Technion Faculty of Medicine, Rappaport Institute and Network Biology Research Laboratories, Fishbach Building, Technion City, Haifa 32000, Israel.
Technion Faculty of Medicine, Rappaport Institute and Network Biology Research Laboratories, Fishbach Building, Technion City, Haifa 32000, Israel
J Neurosci. 2020 Apr 1;40(14):2828-2848. doi: 10.1523/JNEUROSCI.2181-19.2020. Epub 2020 Mar 3.
The extraordinary diversity of excitatory synapse sizes is commonly attributed to activity-dependent processes that drive synaptic growth and diminution. Recent studies also point to activity-independent size fluctuations, possibly driven by innate synaptic molecule dynamics, as important generators of size diversity. To examine the contributions of activity-dependent and independent processes to excitatory synapse size diversity, we studied glutamatergic synapse size dynamics and diversification in cultured rat cortical neurons (both sexes), silenced from plating. We found that in networks with no history of activity whatsoever, synaptic size diversity was no less extensive than that observed in spontaneously active networks. Synapses in silenced networks were larger, size distributions were broader, yet these were rightward-skewed and similar in shape when scaled by mean synaptic size. Silencing reduced the magnitude of size fluctuations and weakened constraints on size distributions, yet these were sufficient to explain synaptic size diversity in silenced networks. Model-based exploration followed by experimental testing indicated that silencing-associated changes in innate molecular dynamics and fluctuation characteristics might negatively impact synaptic persistence, resulting in reduced synaptic numbers. This, in turn, would increase synaptic molecule availability, promote synaptic enlargement, and ultimately alter fluctuation characteristics. These findings suggest that activity-independent size fluctuations are sufficient to fully diversify glutamatergic synaptic sizes, with activity-dependent processes primarily setting the scale rather than the shape of size distributions. Moreover, they point to reciprocal relationships between synaptic size fluctuations, size distributions, and synaptic numbers mediated by the innate dynamics of synaptic molecules as they move in, out, and between synapses. Sizes of glutamatergic synapses vary tremendously, even when formed on the same neuron. This diversity is commonly thought to reflect the outcome of activity-dependent forms of synaptic plasticity, yet activity-independent processes might also play some part. Here we show that in neurons with no history of activity whatsoever, synaptic sizes are no less diverse. We show that this diversity is the product of activity-independent size fluctuations, which are sufficient to generate a full repertoire of synaptic sizes at correct proportions. By combining modeling and experimentation we expose reciprocal relationships between size fluctuations, synaptic sizes and synaptic counts, and show how these phenomena might be connected through the dynamics of synaptic molecules as they move in, out, and between synapses.
兴奋性突触大小的非凡多样性通常归因于活动依赖性过程，这些过程驱动突触的生长和缩小。最近的研究也指出，活动独立性大小波动可能由先天突触分子动力学驱动，是大小多样性的重要产生因素。为了研究活动依赖性和独立性过程对兴奋性突触大小多样性的贡献，我们研究了培养的大鼠皮质神经元（两性）中的谷氨酸能突触大小动态和多样化，这些神经元在种植后被沉默。我们发现，在没有任何活动历史的网络中，突触大小多样性与在自发活跃网络中观察到的一样广泛。沉默网络中的突触较大，分布较宽，但当按平均突触大小缩放时，这些分布呈右偏态且形状相似。沉默减少了大小波动的幅度，并削弱了对大小分布的限制，但这些足以解释沉默网络中的突触大小多样性。基于模型的探索，随后进行实验测试表明，与沉默相关的先天分子动力学和波动特征的变化可能会对突触的持久性产生负面影响，导致突触数量减少。这反过来又会增加突触分子的可用性，促进突触增大，并最终改变波动特征。这些发现表明，活动独立性大小波动足以完全多样化谷氨酸能突触大小，而活动依赖性过程主要设定大小分布的规模而不是形状。此外，它们表明，通过突触分子在突触内外移动的固有动力学，突触大小波动、大小分布和突触数量之间存在相互关系。谷氨酸能突触的大小变化很大，即使是在同一个神经元上形成的。这种多样性通常被认为反映了活动依赖性形式的突触可塑性的结果，但活动独立性过程也可能起一定作用。在这里，我们表明，在没有任何活动历史的神经元中，突触大小的多样性并不低。我们表明，这种多样性是活动独立性大小波动的产物，这些波动足以产生全谱的正确比例的突触大小。通过结合建模和实验，我们揭示了大小波动、突触大小和突触计数之间的相互关系，并展示了这些现象如何通过突触分子在突触内外移动的动力学联系起来。
