Control of Ca2+ signals by astrocyte nanoscale morphology at tripartite synapses

International audienceMuch of the Ca2+ activity in astrocytes is spatially restricted to microdomains and occurs in fine processes that form a complex anatomical meshwork, the so-called spongiform domain. A growing body of literature indicates that those astrocytic Ca2+ signals can influence the activity of neuronal synapses and thus tune the flow of information through neuronal circuits. Because of technical difficulties in accessing the small spatial scale involved, the role of astrocyte morphology on Ca2+ microdomain activity remains poorly understood. Here, we use computational tools and idealized 3D geometries of fine processes based on recent super-resolution microscopy data to investigate the mechanistic link between astrocytic nanoscale morphology and local Ca2+ activity. Simulations demonstrate that the nano-morphology of astrocytic processes powerfully shapes the spatio-temporal properties of Ca2+ signals and promotes local Ca2+ activity. The model predicts that this effect is attenuated upon astrocytic swelling, hallmark of brain diseases, which we confirm experimentally in hypo-osmotic conditions. Upon repeated neurotransmitter release events, the model predicts that swelling hinders astrocytic signal propagation. Overall, this study highlights the influence of the complex morphology of astrocytes at the nanoscale and its remodeling in pathological conditions on neuron-astrocyte communication at so-called tripartite synapses, where astrocytic processes come into close contact with pre- and postsynaptic structures

Control of Ca²⁺ signals by astrocyte nanoscale morphology at tripartite synapses

Much of the Ca²⁺ activity in astrocytes is spatially restricted to microdomains and occurs in fine processes that form a complex anatomical meshwork, the so-called spongiform domain. A growing body of literature indicates that those astrocytic Ca²⁺ signals can influence the activity of neuronal synapses and thus tune the flow of information through neuronal circuits. Because of technical difficulties in accessing the small spatial scale involved, the role of astrocyte morphology on Ca²⁺ microdomain activity remains poorly understood. Here, we use computational tools and idealized 3D geometries of fine processes based on recent super-resolution microscopy data to investigate the mechanistic link between astrocytic nanoscale morphology and local Ca²⁺ activity. Simulations demonstrate that the nano-morphology of astrocytic processes powerfully shapes the spatio-temporal properties of Ca²⁺ signals and promotes local Ca²⁺ activity. The model predicts that this effect is attenuated upon astrocytic swelling, hallmark of brain diseases, which we confirm experimentally in hypo-osmotic conditions. Upon repeated neurotransmitter release events, the model predicts that swelling hinders astrocytic signal propagation. Overall, this study highlights the influence of the complex morphology of astrocytes at the nanoscale and its remodeling in pathological conditions on neuron-astrocyte communication at so-called tripartite synapses, where astrocytic processes come into close contact with pre- and postsynaptic structures

Bidirectional Control of Synaptic GABAAR Clustering by Glutamate and Calcium

SummaryGABAergic synaptic transmission regulates brain function by establishing the appropriate excitation-inhibition (E/I) balance in neural circuits. The structure and function of GABAergic synapses are sensitive to destabilization by impinging neurotransmitters. However, signaling mechanisms that promote the restorative homeostatic stabilization of GABAergic synapses remain unknown. Here, by quantum dot single-particle tracking, we characterize a signaling pathway that promotes the stability of GABAA receptor (GABAAR) postsynaptic organization. Slow metabotropic glutamate receptor signaling activates IP3 receptor-dependent calcium release and protein kinase C to promote GABAAR clustering and GABAergic transmission. This GABAAR stabilization pathway counteracts the rapid cluster dispersion caused by glutamate-driven NMDA receptor-dependent calcium influx and calcineurin dephosphorylation, including in conditions of pathological glutamate toxicity. These findings show that glutamate activates distinct receptors and spatiotemporal patterns of calcium signaling for opposing control of GABAergic synapses

Simulation of Astrocytic Calcium Dynamics in Lattice Light Sheet Microscopy Images

International audienceAstrocytes regulate neuronal information processing through a variety of spatio-temporal calcium signals. Advances in calcium imaging started to reveal astrocytic activities, but the complexity of the recorded data strongly call for computational analysis tools. Their development is hindered by the lack of reliable annotations that are essential for their evaluation and for the design of learning-based methods. To overcome the labeling problem, we present a framework to simulate realistic astrocytic calcium signals in 3D+time lattice light sheet microscopy (LLSM) images by closely modeling calcium kinetics in real astrocytes

Plus vive, plus nette : la microscopie STED du cerveau

La microscopie à super-résolution (SRM) désigne une nouvelle catégorie de techniques de microscopie optique qui permettent de surmonter la barrière de diffraction classique,- barrière qui a rendu difficile l’observation des structures et des activités qui constituent la base de la vie cellulaire biologique. La microscopie STED, qui est l'une des techniques SRM, a attiré l'attention des neurobiologistes, car elle permet de révéler la nanostructure des cellules cérébrales non seulement dans une boîte de Pétri, mais aussi à l'intérieur du tissu cérébral réel, voire dans le cerveau intact in vivo

