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Early defects in mucopolysaccharidosis type IIIC disrupt excitatory synaptic transmission.
- Source :
-
JCI insight [JCI Insight] 2021 Aug 09; Vol. 6 (15). Date of Electronic Publication: 2021 Aug 09. - Publication Year :
- 2021
-
Abstract
- The majority of patients affected with lysosomal storage disorders (LSD) exhibit neurological symptoms. For mucopolysaccharidosis type IIIC (MPSIIIC), the major burdens are progressive and severe neuropsychiatric problems and dementia, primarily thought to stem from neurodegeneration. Using the MPSIIIC mouse model, we studied whether clinical manifestations preceding massive neurodegeneration arise from synaptic dysfunction. Reduced levels or abnormal distribution of multiple synaptic proteins were revealed in cultured hippocampal and CA1 pyramidal MPSIIIC neurons. These defects were rescued by virus-mediated gene correction. Dendritic spines were reduced in pyramidal neurons of mouse models of MPSIIIC and other (Tay-Sachs, sialidosis) LSD as early as at P10. MPSIIIC neurons also presented alterations in frequency and amplitude of miniature excitatory and inhibitory postsynaptic currents, sparse synaptic vesicles, reduced postsynaptic densities, disorganized microtubule networks, and partially impaired axonal transport of synaptic proteins. Furthermore, postsynaptic densities were reduced in postmortem cortices of human MPS patients, suggesting that the pathology is a common hallmark for neurological LSD. Together, our results demonstrate that lysosomal storage defects cause early alterations in synaptic structure and abnormalities in neurotransmission originating from impaired synaptic vesicular transport, and they suggest that synaptic defects could be targeted to treat behavioral and cognitive defects in neurological LSD patients.
- Subjects :
- Animals
Behavior, Animal drug effects
Behavior, Animal physiology
Cells, Cultured
Cognitive Dysfunction drug therapy
Cognitive Dysfunction metabolism
Disease Progression
Drug Discovery
Hippocampus pathology
Mice
Neurodegenerative Diseases drug therapy
Neurodegenerative Diseases metabolism
Protein Transport
Lysosomal Storage Diseases metabolism
Mucopolysaccharidosis III metabolism
Mucopolysaccharidosis III psychology
Pyramidal Cells metabolism
Pyramidal Cells pathology
Secretory Vesicles metabolism
Synaptic Transmission physiology
Subjects
Details
- Language :
- English
- ISSN :
- 2379-3708
- Volume :
- 6
- Issue :
- 15
- Database :
- MEDLINE
- Journal :
- JCI insight
- Publication Type :
- Academic Journal
- Accession number :
- 34156977
- Full Text :
- https://doi.org/10.1172/jci.insight.142073