NOTE: THIS ESSAY HAS TO BE WRITTEN BASED ON THE JOURNALS PROVIDED, DO NOT USE ANY OTHER EXTERNAL REFERENCES.
AND HAS TO INCLUDE ALL THE INFORMATION INDICATED BELOW.
ESSAY QUESTION:
Discuss the lines of evidence, which suggests that astrocytes may play a role in depression. Discuss the evidence that a disruption of astrocytic networks may lead to depressed behaviour.
Introduction:
- Glial cells and astrocytes function in general.
- Main mental disorders and neurodegenerative alterations emphasising depression from the point of view of monoamine imbalance and gliocentric hypothesis.
- Astrocytes and astrocytic network and its possible role in psychiatric disorders.
Main body 1
- Why is challenging to have evidence on this subject? Astrocytic biomarkers.
- Animal models of depression and astrocytic pathology.
- Human post-mortem samples and astrocytic abnormalities.
Main body 2
- Astrocytic network in depressed individuals. Tripartite synapses.
- Altered astrocyte-associated depressive pathology
- Possible answers to understand this pathology.
Main body 3
- Questions and reflection for future research
doi:10.1016/j.tins.2009.05.001 Tripartite synapses: astrocytes process and control synaptic information Gertrudis Perea, Marta Navarrete and Alfonso Araque Instituto Cajal, Consejo Superior de Investigaciones Cientı́ficas, Madrid 28002, Spain Review The term ‘tripartite synapse’ refers to a concept in synaptic physiology based on the demonstration of the existence of bidirectional communication between astrocytes and neurons. Consistent with this concept, in addition to the classic ‘bipartite’ information flow be- tween the pre- and postsynaptic neurons, astrocytes exchange information with the synaptic neuronal elements, responding to synaptic activity and, in turn, regulating synaptic transmission. Because recent evi- dence has demonstrated that astrocytes integrate and process synaptic information and control synaptic trans- mission and plasticity, astrocytes, being active partners in synaptic function, are cellular elements involved in the processing, transfer and storage of information by the nervous system. Consequently, in contrast to the classi- cally accepted paradigm that brain function results exclusively from neuronal activity, there is an emerging view, which we review herein, in which brain function actually arises from the coordinated activity of a network comprising both neurons and glia. Introduction Ten years ago the term ‘tripartite synapse’ was proposed to conceptualize the evidence obtained by many laboratories during the 1990s that revealed the existence of bidirec- tional communication between neurons and astrocytes (Figure 1). It represents a new concept in synaptic physi- ology wherein, in addition to the information flow between the pre- and postsynaptic neurons, astrocytes exchange information with the synaptic neuronal elements, respond- ing to synaptic activity and regulating synaptic trans- mission [1] (Figure 2). The biology of astrocyte–neuron interaction has emerged as a rapidly expanding field and has become one of the most exciting topics in current neuroscience that is changing our vision of the physiology of the nervous system. The classically accepted paradigm that brain function results exclusively from neuronal activity is being challenged by accumulating evidence suggesting that brain function might actually arise from the concerted activity of a neuron–glia network. Here, we briefly summarize early evidence that led to the establishment of the concept of a tripartite synapse and then discussmore recent data regarding the properties and physiological consequences of the astrocyte Ca2+ signal, which has a fundamental role in neuron–astrocyte com- munication as the cellular signal triggered by the neuronal activity and responsible for transmitter release from astro- cytes and the consequent neuromodulation. Although Corresponding author: Araque, A. (araque@cajal.csic.es). 