Characterization of developmental and molecular factors underlying release heterogeneity at Drosophila synapses.
Characterization of developmental and molecular factors underlying release heterogeneity at Drosophila synapses.
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DOI：
10.7554/elife.38268
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发表时间：
2018-07-10
期刊：
影响因子：
7.7
通讯作者：
Littleton JT
中科院分区：
文献类型：
--
作者：
Akbergenova Y;Cunningham KL;Zhang YV;Weiss S;Littleton JT
神经元通过在称为活动区（AZ）的特定突触区域释放神经递质进行通信。使用生物传感器可视化单个突触囊泡融合事件在果蝇神经肌肉接头，我们分析了发展和分子决定因素的释放概率（Pr）的一个定义的连接与~300 AZ。Pr是异质的，但代表了每个AZ的稳定特征。Pr在高频刺激期间保持稳定，并且在缺乏Ca 2+传感器Synaptotagmin 1的突变体中保留异质性。Pr与突触前Ca 2+通道丰度和个别释放位点的Ca 2+内流相关。Pr异质性也与谷氨酸受体丰度，高Pr连接开发受体亚型分离。在整个发展过程中的活体成像显示，AZ获得高Pr在一个多天的成熟期，Pr的异质性在很大程度上反映AZ年龄。突触成熟的速率是活动依赖性的，因为神经元活动的增加和减少都调节谷氨酸受体场的大小和分离。为了向相邻的神经元发送信息，神经元会向它们之间的差距--或突触--释放一种叫做神经递质的化学物质。神经递质分子与受体神经元上的蛋白质结合。但是，首先是什么导致发送神经元释放神经递质呢？当一个叫做动作电位的电脉冲到达发送细胞时，这个过程就开始了。它的到来导致发送神经元膜上的通道打开，从而使钙离子涌入细胞。钙离子与称为突触囊泡的神经递质分子包相互作用。这导致一些囊泡将其内容物排空到突触中。但这个过程并不特别可靠。只有一小部分动作电位导致囊泡与突触膜融合。这种情况发生的可能性在神经元之间有很大差异，甚至在同一神经元形成的突触之间也是如此。可能释放神经递质的突触被认为是强大的。它们擅长将信息从发送者神经元传递到接收者。具有低释放概率的突触被认为是弱的。但是，强突触和弱突触之间到底有什么区别呢？Akbergenova等人研究了果蝇中运动神经元和肌肉细胞之间的突触。每个运动神经元形成几百个突触。其中一些突触释放神经递质的可能性是其他突触的50倍。Akbergenova等人利用钙离子成像和遗传学发现，强突触的发送细胞比弱突触的发送细胞有更多的钙离子通道。受体蛋白的亚型和排列在强突触和弱突触的受体神经元之间也不同。最后，对幼虫的研究表明，新形成的突触开始都很弱，然后逐渐变强。这种强化发生的速度取决于突触处神经元的活跃程度。这项研究以前所未有的细节显示了使某些果蝇突触比其他突触更容易释放神经递质的关键分子因素。哺乳动物突触中的许多蛋白质类似于果蝇突触中的蛋白质。这意味着类似的因素也可以解释哺乳动物大脑中突触强度的差异。突触强度的变化是学习能力的基础。此外，许多神经和精神疾病是由突触破坏引起的。因此，了解突触的分子基础将为某些脑部疾病的起源提供线索。
Neurons communicate through neurotransmitter release at specialized synaptic regions known as active zones (AZs). Using biosensors to visualize single synaptic vesicle fusion events at Drosophila neuromuscular junctions, we analyzed the developmental and molecular determinants of release probability (Pr) for a defined connection with ~300 AZs. Pr was heterogeneous but represented a stable feature of each AZ. Pr remained stable during high frequency stimulation and retained heterogeneity in mutants lacking the Ca2+ sensor Synaptotagmin 1. Pr correlated with both presynaptic Ca2+ channel abundance and Ca2+ influx at individual release sites. Pr heterogeneity also correlated with glutamate receptor abundance, with high Pr connections developing receptor subtype segregation. Intravital imaging throughout development revealed that AZs acquire high Pr during a multi-day maturation period, with Pr heterogeneity largely reflecting AZ age. The rate of synapse maturation was activity-dependent, as both increases and decreases in neuronal activity modulated glutamate receptor field size and segregation. To send a message to its neighbor, a neuron releases chemicals called neurotransmitters into the gap – or synapse – between them. The neurotransmitter molecules bind to proteins on the receiver neuron called receptors. But what causes the sender neuron to release neurotransmitter in the first place? The process starts when an electrical impulse called an action potential arrives at the sender cell. Its arrival causes channels in the membrane of the sender neuron to open, so that calcium ions flood into the cell. The calcium ions interact with packages of neurotransmitter molecules, known as synaptic vesicles. This causes some of the vesicles to empty their contents into the synapse. But this process is not particularly reliable. Only a small fraction of action potentials cause vesicles to fuse with the synaptic membrane. How likely this is to occur varies greatly between neurons, and even between synapses formed by the same neuron. Synapses that are likely to release neurotransmitter are said to be strong. They are good at passing messages from the sender neuron to the receiver. Synapses with a low probability of release are said to be weak. But what exactly differs between strong and weak synapses? Akbergenova et al. studied synapses between motor neurons and muscle cells in the fruit fly Drosophila. Each motor neuron forms several hundred synapses. Some of these synapses are 50 times more likely to release neurotransmitter than others. Using calcium imaging and genetics, Akbergenova et al. showed that sender cells at strong synapses have more calcium channels than sender cells at weak synapses. The subtypes and arrangement of receptor proteins also differ between the receiver neurons of strong versus weak synapses. Finally, studies in larvae revealed that newly formed synapses all start out weak and then gradually become stronger. How fast this strengthening occurs depends on how active the neuron at the synapse is. This study has shown, in unprecedented detail, key molecular factors that make some fruit fly synapses more likely to release neurotransmitter than others. Many proteins at synapses of mammals resemble those at fruit fly synapses. This means that similar factors may also explain differences in synaptic strength in the mammalian brain. Changes in the strength of synapses underlie the ability to learn. Furthermore, many neurological and psychiatric disorders result from disruption of synapses. Understanding the molecular basis of synapses will thus provide clues to the origins of certain brain diseases.