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

Abstract

AimsDynamin‐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.MethodsHeterozygous 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.ResultsHTZ 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.ConclusionOur 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.

Dynamin-2 Mutations Linked to Neonatal-onset Centronuclear Myopathy impair exocytosis and endocytosis in adrenal chromaffin cells

“…Other dynamin-2 mutations that cause CNM, such as the mutants R369W and R465W, or mutations linked to Charcot-Marie-Tooth neuropathy like the K562E, also lead to aberrant actin dynamics (Yamada et al, 2016b; González-Jamett et al, 2017; Hamasaki et al 2022; Arriagada-Diaz et al, 2023). Interestingly, the R465W mutation further perturbs the synaptic plasticity and cognitive function in a mouse model of CNM (Arriagada-Diaz et al, 2023), supporting the pleiotropic role of these mutations. Why these mutations that seem to display increased GTPase activity (Kenniston and Lemmon, 2010) disrupt actin dynamics?…”