Astrocytic Calcium Research Articles

Astrocyte-specific Ca2+ activity: Mechanisms of action, experimental tools, and roles in ethanol-induced dysfunction.

Astrocytes are a subtype of non-neuronal glial cells that reside in the central nervous system. Astrocytes have extensive peripheral astrocytic processes that ensheathe synapses to form the tripartite synapse. Through a multitude of pathways, astrocytes can influence synaptic development and structural maturation, respond to neuronal signals, and modulate synaptic transmission. Over the last decade, strong evidence has emerged demonstrating that astrocytes can influence behavioral outcomes in various animal models of cognition. However, the full extent of how astrocytes influence brain function is still being revealed. Astrocyte calcium (Ca2+) signaling has emerged as an important driver of astrocyte-neuronal communication allowing intricate crosstalk through mechanisms that are still not fully understood. Here, we will review the field's current understanding of astrocyte Ca2+ signaling and discuss the sophisticated state-of-the-art tools and approaches used to continue unraveling astrocytes' interesting role in brain function. Using the field of pre-clinical ethanol (EtOH) studies in the context of alcohol use disorder, we focus on how these novel approaches have helped to reveal an important role for astrocyte Ca2+ function in regulating EtOH consumption and how astrocyte Ca2+ dysfunction contributes to the cognitive deficits that emerge after EtOH exposure in a rodent model.

Analysis of Network Models with Neuron-Astrocyte Interactions

Neural networks, composed of many neurons and governed by complex interactions between them, are a widely accepted formalism for modeling and exploring global dynamics and emergent properties in brain systems. In the past decades, experimental evidence of computationally relevant neuron-astrocyte interactions, as well as the astrocytic modulation of global neural dynamics, have accumulated. These findings motivated advances in computational glioscience and inspired several models integrating mechanisms of neuron-astrocyte interactions into the standard neural network formalism. These models were developed to study, for example, synchronization, information transfer, synaptic plasticity, and hyperexcitability, as well as classification tasks and hardware implementations. We here focus on network models of at least two neurons interacting bidirectionally with at least two astrocytes that include explicitly modeled astrocytic calcium dynamics. In this study, we analyze the evolution of these models and the biophysical, biochemical, cellular, and network mechanisms used to construct them. Based on our analysis, we propose how to systematically describe and categorize interaction schemes between cells in neuron-astrocyte networks. We additionally study the models in view of the existing experimental data and present future perspectives. Our analysis is an important first step towards understanding astrocytic contribution to brain functions. However, more advances are needed to collect comprehensive data about astrocyte morphology and physiology in vivo and to better integrate them in data-driven computational models. Broadening the discussion about theoretical approaches and expanding the computational tools is necessary to better understand astrocytes’ roles in brain functions.

Differential Effects of Astrocyte Manipulations on Learned Motor Behavior and Neuronal Ensembles in the Motor Cortex.

Although motor cortex is crucial for learning precise and reliable movements, whether and how astrocytes contribute to its plasticity and function during motor learning is unknown. Here, we report that astrocyte-specific manipulations in primary motor cortex (M1) during a lever push task alter motor learning and execution, as well as the underlying neuronal population coding. Mice that express decreased levels of the astrocyte glutamate transporter 1 (GLT1) show impaired and variable movement trajectories, whereas mice with increased astrocyte Gq signaling show decreased performance rates, delayed response times, and impaired trajectories. In both groups, which include male and female mice, M1 neurons have altered interneuronal correlations and impaired population representations of task parameters, including response time and movement trajectories. RNA sequencing further supports a role for M1 astrocytes in motor learning and shows changes in astrocytic expression of glutamate transporter genes, GABA transporter genes, and extracellular matrix protein genes in mice that have acquired this learned behavior. Thus, astrocytes coordinate M1 neuronal activity during motor learning, and our results suggest that this contributes to learned movement execution and dexterity through mechanisms that include regulation of neurotransmitter transport and calcium signaling.SIGNIFICANCE STATEMENT We demonstrate for the first time that in the M1 of mice, astrocyte function is critical for coordinating neuronal population activity during motor learning. We demonstrate that knockdown of astrocyte glutamate transporter GLT1 affects specific components of learning, such as smooth trajectory formation. Altering astrocyte calcium signaling by activation of Gq-DREADD upregulates GLT1 and affects other components of learning, such as response rates and reaction times as well as trajectory smoothness. In both manipulations, neuronal activity in motor cortex is dysregulated, but in different ways. Thus, astrocytes have a crucial role in motor learning via their influence on motor cortex neurons, and they do so by mechanisms that include regulation of glutamate transport and calcium signals.

