Early defects in mucopolysaccharidosis type IIIC disrupt excitatory synaptic transmission
Camila Pará, … , Graziella Di Cristo, Alexey V. Pshezhetsky
Camila Pará, … , Graziella Di Cristo, Alexey V. Pshezhetsky
Published June 22, 2021
Citation Information: JCI Insight. 2021;6(15):e142073. https://doi.org/10.1172/jci.insight.142073.
View: Text | PDF
Research Article Genetics Neuroscience

Early defects in mucopolysaccharidosis type IIIC disrupt excitatory synaptic transmission

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.

Authors

Camila Pará, Poulomee Bose, Luigi Bruno, Erika Freemantle, Mahsa Taherzadeh, Xuefang Pan, Chanshuai Han, Peter S. McPherson, Jean-Claude Lacaille, Éric Bonneil, Pierre Thibault, Claire O’Leary, Brian Bigger, Carlos Ramon Morales, Graziella Di Cristo, Alexey V. Pshezhetsky

×

Figure 2

MPSIIIC hippocampal neurons present decreased density of mature dendritic spines, reduced densities of Syn1, and synaptophysin+ puncta in the axons.

Options: View larger image (or click on image) Download as PowerPoint
MPSIIIC hippocampal neurons present decreased density of mature dendriti...
(A) Representative images of dendritic spines in cultured neurons at DIV21 and in CA1 pyramidal EGFP-expressing neurons of mice in vitro and at P10, P20, 3 months and 8 months. In cultured neurons, mature (mushroom) spines are marked with yellow arrows, while immature spines (filopodia) are marked with white arrows. The majority of dendritic spines in MPSIIIC are immature. Dendrites in pyramidal MPSIIIC neurons have wider areas resembling spheroids. (B) Top: Quantification (left) and distribution of different types of spines (right) in cultured neurons. Bottom: Quantification of dendritic spines in pyramidal neurons. (C) Representative images and quantification of dendritic spines in CA1 pyramidal EGFP-expressing neurons of a 3-month-old sialidosis (Neu1–/–) mouse and a Tay-Sachs (Hexa–/–) mouse and their respective WT littermates. The quantification of spines was performed in a blinded manner for 20 μm–long dendrite segments starting at 30 μm from the soma. Scale bar: 25 μm for panels and 10 μm for enlargements. (D) Representative images of cultured hippocampal neurons at DIV21 from WT and MPSIIIC mice stained for Syn1 and synaptophysin. MPSIIIC neurons have lower density of Syn1+ and synaptophysin+ puncta. (E) Representative images of cultured neurons, stained for Syn1 and an axonal marker, neurofilament medium chain protein. MPSIIIC neurons have lower density of Syn1+ puncta per length of the axon. (F) Representative images of CA1 pyramidal neurons of 2-month-old MPSIIIC and WT mice stained for synaptophysin and NeuN. MPSIIIC mice have lower density of synaptophysin+ puncta. Scale bar: 25 μm (D and F) and 10 μm (E). Graphs show quantification values, mean ± SD obtained for at least 30 cells from 3 mice per each age and genotype. P values were calculated using unpaired 2-tailed t test (B [upper graph] and D–F); 1-way ANOVA with Tukey post hoc test (C), and 2-way ANOVA with Bonferoni post hoc test (B, lower graph).