Snapin is critical for presynaptic homeostatic plasticity.
Snapin is critical for presynaptic homeostatic plasticity.
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DOI：
10.1523/jneurosci.5465-11.2012
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发表时间：
2012-06-20
期刊：
影响因子：
--
通讯作者：
Davis GW
中科院分区：
文献类型：
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作者：
Dickman DK;Tong A;Davis GW
突触前神经递质释放的稳态调节的分子机制很大程度上是未知的。我们之前使用基于电生理学的正向遗传筛选来评估 400 多个神经元表达基因的功能，以了解其在果蝇神经肌肉接头突触传递稳态控制中的作用。该筛选确定了失调蛋白（一种与人类精神分裂症相关的基因）的关键功能。其他系统的生化研究表明 Snapin 与 Dysbindin 相互作用，促使我们测试 Snapin 是否可能参与突触稳态机制。在这里，我们证明，在抑制突触后谷氨酸受体后，Snapin 的丢失会阻碍突触前囊泡释放的稳态调节。对于突触后谷氨酸受体的药理抑制所诱导的突触稳态的快速诱导，以及肌肉特异性 GluRIIA 谷氨酸受体亚基的基因删除所诱导的突触稳态的长期表达都是如此。 Snapin 的丢失不会改变基线突触传递、突触形态、突触生长或活动区域的数量或密度，表明突触稳态的阻滞不是突触发育受损的次要后果。其他遗传证据表明，Snapin 与 Dysbindin 协同作用，调节囊泡释放和可能的稳态可塑性。最后，我们提供了遗传证据，表明 Snapin 与 SNARE 复合体的一个组成部分 SNAP25 的相互作用也参与突触稳态。
The molecular mechanisms underlying the homeostatic modulation of presynaptic neurotransmitter release are largely unknown. We have previously used an electrophysiology-based forward genetic screen to assess the function of over 400 neuronally expressed genes for a role in the homeostatic control of synaptic transmission at the neuromuscular junction of Drosophila melanogaster. This screen identified a critical function for dysbindin, a gene linked to schizophrenia in humans. Biochemical studies in other systems have shown that Snapin interacts with Dysbindin, prompting us to test whether Snapin might be involved in the mechanisms of synaptic homeostasis. Here, we demonstrate that loss of snapin blocks the homeostatic modulation of presynaptic vesicle release following inhibition of postsynaptic glutamate receptors. This is true for both the rapid induction of synaptic homeostasis induced by pharmacological inhibition of postsynaptic glutamate receptors, and the long-term expression of synaptic homeostasis induced by the genetic deletion of the muscle-specific GluRIIA glutamate receptor subunit. Loss of snapin does not alter baseline synaptic transmission, synapse morphology, synapse growth, or the number or density of active zones, indicating that the block of synaptic homeostasis is not a secondary consequence of impaired synapse development. Additional genetic evidence to suggests that snapin functions in concert with dysbindin to modulate vesicle release and possibly homeostatic plasticity. Finally, we provide genetic evidence that the interaction of Snapin with SNAP25, a component of the SNARE complex, is also involved in synaptic homeostasis.