Wahis Jérôme, Holt Matthew G
Laboratory of Glia Biology, VIB-KU Leuven Center for Brain and Disease Research, Leuven, Belgium.
Department of Neurosciences, KU Leuven, Leuven, Belgium.
Front Cell Neurosci. 2021 Feb 25;15:645691. doi: 10.3389/fncel.2021.645691. eCollection 2021.
Noradrenaline is a major neuromodulator in the central nervous system (CNS). It is released from varicosities on neuronal efferents, which originate principally from the main noradrenergic nuclei of the brain - the locus coeruleus - and spread throughout the parenchyma. Noradrenaline is released in response to various stimuli and has complex physiological effects, in large part due to the wide diversity of noradrenergic receptors expressed in the brain, which trigger diverse signaling pathways. In general, however, its main effect on CNS function appears to be to increase arousal state. Although the effects of noradrenaline have been researched extensively, the majority of studies have assumed that noradrenaline exerts its effects by acting directly on neurons. However, neurons are not the only cells in the CNS expressing noradrenaline receptors. Astrocytes are responsive to a range of neuromodulators - including noradrenaline. In fact, noradrenaline evokes robust calcium transients in astrocytes across brain regions, through activation of α1-adrenoreceptors. Crucially, astrocytes ensheath neurons at synapses and are known to modulate synaptic activity. Hence, astrocytes are in a key position to relay, or amplify, the effects of noradrenaline on neurons, most notably by modulating inhibitory transmission. Based on a critical appraisal of the current literature, we use this review to argue that a better understanding of astrocyte-mediated noradrenaline signaling is therefore essential, if we are ever to fully understand CNS function. We discuss the emerging concept of astrocyte heterogeneity and speculate on how this might impact the noradrenergic modulation of neuronal circuits. Finally, we outline possible experimental strategies to clearly delineate the role(s) of astrocytes in noradrenergic signaling, and neuromodulation in general, highlighting the urgent need for more specific and flexible experimental tools.
去甲肾上腺素是中枢神经系统（CNS）中的一种主要神经调质。它从神经元传出纤维的曲张体释放，这些传出纤维主要起源于大脑的主要去甲肾上腺素能核团——蓝斑，并散布于整个实质组织。去甲肾上腺素会因各种刺激而释放，并具有复杂的生理效应，这在很大程度上归因于大脑中表达的去甲肾上腺素能受体的广泛多样性，这些受体会触发多种信号通路。然而，一般来说，它对中枢神经系统功能的主要作用似乎是提高觉醒状态。尽管对去甲肾上腺素的作用已进行了广泛研究，但大多数研究都假定去甲肾上腺素通过直接作用于神经元来发挥其效应。然而，神经元并不是中枢神经系统中唯一表达去甲肾上腺素受体的细胞。星形胶质细胞对一系列神经调质有反应，包括去甲肾上腺素。事实上，去甲肾上腺素通过激活α1 - 肾上腺素能受体，在整个脑区的星形胶质细胞中引发强烈的钙瞬变。至关重要的是，星形胶质细胞在突触处包裹神经元，并且已知其能调节突触活动。因此，星形胶质细胞处于传递或放大去甲肾上腺素对神经元作用的关键位置，最显著的是通过调节抑制性传递。基于对当前文献的批判性评估，我们在本综述中指出，如果我们想要全面理解中枢神经系统功能，那么更好地理解星形胶质细胞介导的去甲肾上腺素信号传导至关重要。我们讨论了星形胶质细胞异质性这一新兴概念，并推测其可能如何影响神经元回路的去甲肾上腺素能调节。最后，我们概述了可能的实验策略，以明确界定星形胶质细胞在去甲肾上腺素能信号传导以及一般神经调节中的作用，强调了对更具特异性和灵活性的实验工具的迫切需求。
