Tomàs Josep, Cilleros-Mañé Víctor, Just-Borràs Laia, Balanyà-Segura Marta, Polishchuk Aleksandra, Nadal Laura, Tomàs Marta, Silvera-Simón Carolina, Santafé Manel M, Lanuza Maria A
Unitat d'Histologia i Neurobiologia (UHNeurob), Facultat de Medicina i Ciències de la Salut, Universitat Rovira i Virgili, Reus, Spain.
Neural Regen Res. 2025 Feb 1;20(2):394-401. doi: 10.4103/1673-5374.391314. Epub 2023 Dec 21.
During the development of the nervous system, there is an overproduction of neurons and synapses. Hebbian competition between neighboring nerve endings and synapses performing different activity levels leads to their elimination or strengthening. We have extensively studied the involvement of the brain-derived neurotrophic factor-Tropomyosin-related kinase B receptor neurotrophic retrograde pathway, at the neuromuscular junction, in the axonal development and synapse elimination process versus the synapse consolidation. The purpose of this review is to describe the neurotrophic influence on developmental synapse elimination, in relation to other molecular pathways that we and others have found to regulate this process. In particular, we summarize our published results based on transmitter release analysis and axonal counts to show the different involvement of the presynaptic acetylcholine muscarinic autoreceptors, coupled to downstream serine-threonine protein kinases A and C (PKA and PKC) and voltage-gated calcium channels, at different nerve endings in developmental competition. The dynamic changes that occur simultaneously in several nerve terminals and synapses converge across a postsynaptic site, influence each other, and require careful studies to individualize the mechanisms of specific endings. We describe an activity-dependent balance (related to the extent of transmitter release) between the presynaptic muscarinic subtypes and the neurotrophin-mediated TrkB/p75NTR pathways that can influence the timing and fate of the competitive interactions between the different axon terminals. The downstream displacement of the PKA/PKC activity ratio to lower values, both in competing nerve terminals and at postsynaptic sites, plays a relevant role in controlling the elimination of supernumerary synapses. Finally, calcium entry through L- and P/Q- subtypes of voltage-gated calcium channels (both channels are present, together with the N-type channel in developing nerve terminals) contributes to reduce transmitter release and promote withdrawal of the most unfavorable nerve terminals during elimination (the weakest in acetylcholine release and those that have already become silent). The main findings contribute to a better understanding of punishment-rewarding interactions between nerve endings during development. Identifying the molecular targets and signaling pathways that allow synapse consolidation or withdrawal of synapses in different situations is important for potential therapies in neurodegenerative diseases.
在神经系统发育过程中，神经元和突触会过度产生。相邻神经末梢和执行不同活动水平的突触之间的赫布竞争会导致它们的消除或强化。我们广泛研究了脑源性神经营养因子-原肌球蛋白相关激酶B受体神经营养逆行通路在神经肌肉接头处，在轴突发育和突触消除过程与突触巩固方面的作用。本综述的目的是描述神经营养对发育性突触消除的影响，以及与我们和其他人发现的调节这一过程的其他分子途径的关系。特别是，我们基于递质释放分析和轴突计数总结已发表的结果，以显示发育竞争中不同神经末梢处与下游丝氨酸-苏氨酸蛋白激酶A和C（PKA和PKC）以及电压门控钙通道偶联的突触前乙酰胆碱毒蕈碱型自身受体的不同作用。在几个神经末梢和突触中同时发生的动态变化在突触后位点汇聚、相互影响，需要仔细研究以区分特定末梢的机制。我们描述了突触前毒蕈碱亚型与神经营养因子介导的TrkB/p75NTR通路之间的活动依赖性平衡（与递质释放程度有关），这可能影响不同轴突末梢之间竞争相互作用的时间和结果。在竞争的神经末梢和突触后位点，PKA/PKC活性比向下游位移至较低值，在控制多余突触的消除中起重要作用。最后，通过电压门控钙通道的L型和P/Q型亚型（这两种通道与发育中的神经末梢中的N型通道一起存在）的钙内流有助于减少递质释放，并在消除过程中促进最不利神经末梢的退缩（乙酰胆碱释放最弱且已沉默的那些末梢）。这些主要发现有助于更好地理解发育过程中神经末梢之间的奖惩相互作用。确定在不同情况下允许突触巩固或突触退缩的分子靶点和信号通路，对于神经退行性疾病的潜在治疗很重要。
