A centronuclear myopathy‐causing mutation in dynamin‐2 disrupts neuronal morphology and excitatory synaptic transmission in a murine model of the disease

Aims Dynamin‐2 is a large GTPase, a member of the dynamin superfamily that regulates membrane remodelling and cytoskeleton dynamics. Mutations in the dynamin‐2 gene (DNM2) cause autosomal dominant centronuclear myopathy (CNM), a congenital neuromuscular disorder characterised by progressive weakness...

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Published in:Neuropathology and applied neurobiology 2023-08, Vol.49 (4), p.e12918-n/a
Main Authors: Arriagada‐Diaz, Jorge, Flores‐Muñoz, Carolina, Gómez‐Soto, Bárbara, Labraña‐Allende, Marjorie, Mattar‐Araos, Michelle, Prado‐Vega, Lorena, Hinostroza, Fernando, Gajardo, Ivana, Guerra‐Fernández, María José, Bevilacqua, Jorge A., Cárdenas, Ana M., Bitoun, Marc, Ardiles, Alvaro O., Gonzalez‐Jamett, Arlek M.
Format: Article
Language:English
Subjects:
Animal models
Atrophy
Central nervous system
centronuclear myopathy
Cognitive ability
Cytoskeleton
dendritic arborisation
Dendritic spines
Dynamin
dynamin‐2
Hippocampus
Morphology
Mutation
Myopathy
neuronal morphology
Neurons
RNA-mediated interference
Skeletal muscle
Synaptic transmission
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Summary:Aims Dynamin‐2 is a large GTPase, a member of the dynamin superfamily that regulates membrane remodelling and cytoskeleton dynamics. Mutations in the dynamin‐2 gene (DNM2) cause autosomal dominant centronuclear myopathy (CNM), a congenital neuromuscular disorder characterised by progressive weakness and atrophy of the skeletal muscles. Cognitive defects have been reported in some DNM2‐linked CNM patients suggesting that these mutations can also affect the central nervous system (CNS). Here we studied how a dynamin‐2 CNM‐causing mutation influences the CNS function. Methods Heterozygous mice harbouring the p.R465W mutation in the dynamin–2 gene (HTZ), the most common causing autosomal dominant CNM, were used as disease model. We evaluated dendritic arborisation and spine density in hippocampal cultured neurons, analysed excitatory synaptic transmission by electrophysiological field recordings in hippocampal slices, and evaluated cognitive function by performing behavioural tests. Results HTZ hippocampal neurons exhibited reduced dendritic arborisation and lower spine density than WT neurons, which was reversed by transfecting an interference RNA against the dynamin‐2 mutant allele. Additionally, HTZ mice showed defective hippocampal excitatory synaptic transmission and reduced recognition memory compared to the WT condition. Conclusion Our findings suggest that the dynamin‐2 p.R465W mutation perturbs the synaptic and cognitive function in a CNM mouse model and support the idea that this GTPase plays a key role in regulating neuronal morphology and excitatory synaptic transmission in the hippocampus. Centronuclear myopathy (CNM) is a congenital disease mainly affecting skeletal muscles. One of the main causes of CNM is mutations in the DNM2 gene, which encodes dynamin‐2. Clinical reports suggest that DNM2‐linked CNM patients exhibit cognitive defects, although the mechanisms are unknown. In this work, we show that a mouse expressing the most common mutation in DNM2 causing CNM exhibits loss of recognition memory, associated with alterations in neuronal morphology, loss of dendritic spines, and defects in hippocampal excitatory synaptic transmission.
ISSN:0305-1846
1365-2990
DOI:10.1111/nan.12918