Abstract:
Astrocytes are highly complex cells with many emerging putative roles in brain function. Of these, gliotransmission (active information transfer from glia to neurons) has probably the widest implications on our understanding of how the brain works: do astrocytes really contribute to information processing within the neural circuitry? \"Positive evidence\" for this stems from work of multiple laboratories reporting many examples of modulatory chemical signaling from astrocytes to neurons in the timeframe of hundreds of milliseconds to several minutes. This signaling involves, but is not limited to, Ca2+-dependent vesicular transmitter release, and results in a variety of regulatory effects at synapses in many circuits that are abolished by preventing Ca2+ elevations or blocking exocytosis selectively in astrocytes. In striking contradiction, methodologically advanced studies by a few laboratories produced \"negative evidence,\" triggering a heated debate on the actual existence and properties of gliotransmission. In this context, a skeptics\' camp arose, eager to dismiss the whole positive evidence based on a number of assumptions behind the negative data, such as the following: (1) deleting a single Ca2+ release pathway (IP3R2) removes all the sources for Ca2+-dependent gliotransmission; (2) stimulating a transgenically expressed Gq-GPCR (MrgA1) mimics the physiological Ca2+ signaling underlying gliotransmitter release; (3) age-dependent downregulation of an endogenous GPCR (mGluR5) questions gliotransmitter release in adulthood; and (4) failure by transcriptome analysis to detect vGluts or canonical synaptic SNAREs in astrocytes proves inexistence/functional irrelevance of vesicular gliotransmitter release. We here discuss how the above assumptions are likely wrong and oversimplistic. In light of the most recent literature, we argue that gliotransmission is a more complex phenomenon than originally thought, possibly consisting of multiple forms and signaling processes, whose correct study and understanding require more sophisticated tools and finer scientific experiments than done until today. Under this perspective, the opposing camps can be reconciled and the field moved forward. Along the path, a more cautious mindset and an attitude to open discussion and mutual respect between opponent laboratories will be good companions.Dual Perspectives Companion Paper: Multiple Lines of Evidence Indicate That Gliotransmission Does Not Occur under Physiological Conditions, by Todd A. Fiacco and Ken D. McCarthy.
摘要:
星形胶质细胞是高度复杂的细胞,在脑功能中具有许多新兴的推定作用。其中,胶质细胞传递(从神经胶质细胞到神经元的主动信息传递)可能对我们对大脑工作方式的理解具有最广泛的影响:星形胶质细胞真的有助于神经回路内的信息处理吗?\“阳性证据”源于多个实验室的工作,报告了许多在数百毫秒到几分钟的时间范围内从星形胶质细胞到神经元的调节化学信号传导的例子。这个信号涉及,但不限于,Ca2+依赖性囊泡递质释放,并导致许多回路中突触的各种调节作用,这些调节作用通过防止Ca2升高或选择性地阻断星形胶质细胞的胞吐作用而被废除。在惊人的矛盾中,一些实验室的先进方法学研究产生了“负面证据,“引发了关于胶质传递的实际存在和性质的激烈辩论。在这种情况下,一个怀疑论者的阵营出现了,急于驳回基于负面数据背后的许多假设的所有积极证据,例如:(1)删除单个Ca2释放途径(IP3R2),消除了Ca2依赖性胶质细胞转运的所有来源;(2)刺激转基因表达的Gq-GPCR(MrgA1)模拟了神经胶质转运蛋白释放的生理Ca2信号传导;(3)内源性GPCR的年龄依赖性下调(mGluR5)通过神经胶质转运蛋白的功能分析检测到神经胶质转运蛋白的存在;我们在这里讨论上述假设如何可能是错误的和过于简单的。根据最近的文献,我们认为胶质传递是一种比最初想象的更复杂的现象,可能由多种形式和信令过程组成,他们的正确学习和理解需要比今天更复杂的工具和更精细的科学实验。在这个视角下,对立的阵营可以和解,战场向前发展。沿着小路,更谨慎的心态和开放讨论的态度以及对手实验室之间的相互尊重将是很好的伙伴。双视角伴侣论文:多行证据表明在生理条件下不会发生胶质传递,ToddA.Fiacco和KenD.McCarthy.