Laboratory of Morphology of Neuronal Network, Department of Public Medicine, University of Campania "Luigi Vanvitelli", 80138 Napoli, Italy.
Laboratory of Neuroscience "R. Levi-Montalcini", Dept. of Biotechnology and Biosciences, University of Milano-Bicocca, 20126 Milano, Italy.
Int J Mol Sci. 2020 Feb 24;21(4):1539. doi: 10.3390/ijms21041539.
The synaptic cleft has been vastly investigated in the last decades, leading to a novel and fascinating model of the functional and structural modifications linked to synaptic transmission and brain processing. The classic neurocentric model encompassing the neuronal pre- and post-synaptic terminals partly explains the fine-tuned plastic modifications under both pathological and physiological circumstances. Recent experimental evidence has incontrovertibly added oligodendrocytes, astrocytes, and microglia as pivotal elements for synapse formation and remodeling (tripartite synapse) in both the developing and adult brain. Moreover, synaptic plasticity and its pathological counterpart (maladaptive plasticity) have shown a deep connection with other molecular elements of the extracellular matrix (ECM), once considered as a mere extracellular structural scaffold altogether with the cellular glue (i.e., glia). The ECM adds another level of complexity to the modern model of the synapse, particularly, for the long-term plasticity and circuit maintenance. This model, called tetrapartite synapse, can be further implemented by including the neurovascular unit (NVU) and the immune system. Although they were considered so far as tightly separated from the central nervous system (CNS) plasticity, at least in physiological conditions, recent evidence endorsed these elements as structural and paramount actors in synaptic plasticity. This scenario is, as far as speculations and evidence have shown, a consistent model for both adaptive and maladaptive plasticity. However, a comprehensive understanding of brain processes and circuitry complexity is still lacking. Here we propose that a better interpretation of the CNS complexity can be granted by a systems biology approach through the construction of predictive molecular models that enable to enlighten the regulatory logic of the complex molecular networks underlying brain function in health and disease, thus opening the way to more effective treatments.
在过去的几十年里，突触间隙得到了广泛的研究，提出了一个新的、引人入胜的功能和结构修饰模型，与突触传递和大脑处理有关。经典的神经中心模型包含神经元的前突触和后突触末端，部分解释了在病理和生理条件下的微调可塑性修饰。最近的实验证据无可争议地增加了少突胶质细胞、星形胶质细胞和小胶质细胞作为突触形成和重塑（三突触）的关键因素，无论是在发育中和成年大脑中。此外，突触可塑性及其病理对应物（适应性可塑性）与细胞外基质（ECM）的其他分子元素之间表现出了深层次的联系，这些分子元素曾经被认为只是细胞外结构支架，与细胞胶（即胶质）一起。ECM 为现代突触模型增加了另一个层次的复杂性，特别是对于长期可塑性和回路维护。这个模型，称为四突触，通过包括神经血管单元（NVU）和免疫系统，可以进一步实现。尽管到目前为止，它们被认为与中枢神经系统（CNS）可塑性紧密分离，至少在生理条件下是如此，但最近的证据支持这些元素作为突触可塑性的结构和主要因素。就目前的推测和证据而言，这种情况是一种适应和不适应可塑性的一致模型。然而，对大脑过程和电路复杂性的全面理解仍然缺乏。在这里，我们提出，通过构建能够阐明健康和疾病状态下大脑功能背后复杂分子网络的调节逻辑的预测分子模型，系统生物学方法可以更好地解释中枢神经系统的复杂性，从而为更有效的治疗方法开辟道路。