0166-2236/$ – see front matter � 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.tins.2009. astrocytes have important roles in key aspects of brain development and function, such as neuronal metabolism, synaptogenesis, homeostasis of the extracellular milieu, or cerebral microcirculation [2], we focus on the role of astro- cytes in synaptic physiology, discussing data indicating that astrocytes integrate and process synaptic information and finally regulate synaptic transmission and plasticity through the release of gliotransmitters (i.e. transmitters released by glial cells implicated in rapid glial–neuron and glial–glial communication) [3]. Ca2+-mediated cellular excitability of astrocytes The astrocytic revolution in current neuroscience began in the early 1990s when pioneering studies used the fluor- escence imaging techniques to monitor intracellular Ca2+ levels in living astrocytes. Those studies revealed that cultured astrocytes display a form of excitability based on variations of the intracellular Ca2+ concentration [4,5]. Until then, astrocytes had been considered as non- excitable cells because, unlike neurons, they do not show electrical excitability (e.g. see Refs [6–9]). Since these pioneering findings, subsequent studies performed in cul- tured cells, brain slices and, more recently, in vivo have firmly established the astrocyte excitability, which is man- ifested as elevations of cytosolic Ca2+ mainly as a result of the mobilization of Ca2+ stored in the endoplasmic reticu- lum. The elevated Ca2+ then acts as a cellular signal [10]. Whereas neurons base their cellular excitability on elec- trical signals generated across the plasma membrane [11], astrocytes base their cellular excitability on variations of Ca2+ concentration in the cytoplasm. Astrocyte Ca2+ signal is controlled by synaptic activity Astrocyte Ca2+ elevations can occur spontaneously as intrinsic oscillations in the absence of neuronal activity [12–15], and they can also be triggered by neurotransmit- ters released during synaptic activity [10] (Table 1), which is of crucial importance because it indicates the existence of neuron-to-astrocyte communication (Figure 3a). The synaptic control of the astrocyte Ca2+ signal is based on the fact that astrocytes express a wide variety of func- tional neurotransmitter receptors. Many of these receptors are of metabotropic type, being associated with G proteins that, upon activation, stimulate phospholipase C and for- mation of inositol (1,4,5)-triphosphate (Ins(1,4,5)P3), which increases the intracellular Ca2+ concentration through the release of Ca2+ from intracellular Ins(1,4,5)P3-sensitive Ca2+ stores [16–21]. Early studies using cultured cells showed that the astrocyte Ca2+ signal can propagate to 05.001 Available online 15 July 2009 421 mailto:araque@cajal.csic.es http://dx.doi.org/10.1016/j.tins.2009.05.001 Figure 1. Views of the neuron–astrocyte interaction at the tripartite synapse. (a) Cajal’s drawing showing ‘neuroglia’ of the pyramidal layer and stratum radiatum of the Ammon horn (from adult man autopsied three hours after death). Original labels: A, large astrocyte embracing a pyramidal neuron; B, twin astrocytes forming a nest around a cell, C, while one of them sends two branches forming another nest, D; E, cell with signs of ‘autolysis’; F, capillary vessel. Reproduced from an original drawing, with permission of the Instituto Cajal [106]. (b) Neuron and astrocyte stained with the Golgi method from a rat hippocampus. Inset: astrocyte and neuronal somas. Image generously given by Dr Lopez-Mascaraque (Instituto Cajal). (c) Electron microscopy image of astrocyte process at the axon–spine interface: astrocyte process (astro, blue); postsynaptic density (psd, red); dendritic spine head (sp, yellow); axonal bouton (ax, green). Reproduced, with permission, from Ref. [107]. (d) 3D reconstruction of a single astrocyte process (blue) interdigitating among four dendrites (gold, yellow, red and purple). Reproduced, with permission, from Ref. [107]. Review Trends in Neurosciences Vol.32 No.8 neighboring astrocytes as an intercellular Ca2+ wave invol- ving dozens of cells [4,5,22]. By contrast, in brain slices such waves seem to involve few astrocytes, and their actual existence in more intact preparations is currently under debate [23]. The synaptically evoked as well as the spon- taneous Ca2+ signal originates in spatially restricted areas – called ‘microdomains’ – of the astrocyte processes [24,25] from where it can eventually propagate intracellularly to other regions of the cell [20,25,26]. As a single astrocyte might contact �100 000 synapses [27], the control of the spatial extension of the Ca2+ signal could have relevant functional consequences for the physiology of the nervous system, because not all synapses covered by a single astro- cyte are necessarily functionally locked to be similarly and simultaneously modulated (see below). Therefore, differ- ential neuromodulation of specific synapses would provide an extraordinary increase of the degrees of freedom to the system [28,29]. Astrocyte Ca2+ signal in vivo For many years, technical constraints limited astrocyte Ca2+-signal studies to cultured cells and brain slices. The recent use of novel imaging techniques, that