Early defects in mucopolysaccharidosis type IIIC disrupt excitatory synaptic transmission
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
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
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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

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Figure 6

Alteration of miniature excitatory and inhibitory postsynaptic currents in MPSIIIC neurons.

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Alteration of miniature excitatory and inhibitory postsynaptic currents ...
(A) Distribution of mEPSC amplitudes showing significant decrease in the mEPSC amplitude in MPSIIIC mice at P14–P20 and P45–P60. (B and C) No significant difference in the decay constant (B) or rise time (C) of mEPSC events was detected at P14–P20 or P45–P60. (D) Distribution of mEPSC instantaneous frequencies showing significant decrease in the mEPSC frequency in MPSIIIC mice as compared with WT in P14–P20 and P45–P60 hippocampal slices. (E and F) Representative traces of mEPSCs at P14–P20 and P45–P60 (E) and overlay of representative individual events from MPSIIIC and WT mice at P45–P60 (F). (G) Distribution of mIPSC amplitudes showing significant decrease in the mIPSC amplitude in MPSIIIC as compared with WT in P14–P20 and P45–P60 hippocampal slices. (H) No significant differences in the fast decay constant or the fast rise time at both ages. (I) No significant differences in the slow decay constant or the slow rise time of mIPSCs. (J) Distribution of mIPSC instantaneous frequencies showing significant decrease in the mIPSCs frequency in MPSIIIC mice as compared with WT in P45–P60 hippocampal slices. (K and L) Representative traces of mIPSCs at P14–P20 and P45–P60 (K) and overlay of representative individual mIPSC events with fast kinetics (left panel) and slow kinetics (right panel) for MPSIIIC and WT mice at P45–P60 (L). Statistical analyses for Gaussian-distributed events were performed using 1-way ANOVA with Tukey’s post test. Non-Gaussian–distributed events were analyzed by Kruskal-Wallis test, followed by Dunn’s test. * P < 0.05, ** P < 0.01, *** P < 0.001, and **** P < 0.0001. Kolmogorov-Smirnov test was performed for not normally distributed events.