Computational Model of Noradrenaline Modulation of Astrocyte Responses to Synaptic Activity

The mathematical modeling of synaptically connected neuronal networks is an established instrument for gaining insights into dynamics of neuronal ensembles and information processing in the nervous system. Recently, calcium signaling in astrocytes—glial cells controlling local tissue metabolism and synapse homeostasis—and its corresponding downstream effect on synaptic plasticity and neuromodulation appeared in the limelight of modeling studies. Here, we used mechanism-based mathematical modeling to disentangle signaling pathways and feedback loops in the astrocytic calcium response to noradrenaline, an important neuromodulator marking periods of heightened alertness and arousal. The proposed model is based on an experiment-based 2D representation of astrocyte morphology, discrete random glutamate synapses with placement probability defined by the morphology pattern, and spatially heterogeneous noradrenaline sources, reflecting axonal varicosities of the adrenergic axons. Both glutamate and noradrenaline drive Ca2+ dynamics in the astrocyte in an additive or synergistic manner. Our simulations replicate the global activation of astrocytes by noradrenaline and predict the generation of high-frequency Ca2+ waves in a dose-dependent manner and the preferred Ca2+ wave origination near noradrenaline release sites if they colocalise with high-density clusters of glutamate synapses. We tested positive feedback loops between noradrenaline release and glutamate spillover directly or mediated by gliotransmitter release from the activated astrocyte. The simulations suggest that the coupled stochastic drive by glutamate and noradrenaline release converges on the graded modulation of the IP3 level, which is translated into whole-cell Ca2+ waves of different frequencies. Thus, the proposed approach is supported by experimental data and can be used to address situations inaccessible directly by experiment, and is a starting point for a more detailed model that includes other signaling mechanisms providing negative feedback.

Photobiomodulation treatment inhibits neurotoxic astrocytic polarization and protects neurons in in vitro and in vivo stroke models

The beneficial effects of photobiomodulation (PBM) on function recovery after stroke have been well-established, while its molecular and cellular mechanisms remain to be elucidated. The current study was designed to investigate the effect of PBM on synaptic proteins and astrocyte polarization of photothrombotic (PT)-stroke induced rats in vivo, and explore the possible effect of PBM treatment on oxygen-glucose deprivation (OGD)-induced neurotoxic astrocytic polarization in vitro. We reported that 2-min PBM treatment (808 nm) for 7 days significantly increased synaptic proteins and neuroprotective astrocytic marker S100 Calcium Binding Protein A10 (S100A10) and inhibited neurotoxic astrocytic marker C3d in the peri-infarct region after ischemic stroke. Cell culture studies of primary cortical neurons and N2a cells showed that single-dose PBM treatment could increase cellular viability, regulate the apoptotic proteins (Caspase 9, Bcl-xL and BAX) and preserve synaptic proteins following OGD exposure. Additionly, PBM decreased the levels of C3d, inducible nitric oxide synthase (iNOS) and interleukin 1β (IL-1β) on astrocytes exposed to OGD. In summary, we demonstrated that PBM could inhibit neurotoxic astrocytic polarization, preserve synaptic integrity and protect neurons against stroke injury both in vitro and in vivo.

Astrocytes mediate neuronal network hyperactivity in early AD

AbstractBackgroundDysfunctions of network activity and functional connectivity (FC) represent early events in Alzheimer’s disease (AD), but the underlying mechanisms remain unclear. Astrocytes regulate neuronal activity in the healthy brain, but their involvement in early network hyperactivity in AD is unknown.MethodWe analyzed resting‐state functional MRI data from a prospective cohort of patients and from the APP NLF knock‐in mouse model, with the aim to define which regions show early disruptions of functional connectivity (FC) before the presence of amyloid plaques. Next we used in‐vivo two photon calcium imaging to assess activity of astrocytes and neurons. Finally, we modulated calcium activity in astrocytes and assessed the effects on neuronal activity, FC and clinically relevant behavior readouts, i.e. seizure susceptibility and day/night activity.ResultWe found that, prior to amyloid accumulation, the human brain shows increased functional connectivity (FC) of the anterior cingulate cortex. Moreover, early increases of cingulate FC showed a positive correlation to amyloid load several years later in the human brain. Interestingly, we found the same FC deficit in the cingulate cortex of the APP NLF knock‐in mouse model, before amyloid deposition. We demonstrate that these FC deficits coincide with decreased calcium activity of astrocytes and increased neuronal activity. Recovery of the early astrocyte calcium deficits resulted in normalization of neuronal hyperactivity, increased FC as well as seizure susceptibility and day/night behavior disruptions.ConclusionIn conclusion, we show for the first time that astrocytes mediate initial features of AD and drive clinically relevant phenotypes.