Astrocytic IP3Rs: Beyond IP3R2

International audienceAstrocytes are sensitive to ongoing neuronal/network activities and, accordingly, regulate neuronal functions (synaptic transmission, synaptic plasticity, behavior, etc.) by the context-dependent release of several gliotransmitters (e.g., glutamate, glycine, D -serine, ATP). To sense diverse input, astrocytes express a plethora of G-protein coupled receptors, which couple, via G i/o and G q , to the intracellular Ca 2+ release channel IP 3 -receptor (IP 3 R). Indeed, manipulating astrocytic IP 3 R-Ca 2+ signaling is highly consequential at the network and behavioral level: Depleting IP 3 R subtype 2 (IP 3 R2) results in reduced GPCR-Ca 2+ signaling and impaired synaptic plasticity; enhancing IP 3 R-Ca 2+ signaling affects cognitive functions such as learning and memory, sleep, and mood. However, as a result of discrepancies in the literature, the role of GPCR-IP 3 R-Ca 2+ signaling, especially under physiological conditions, remains inconclusive. One primary reason for this could be that IP 3 R2 has been used to represent all astrocytic IP 3 Rs, including IP 3 R1 and IP 3 R3. Indeed, IP 3 R1 and IP 3 R3 are unique Ca 2+ channels in their own right; they have unique biophysical properties, often display distinct distribution, and are differentially regulated. As a result, they mediate different physiological roles to IP 3 R2. Thus, these additional channels promise to enrich the diversity of spatiotemporal Ca 2+ dynamics and provide unique opportunities for integrating neuronal input and modulating astrocyte–neuron communication. The current review weighs evidence supporting the existence of multiple astrocytic-IP 3 R isoforms, summarizes distinct sub-type specific properties that shape spatiotemporal Ca 2+ dynamics. We also discuss existing experimental tools and future refinements to better recapitulate the endogenous activities of each IP 3 R isoform

Simulation of calcium signaling in fine astrocytic processes: effect of spatial properties on spontaneous activity

International audienceAstrocytes, a glial cell type of the central nervous system, have emerged as detectors and regulators of neuronal information processing. Astrocyte excitability resides in transient variations of free cytosolic calcium concentration over a range of temporal and spatial scales, from sub-microdomains to waves propagating throughout the cell. Despite extensive experimental approaches, it is not clear how these signals are transmitted to and integrated within an astrocyte. The localization of the main molecular actors and the geometry of the system, including the spatial organization of calcium channels IP3R, are deemed essential. However, as most calcium signals occur in astrocytic ramifications that are too fine to be resolved by conventional light microscopy, most of those spatial data are unknown and computational modeling remains the only methodology to study this issue. Here, we propose an IP3R-mediated calcium signaling model for dynamics in such small sub-cellular volumes. To account for the expected stochasticity and low copy numbers, our model is both spatially explicit and particle-based. Extensive simulations show that spontaneous calcium signals arise in the model via the interplay between excitability and stochasticity. The model reproduces the main forms of calcium signals and indicates that their frequency crucially depends on the spatial organization of the IP3R channels. Importantly, we show that two processes expressing exactly the same calcium channels can display different types of calcium signals depending on the spatial organization of the channels. Our model with realistic process volume and calcium concentrations successfully reproduces spontaneous calcium signals that we measured in calcium micro-domains with confocal microscopy and predicts that local variations of calcium indicators might contribute to the diversity of calcium signals observed in astrocytes. To our knowledge, this model is the first model suited to investigate calcium dynamics in fine astrocytic processes and to propose plausible mechanisms responsible for their variability

Control of Ca 2+ signals by astrocyte nanoscale morphology at tripartite synapses

Astrocytic Ca2+ signals regulate synaptic activity. Most of those signals are spatially restricted to microdomains and occur in fine processes that cannot be resolved by diffraction-limited light microscopy, restricting our understanding of their physiology. Those fine processes are characterized by an elaborate morphology, forming the so-called spongiform domain, which could, similarly to dendritic spines, shapes local Ca2+ dynamics. Because of the technical limitations to access the small spatial scale involved, the effect of astrocyte morphology on Ca2+ microdomain activity remains poorly understood. Here, we use computational tools and realistic 3D geometries of fine processes based on recent super-resolution microscopy data to investigate the mechanistic link between astrocytic nanoscale morphology and local Ca2+ activity. Simulations demonstrate that the nano-morphology of astrocytic processes powerfully shapes the spatio-temporal properties of Ca2+ signals and promotes local Ca2+ activity. The model predicts that this effect is attenuated upon astrocytic swelling, hallmark of brain diseases, which we confirm experimentally in hypo-osmotic conditions. Upon repeated neurotransmitter release events, the model predicts that swelling hinders astrocytic signal propagation. Overall, this study highlights the influence of the complex morphology of astrocytes at the nanoscale and its remodeling in pathological conditions on neuron-astrocyte communication at tripartite synapses