A centronuclear myopathy-causing mutation in dynamin-2 perturbs the actin-dependent structure of dendritic spines leading to excitatory synaptic defects in a murine model of the disease

ARRIAGADA-DIAZ, J.; Gomez, B.; Prado-Vega, L.; MATTAR-ARAOS, M.; LABRANA-ALLENDE, M.; HINOSTROZA, F.; Gajardo, I.; Guerra-Fernandez, M. J.; Bevilacqua, J. A.; CARDENAS, A. M.; Bitoun, M.; ARDILES, A. O.; GONZALEZ-JAMETT, A. M.

doi:10.1101/2021.06.28.450172

bioRxiv · 10.1101/2021.06.28.450172

A centronuclear myopathy-causing mutation in dynamin-2 perturbs the actin-dependent structure of dendritic spines leading to excitatory synaptic defects in a murine model of the disease

ARRIAGADA-DIAZ, J.·Gomez, B.·Prado-Vega, L.·MATTAR-ARAOS, M.·LABRANA-ALLENDE, M.·HINOSTROZA, F.·Gajardo, I.·Guerra-Fernandez, M. J.·Bevilacqua, J. A.·CARDENAS, A. M.·Bitoun, M.·ARDILES, A. O.·GONZALEZ-JAMETT, A. M.

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Abstract

Dynamin-2 is a large GTP-ase, member of the dynamin superfamily, that regulates membrane remodeling and cytoskeleton dynamics. In the mammalian nervous system dynamin-2 modulates synaptic vesicle (SV)-recycling at the nerve terminals and receptor-trafficking to and from postsynaptic densities (PSDs). Mutations in dynamin-2 cause autosomal dominant centronuclear myopathy (CNM), a congenital neuromuscular disorder characterized by progressive weakness and atrophy of distal skeletal muscles. Cognitive defects have also been reported in dynamin-2-linked CNM patients suggesting a concomitant impairment of the central nervous system. Here we addressed the mechanisms that lead to cognitive defects in dynamin-2-linked CNM using a knock-in mouse model that harbors the p.R465W mutation in dynamin-2, the most common causing CNM. Our results show that these mice exhibit reduced capability to learn and acquire spatial and recognition memory, impaired long-term potentiation of the excitatory synaptic strength and perturbed dendritic spine morphology, which seem to be associated with actin defects. Together, these data reveal for the first time that structural and functional synaptic defects underlie cognitive defects in the CNM context. In addition our results contribute to the still scarce knowledge about the importance of dynamin-2 at central synapses.

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ARRIAGADA-DIAZ, J., Gomez, B., Prado-Vega, L., MATTAR-ARAOS, M., LABRANA-ALLENDE, M., HINOSTROZA, F., Gajardo, I., Guerra-Fernandez, M. J., Bevilacqua, J. A., CARDENAS, A. M., Bitoun, M., ARDILES, A. O., GONZALEZ-JAMETT, A. M.. 2021-06-29. A centronuclear myopathy-causing mutation in dynamin-2 perturbs the actin-dependent structure of dendritic spines leading to excitatory synaptic defects in a murine model of the disease. https://doi.org/10.1101/2021.06.28.450172

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