Hippocampal astrocytes modulate anxiety-like behavior

Astrocytes can affect animal behavior by regulating tripartite synaptic transmission, yet their influence on affective behavior remains largely unclear. Here we showed that hippocampal astrocyte calcium activity reflects mouse affective state during virtual elevated plus maze test using two-photon calcium imaging in vivo. Furthermore, optogenetic hippocampal astrocyte activation elevating intracellular calcium induced anxiolytic behaviors in astrocyte-specific channelrhodopsin 2 (ChR2) transgenic mice (hGFAP-ChR2 mice). As underlying mechanisms, we found ATP released from the activated hippocampal astrocytes increased excitatory synaptic transmission in dentate gyrus (DG) granule cells, which exerted anxiolytic effects. Our data uncover a role of hippocampal astrocytes in modulating mice anxiety-like behaviors by regulating ATP-mediated synaptic homeostasis in hippocampal DG granule cells. Thus, manipulating hippocampal astrocytes activity can be a therapeutic strategy to treat anxiety.

Astrocytes Learn to Detect and Signal Deviations From Critical Brain Dynamics.

Astrocytes are nonneuronal brain cells that were recently shown to actively communicate with neurons and are implicated in memory, learning, and regulation of cognitive states. Interestingly, these information processing functions are also closely linked to the brain's ability to self-organize at a critical phase transition. Investigating the mechanistic link between astrocytes and critical brain dynamics remains beyond the reach of cellular experiments, but it becomes increasingly approachable through computational studies. We developed a biologically plausible computational model of astrocytes to analyze how astrocyte calcium waves can respond to changes in underlying network dynamics. Our results suggest that astrocytes detect synaptic activity and signal directional changes in neuronal network dynamics using the frequency of their calcium waves. We show that this function may be facilitated by receptor scaling plasticity by enabling astrocytes to learn the approximate information content of input synaptic activity. This resulted in a computationally simple, information-theoretic model, which we demonstrate replicating the signaling functionality of the biophysical astrocyte model with receptor scaling. Our findings provide several experimentally testable hypotheses that offer insight into the regulatory role of astrocytes in brain information processing.

Hippocampal astrocytes encode reward location.

Astrocytic calcium dynamics has been implicated in the encoding of sensory information1-5, and modulation of calcium in astrocytes has been shown to affect behaviour6-10. However, longitudinal investigation of the real-time calcium activity of astrocytes in the hippocampus of awake mice is lacking. Here we used two-photon microscopy to chronically image CA1 astrocytes as mice ran in familiar or new virtual environments to obtain water rewards. We found that astrocytes exhibit persistent ramping activity towards the reward location in a familiar environment, but not in a new one. Shifting the reward location within a familiar environment also resulted in diminished ramping. After additional training, as the mice became familiar with the new context or new reward location, the ramping was re-established. Using linear decoders, we could predict the location of the mouse in a familiar environment from astrocyte activity alone. We could not do the same in a new environment, suggesting that the spatial modulation of astrocytic activity is experience dependent. Our results indicate that astrocytes can encode the expected reward location in spatial contexts, thereby extending their known computational abilities and their role in cognitive functions.

Astrocyte calcium dysfunction causes early network hyperactivity in Alzheimer's disease.

SummaryDysfunctions of network activity and functional connectivity (FC) represent early events in Alzheimer’s disease (AD), but the underlying mechanisms remain unclear. Astrocytes regulate local neuronal activity in the healthy brain, but their involvement in early network hyperactivity in AD is unknown. We show increased FC in the human cingulate cortex several years before amyloid deposition. We find the same early cingulate FC disruption and neuronal hyperactivity in AppNL-F mice. Crucially, these network disruptions are accompanied by decreased astrocyte calcium signaling. Recovery of astrocytic calcium activity normalizes neuronal hyperactivity and FC, as well as seizure susceptibility and day/night behavioral disruptions. In conclusion, we show that astrocytes mediate initial features of AD and drive clinically relevant phenotypes.

Amyloid pathology disrupts gliotransmitter release in astrocytes.

