Abstract：
Precise synapse elimination is essential for the establishment of a fully developed neural circuit during brain development and higher function in adult brain. Beyond immune and nutrition support, recent groundbreaking studies have revealed that phagocytic microglia and astrocytes can actively and selectively eliminate synapses in normal and diseased brains, thereby mediating synapse loss and maintaining circuit homeostasis. Multiple lines of evidence indicate that the mechanisms of synapse elimination by phagocytic glia are not universal but rather depend on specific contexts and detailed neuron-glia interactions. The mechanism of synapse elimination by phagocytic glia is dependent on neuron-intrinsic factors, many innate immune and local apoptosis related molecules. During development, microglial synapse engulfment in the visual thalamus is primarily influenced by the classic complement pathway, whereas in the barrel cortex, the fractalkine pathway is dominant. In Alzheimer\'s disease, microglia employ complement-dependent mechanisms for synapse engulfment in tauopathy and early β-amyloid pathology. But microglia are not involved in synapse loss at late β-amyloid stages. Phagocytic microglia also engulfment synapses in complement dependent way in schizophrenia, anxiety and stress. Besides, phagocytic astrocytes engulf synapses in a MEGF10 dependent way during visual development, memory and stroke. Furthermore, the mechanism of a phenomenon that phagocytes selectively eliminating excitatory and inhibitory synapses is also emphasized in this review. We hypothesize that elucidating context-dependent synapse elimination by phagocytic microglia and astrocytes may reveal the molecular basis of synapse loss in neural disorders and provide a rationale for developing novel candidate therapies that target synapse loss and circuit homeostasis.
摘要：
精确的突触消除对于在大脑发育过程中建立完全发育的神经回路和成人大脑的更高功能至关重要。除了免疫和营养支持，最近的开创性研究表明，吞噬小胶质细胞和星形胶质细胞可以主动和选择性地消除正常和患病大脑的突触，从而介导突触丢失和维持电路稳态。多条证据表明，吞噬细胞神经胶质消除突触的机制并不普遍，而是取决于特定的环境和详细的神经元-神经胶质相互作用。吞噬神经胶质细胞消除突触的机制取决于神经元的内在因素，许多与先天免疫和局部凋亡相关的分子。在开发过程中,视丘脑中的小胶质细胞突触吞噬主要受经典补体途径的影响，而在桶状皮层中，fractalkine途径占主导地位。在阿尔茨海默病中，小胶质细胞在tau蛋白病和早期β-淀粉样蛋白病理学中使用补体依赖性突触吞噬机制。但是小胶质细胞在β-淀粉样蛋白晚期阶段不参与突触丢失。在精神分裂症中，吞噬小胶质细胞也以补体依赖的方式吞噬突触，焦虑和压力。此外,在视觉发育过程中，吞噬星形胶质细胞以MEGF10依赖性方式吞噬突触，记忆和中风。此外，本文还强调了吞噬细胞选择性消除兴奋性和抑制性突触现象的机制。我们假设，通过吞噬细胞小胶质细胞和星形胶质细胞阐明上下文依赖性突触消除可能揭示神经疾病中突触丢失的分子基础，并为开发针对突触丢失和回路稳态的新型候选疗法提供了理论基础。
