Abstract：
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.
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.
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.
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.
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.
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.
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.
摘要：
目的：Dynamin-2（DNM2）是一种大的GTP酶，调节膜重塑和细胞骨架动力学的动力蛋白超家族成员。DNM2的突变导致常染色体显性遗传性中央核型肌病（CNM），一种以骨骼肌进行性无力和萎缩为特征的先天性神经肌肉疾病。在一些DNM2相关的CNM患者中已经报道了认知缺陷，表明这些突变也可以影响中枢神经系统（CNS）。在这里，我们研究了DNM2引起CNM的突变如何影响CNS功能。
方法：在Dnm2（HTZ）中携带p.R465W突变的杂合小鼠，最常见的常染色体显性遗传CNM，用作疾病模型。我们评估了海马培养神经元的树突状树干化和脊柱密度，通过海马切片中的电生理场记录分析兴奋性突触传递，并通过行为测试评估认知功能。
结果：HTZ海马神经元表现出比WT神经元减少的树突乔化和更低的脊柱密度，通过转染针对Dnm2突变等位基因的干扰RNA来逆转。此外,与WT条件相比，HTZ小鼠显示出海马兴奋性突触传递缺陷和识别记忆降低。
结论：我们的发现表明，Dnm2p.R465W突变扰乱了CNM小鼠模型的突触和认知功能，并支持Dnm2在调节神经元形态和兴奋性突触传递中起关键作用的观点海马。
方法：在Dnm2（HTZ）中携带p.R465W突变的杂合小鼠，最常见的常染色体显性遗传CNM，用作疾病模型。我们评估了海马培养神经元的树突状树干化和脊柱密度，通过海马切片中的电生理场记录分析兴奋性突触传递，并通过行为测试评估认知功能。
结果：HTZ海马神经元表现出比WT神经元减少的树突乔化和更低的脊柱密度，通过转染针对Dnm2突变等位基因的干扰RNA来逆转。此外,与WT条件相比，HTZ小鼠显示出海马兴奋性突触传递缺陷和识别记忆降低。
结论：我们的发现表明，Dnm2p.R465W突变扰乱了CNM小鼠模型的突触和认知功能，并支持Dnm2在调节神经元形态和兴奋性突触传递中起关键作用的观点海马。
