美国加州大学旧金山分校Robert H. Edwards等合作在研究中取得进展。他们发现SNARE蛋白VAMP7的胞吐介导突触前稳态。2026年10月28日出版的《自然》杂志发表了这项成果。

适应和学习所依赖的神经可塑性需要代偿性稳态机制来维持神经回路的稳定性和反应性。此前的工作已描述了多种形式的突触稳态，但检测活动变化并将其转化为神经传递改变的机制仍知之甚少。在此，研究人员表明，高频刺激改变随后的神经递质释放特性，从而赋予一种突触前形式的稳态，且不依赖于突触后受体。该机制涉及囊泡SNARE蛋白（v-SNARE）VAMP7（囊泡相关膜蛋白7），它通过特异性抑制经P/Q型突触前Ca²?通道的Ca²?内流来减少神经递质释放。此前的工作曾将靶SNARE蛋白（t-SNARE）与Ca²?通道的抑制联系起来，但缺乏明确的生理学依据。研究人员表明，VAMP7介导的活动依赖性释放调控需要t-SNARE突触融合蛋白（syntaxin）。尽管VAMP7在质膜上发挥作用以抑制P/Q型通道，但它主要定位于由衔接蛋白3（AP-3）产生的一部分突触囊泡上，这些囊泡特异性响应高频刺激。因此，VAMP7定位于AP-3来源的突触囊泡，提供了一种活动依赖性将VAMP7递送至质膜的机制，在那里它与syntaxin结合，抑制P/Q型Ca²?通道和递质释放。这种稳态形式的元可塑性在多个兴奋性突触中发挥作用，在其缺失时，FOS?神经元的比例增加数倍，揭示了兴奋性神经传递的一种一般特性，该特性可能也有助于维持神经连接的稀疏性。

附：英文原文

Title: Presynaptic homeostasis mediated by exocytosis of a SNARE protein

Author: Xu, Hongfei, Rao, Lee, Edwards, Robert H.

Issue&Volume: 2026-10-28

Abstract: The neural plasticity that underlies adaptation and learning requires countervailing homeostatic mechanisms to maintain the stability and responsiveness of neural circuits. Previous work has described several forms of synaptic homeostasis1, but the mechanisms that detect changes in activity and transduce these into altered neurotransmission have remained poorly understood. Here we show that high-frequency stimulation alters the subsequent properties of neurotransmitter release to confer a presynaptic form of homeostasis, independent of postsynaptic receptors. The mechanism involves vesicular SNARE protein (v-SNARE) VAMP7 (vesicle-associated membrane protein 7), which reduces neurotransmitter release by inhibiting the entry of Ca2+ specifically through P/Q-type presynaptic Ca2+ channels. Previous work has implicated target SNARE proteins (t-SNAREs) in the inhibition of Ca2+ channels2, but without clear physiological rationale. We show that the activity-dependent regulation of release mediated by VAMP7 requires the t-SNARE syntaxin. Although VAMP7 acts at the plasma membrane to inhibit P/Q-type channels, it localizes predominantly to a subset of synaptic vesicles made by adaptor protein-3 (AP-3) that respond specifically to high-frequency stimulation3,4. The localization of VAMP7 to AP-3-derived synaptic vesicles thus provides a mechanism for the activity-dependent delivery of VAMP7 to the plasma membrane, where it associates with syntaxin to inhibit P/Q-type Ca2+ channels and transmitter release. This homeostatic form of metaplasticity operates at multiple excitatory synapses, and in its absence, the fraction of FOS+ neurons increases several fold, revealing a general property of excitatory neurotransmission that might also maintain the sparsity of neural connections.

DOI: 10.1038/s41586-026-11201-3

Source:https://www.nature.com/articles/s41586-026-11201-3