Delayed recruitment of activity-dependent bulk endocytosis in Fmr1 knockout neurons

IF 4.2 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Nawon Kim, Katherine Bonnycastle, Peter C. Kind, Michael A. Cousin
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Abstract

The presynapse performs an essential role in brain communication via the activity-dependent release of neurotransmitters. However, the sequence of events through which a presynapse acquires functionality is relatively poorly understood, which is surprising, since mutations in genes essential for its operation are heavily implicated in neurodevelopmental disorders. We addressed this gap in knowledge by determining the developmental trajectory of synaptic vesicle (SV) recycling pathways in primary cultures of rat hippocampal neurons. Exploiting a series of optical and morphological assays, we revealed that the majority of nerve terminals displayed activity-dependent calcium influx from 3 days in vitro (DIV), immediately followed by functional evoked exocytosis and endocytosis, although the number of responsive nerve terminals continued to increase until the second week in vitro. However, the most intriguing discovery was that activity-dependent bulk endocytosis (ADBE) was only observed from DIV 14 onwards. Importantly, optimal ADBE recruitment was delayed until DIV 21 in Fmr1 knockout neurons, which model Fragile X Syndrome (FXS). This implicates the delayed recruitment of ADBE as a potential contributing factor in the development of circuit dysfunction in FXS, and potentially other neurodevelopmental disorders.

Abstract Image

Fmr1 基因敲除神经元中活动依赖性大量内吞的延迟招募。
突触前通过依赖于活动的神经递质释放,在大脑通信中发挥着重要作用。然而,人们对突触前体获得功能的一系列事件却知之甚少,这一点令人惊讶,因为突触前体运作所必需的基因突变与神经发育障碍有很大关系。我们通过确定大鼠海马神经元原代培养物中突触囊泡 (SV) 循环途径的发育轨迹,填补了这一知识空白。通过一系列光学和形态学检测,我们发现大多数神经末梢从体外 3 天(DIV)起就显示出活动依赖性钙离子流入,紧接着是功能诱发的外吞和内吞,尽管反应性神经末梢的数量直到体外第二周还在继续增加。然而,最引人入胜的发现是,只有从 DIV 14 开始才能观察到活动依赖性大量内吞(ADBE)。重要的是,在模拟脆性X综合征(FXS)的Fmr1基因敲除神经元中,最佳的ADBE招募延迟到DIV 21。这表明,ADBE的招募延迟是导致FXS以及其他潜在神经发育障碍的电路功能障碍的一个潜在因素。
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来源期刊
Journal of Neurochemistry
Journal of Neurochemistry 医学-神经科学
CiteScore
9.30
自引率
2.10%
发文量
181
审稿时长
2.2 months
期刊介绍: Journal of Neurochemistry focuses on molecular, cellular and biochemical aspects of the nervous system, the pathogenesis of neurological disorders and the development of disease specific biomarkers. It is devoted to the prompt publication of original findings of the highest scientific priority and value that provide novel mechanistic insights, represent a clear advance over previous studies and have the potential to generate exciting future research.
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