, Jonathan D. ; Slaugenhaupt, Susan A. / Behavioral deficits, early gliosis, dysmyelination and synaptic dysfunction in a mouse model of mucolipidosis IV. In: Acta neuropathologica communications. 2014 ; Vol. 2, No. 1.
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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 [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.",
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