is, two-photon microscopy and specific fluorescent dyes that selectively 422 label astrocytes in vivo [30], which enable the study of astrocyte Ca2+ signals in the whole animal, has revealed important findings (Figure 3b). First, reports from studies of rat, mouse and ferret have demonstrated that astrocytes in vivo exhibit intracellular Ca2+ variations, indicating that astrocyte Ca2+ excitability is not a peculiarity of slice preparations. Second, like in brain slices, astrocyte Ca2+ variations occur spontaneously [30–33] and are also evoked by neurotransmitters released during synaptic activity [31,33–37], indicating that neuron-to-astrocyte communi- cation is present in vivo. Finally, and of special relevance, astrocyte Ca2+ elevations might be triggered by physiologi- cal sensory stimuli. Indeed, stimulation of whiskers increased the astrocyte Ca2+ in mouse barrel cortex [33] (Figure 3b). Astrocytes of the sensory cortex also elevate their Ca2+ in response to a robust peripheral stimulation that is known to activate the locus coeruleus or to direct electrical stimulation of this nucleus [34], as well as during running behavior in alert mice [35]. Astrocytes from other brain regions also respond to stimuli of corresponding sensory modalities. Astrocytes in the visual cortex not only show Ca2+ elevations in response to visual stimuli but also the properties of these responses indicate the existence of distinct spatial receptive fields and reveal an even sharper Figure 2. Scheme of the tripartite synapse. Cartoon representing the transfer of information between neuronal elements and astrocyte at the tripartite synapse. Astrocytes respond with Ca2+ elevations to neurotransmitters (Nt) released during synaptic activity and, in turn, control neuronal excitability and synaptic transmission through the Ca2+-dependent release of gliotransmitters (Gt). Review Trends in Neurosciences Vol.32 No.8 tuning than neurons to visual stimuli [37]. In summary, astrocytes in vivo display Ca2+ excitability and respond to neuronal activity. Furthermore, because astrocytes in specific sensory areas respond to a variety of sensory stimuli, it is feasible that astrocytes participate in the brain representation of the external world. Synaptic information processing by astrocytes In contrast to the view of astrocytes as passive elements that provide the adequate environmental conditions for Table 1. Ca2+ signaling in astrocytes Neurotransmitter Experimen Spontaneous activity Non-applicable Brain slice In vivo Synaptically evoked Norepinephrine Brain slice In vivo ATP Brain slice GABA Brain slice Glutamate Brain slice In vivo Acetylcholine Brain slice Nitric Oxide Brain slice Endocannabinoids Brain slice appropriate neuronal function and that respond to neuro- transmitters, simply performing a linear readout of the synaptic activity, experimental evidence supports the idea that astrocytes integrate and process synaptic information elaborating a complex nonlinear response to the incoming information from adjacent synapses (Box 1). As described earlier, it is firmly established that astrocytes respondwith Ca2+ elevations to synaptic activity [25]. However, to understand the actual role of astrocytes in brain infor- mation processing, it is necessary to define whether the astrocyte Ca2+ signal passively results from different neu- rotransmitter concentrations attained during synaptic activity or, alternatively, whether neuron-to-astrocyte communication presents properties of complex information processing that are classically considered to be exclusive to neuron-to-neuron communication. In Box 1 and in the following discussion we will elaborate the evidence that supports the idea that astrocytes are cellular processors of synaptic information. Astrocytes discriminate the activity of different synaptic pathways The astrocyte Ca2+ signal does not result from a nonspecific spillover of neurotransmitters; instead, it is selectively mediated by the activity of specific synaptic terminals (Figure 4). Astrocytes located in the stratum oriens of the CA1 area of the hippocampus respond to the stimu- lation of the alveus (which contains glutamatergic and cholinergic axons) with Ca2+ elevations that are specifi- callymediated by acetylcholine (ACh) but not by glutamate [16]. By contrast, these astrocytes do respond to glutamate when it is released by different glutamatergic synapses, that is, the Schaffer collateral (SC) synaptic terminals [25]. Hence, astrocytes selectively respond to different synapses that use different neurotransmitters (i.e. glutamate and ACh), and they discriminate between