Electron Microscopy Core Facility, National Heart Lung and Blood Institute, National Institutes of Health, 50 Service Road West, Building 14E, Room 111B, Bethesda, MD 20892-5570, USA.
Neurochem Int. 2012 Nov;61(6):848-53. doi: 10.1016/j.neuint.2012.02.028. Epub 2012 Mar 5.
Development of the neuromuscular junction (NMJ) requires secretion of specific isoforms of the proteoglycan agrin by motor neurons. Secreted agrin is widely expressed in the basal lamina of various tissues, whereas a transmembrane form is highly expressed in the brain. Expression in the brain is greatest during the period of synaptogenesis, but remains high in regions of the adult brain that show extensive synaptic plasticity. The well-established role of agrin in NMJ development and its presence in the brain elicited investigations of its possible role in synaptogenesis in the brain. Initial studies on the embryonic brain and neuronal cultures of agrin-null mice did not reveal any defects in synaptogenesis. However, subsequent studies in culture demonstrated inhibition of synaptogenesis by agrin antisense oligonucleotides or agrin siRNA. More recently, a substantial loss of excitatory synapses was found in the brains of transgenic adult mice that lacked agrin expression everywhere but in motor neurons. The mechanisms by which agrin influences synapse formation, maintenance and plasticity may include enhancement of excitatory synaptic signaling, activation of the "muscle-specific" receptor tyrosine kinase (MuSK) and positive regulation of dendritic filopodia. In this article I will review the evidence that agrin regulates synapse development, plasticity and signaling in the brain and discuss the evidence for the proposed mechanisms.
神经肌肉接头（NMJ）的发育需要运动神经元分泌特定的蛋白聚糖聚集素同工型。分泌的聚集素广泛表达于各种组织的基底膜中，而跨膜形式则在大脑中高度表达。在突触发生期间，大脑中的表达最为强烈，但在具有广泛突触可塑性的成年大脑区域仍然很高。聚集素在 NMJ 发育中的既定作用及其在大脑中的存在引发了对其在大脑中突触发生中可能作用的研究。最初对聚集素缺失胚胎脑和神经元培养物的研究并未揭示突触发生的任何缺陷。然而，随后的培养研究表明，聚集素反义寡核苷酸或聚集素 siRNA 抑制了突触发生。最近，在缺乏聚集素表达的转基因成年小鼠的大脑中发现兴奋性突触大量丢失，但在运动神经元中除外。聚集素影响突触形成、维持和可塑性的机制可能包括增强兴奋性突触信号传导、激活“肌肉特异性”受体酪氨酸激酶（MuSK）和正调节树突丝状伪足。在本文中，我将回顾聚集素调节大脑中突触发育、可塑性和信号传导的证据，并讨论提出的机制的证据。
