Abstract
Dynamin-2 (DNM2) is a large GTPase, a member of the dynamin superfamily that regulates membrane remodelling and cytoskeleton dynamics. Mutations in DNM2 cause autosomal dominant centronuclear myopathy (CNM), a congenital neuromuscular disorder characterized 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 DNM2 CNM-causing mutation influences the CNS function. Heterozygous mice harbouring the p.R465W mutation in Dnm2 (HTZ), the most common causing autosomal dominant CNM, were used as the disease model. We evaluated dendritic arborization 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. HTZ hippocampal neurons exhibited reduced dendritic arborization and lower spine density than WT neurons, which was reversed by transfecting an interference RNA against the Dnm2 mutant allele. Additionally, HTZ mice showed defective hippocampal excitatory synaptic transmission and reduced recognition memory compared to the WT condition. Our findings suggest that the Dnm2 p.R465W mutation perturbs the synaptic and cognitive function in a CNM mouse model and support the idea that Dnm2 plays a key role in regulating neuronal morphology and excitatory synaptic transmission in the hippocampus.
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