The BDNF val-66-met Polymorphism Affects Neuronal Morphology and Synaptic Transmission in Cultured Hippocampal Neurons from Rett Syndrome Mice.
The BDNF val-66-met Polymorphism Affects Neuronal Morphology and Synaptic Transmission in Cultured Hippocampal Neurons from Rett Syndrome Mice.
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DOI：
10.3389/fncel.2017.00203
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发表时间：
2017
影响因子：
5.3
通讯作者：
Pozzo-Miller L
中科院分区：
文献类型：
--
作者：
Xu X;Garcia J;Ewalt R;Nason S;Pozzo-Miller L
脑源性神经营养因子（Bdnf）与多种神经系统疾病有关，包括Rett综合征（RTT），这是一种由转录调节剂甲基cpg结合蛋白2 （MECP2）功能丧失突变引起的x连锁神经发育障碍。人类BDNF基因具有单核苷酸多态性（SNP）——在密码子66上蛋氨酸（met）取代缬氨酸（val）——影响BDNF的转运和活性依赖性释放，并导致认知功能障碍。携带met-BDNF等位基因的人有亚临床记忆缺陷，海马体积和激活减少。目前尚不清楚这种BDNF SNP是否会影响RTT个体的临床结果。为了评估这种BDNF SNP是否有助于RTT病理生理，我们检测了val-BDNF或met-BDNF表达对野生型（WT）和Mecp2敲除（KO）小鼠培养海马神经元树突和树突棘形态以及突触功能的影响。我们的研究结果表明，met-BDNF不像val-BDNF那样增加WT神经元的树突生长和分支、树突棘密度和单个脊柱体积以及兴奋性突触的数量。此外，met-BDNF减少Mecp2 KO神经元的树突复杂性、树突棘体积和量子兴奋性突触传递。这些结果表明，val-BDNF变异有助于RTT病理生理，基于BDNF的治疗应考虑RTT个体的BDNF基因型。
Brain-derived neurotrophic factor (Bdnf) has been implicated in several neurological disorders including Rett syndrome (RTT), an X-linked neurodevelopmental disorder caused by loss-of-function mutations in the transcriptional modulator methyl-CpG-binding protein 2 (MECP2). The human BDNF gene has a single nucleotide polymorphism (SNP)—a methionine (met) substitution for valine (val) at codon 66—that affects BDNF’s trafficking and activity-dependent release and results in cognitive dysfunction. Humans that are carriers of the met-BDNF allele have subclinical memory deficits and reduced hippocampal volume and activation. It is still unclear whether this BDNF SNP affects the clinical outcome of RTT individuals. To evaluate whether this BDNF SNP contributes to RTT pathophysiology, we examined the consequences of expression of either val-BDNF or met-BDNF on dendrite and dendritic spine morphology, and synaptic function in cultured hippocampal neurons from wildtype (WT) and Mecp2 knockout (KO) mice. Our findings revealed that met-BDNF does not increase dendritic growth and branching, dendritic spine density and individual spine volume, and the number of excitatory synapses in WT neurons, as val-BDNF does. Furthermore, met-BDNF reduces dendritic complexity, dendritic spine volume and quantal excitatory synaptic transmission in Mecp2 KO neurons. These results suggest that the val-BDNF variant contributes to RTT pathophysiology, and that BDNF-based therapies should take into consideration the BDNF genotype of the RTT individuals.
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影响因子：
64.8
作者：
COHENCORY, S;FRASER, SE
通讯作者：
FRASER, SE
影响因子：
1.7
作者：
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2
作者：
Alonso, M;Medina, JH;Pozzo-Miller, L
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Pozzo-Miller, L
影响因子：
5.3
作者：
Amaral, Michelle D.;Pozzo-Miller, Lucas
通讯作者：
Pozzo-Miller, Lucas
影响因子：
16.2
作者：
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