Accumulation of amyloid-beta (Aβ) is associated with synaptic dysfunction and destabilization of astrocytic calcium homeostasis. A growing body of evidence support astrocytes as active modulators of synaptic transmission via calcium-mediated gliotransmission. However, the details of mechanisms linking Aβ signaling, astrocytic calcium dynamics, and gliotransmission are not known. We developed a biophysical model that describes calcium signaling and the ensuing gliotransmitter release from a single astrocytic process when stimulated by glutamate release from hippocampal neurons. The model accurately captures the temporal dynamics of microdomain calcium signaling and glutamate release via both kiss-and-run and full-fusion exocytosis. We investigate the roles of two crucial calcium regulating machineries affected by Aβ: plasma-membrane calcium pumps (PMCA) and metabotropic glutamate receptors (mGluRs). When we implemented these Aβ-affected molecular changes in our astrocyte model, it led to an increase in the rate and synchrony of calcium events. Our model also reproduces several previous findings of Aβ associated aberrant calcium activity, such as increased intracellular calcium level and increased spontaneous calcium activity, and synchronous calcium events. The study establishes a causal link between previous observations of hyperactive astrocytes in Alzheimer's disease (AD) and Aβ-induced modifications in mGluR and PMCA functions. Analogous to neurotransmitter release, gliotransmitter exocytosis closely tracks calcium changes in astrocyte processes, thereby guaranteeing tight control of synaptic signaling by astrocytes. However, the downstream effects of AD-related calcium changes in astrocytes on gliotransmitter release are not known. Our results show that enhanced rate of exocytosis resulting from modified calcium signaling in astrocytes leads to a rapid depletion of docked vesicles that disrupts the crucial temporal correspondence between a calcium event and vesicular release. We propose that the loss of temporal correspondence between calcium events and gliotransmission in astrocytes pathologically alters astrocytic modulation of synaptic transmission in the presence of Aβ accumulation.

Astrocyte Dysregulation and Calcium Ion Imbalance May Link the Development of Osteoporosis and Alzheimer's Disease.

The typical symptoms of patients with Alzheimer's disease (AD) are amyloid-β (Aβ) plaques and tau hyperphosphorylation. However, recent studies show that these symptoms are not the cause of the disease but are generated after the pathogenesis. Compared with other types of dementia, AD has the obvious features of pineal gland calcification and decreased melatonin production. The pineal gland is mainly composed of pinealocytes that release melatonin and astrocytes. Astrocytes function to maintain a balanced concentration of calcium ions, provide nerve cell nutrients, and migrate nutrients in vivo. Calcium ions are among the most important neurotransmitters. Once triggered, a calcium wave can be formed between astrocytes to activate other astrocytes to transmit information. Most calcium is stored in the skeleton. Bone tissue is composed mainly of osteocytes, osteoblasts, and osteoclasts. Of these, osteocyte is a kind of astrocyte which regulates the activity of osteoclasts and osteoblasts. The pineal gland is composed mainly of astrocytes; osteocytes are also a kind of astrocyte. Therefore, we conclude that when astrocytes are gradually disabled, calcium may be lost from the bones, prompting osteoporosis. The calcium ions then released into the blood may accumulate and cause ectopic calcification in the pineal gland, which promotes the occurrence of AD. Finally, this study used aspects of drugs and hormones (bone and calcium metabolism hormones and melatonin) to infer the hypothesis, which proposes that astrocyte dysregulation promotes the long-term imbalance of calcium ions in vivo and leads to osteoporosis and AD.

Background: Nonalcoholic fatty liver disease (NAFLD) is the commonest cause of chronic liver disease worldwide, being nonalcoholic steatohepatitis (NASH) its most clinically relevant form. Given the risks associated with taking a liver biopsy, the design of accurate non-invasive methods to identify NASH patients is of upmost importance. BMP2 plays a key role in metabolic homeostasis; however, little is known about

Drug use is a growing problem in actual society. Usually, the first experience with drugs takes place during adolescence, being cannabis the most used illicit drug. Although cannabis could be considered a harmless drug, we are beginning to appreciate its consequences. Chronic exposure to addictive drugs has shown to imbalance glutamate homeostasis in Nucleus Accumbens (NAc), altering plasticity mechanisms such as long-term depression. Therefore, it is crucial to elucidate the mechanisms underlying these alterations and how to reverse them. It is known the activation of cannabinoid receptors in astrocytes modulate synaptic plasticity and could be involved in glutamate homeostasis. However, the functional role of astrocytes in alterations derived from chronic drug exposure is not fully understood. In this study, we analyzed how astrocytes contribute to alterations produced by tetrahydrocannabinol (THC). Using fiber photometry in vivo we analyzed astrocytic activity (Ca2+ and glutamate dynamics) in NAc after 1mg/kg THC chronic administration in wildtype and p38αMAPK-/- (Astrop38α) mice4 and we performed electrophysiology experiments to analyze synaptic plasticity. Moreover, we performed behavioral tests to assess whether THC had reinforcing properties or affected learning and memory. Furthermore, using a chemogenetic approaches (DREADDs) we activated NAc astrocytes to analyze their behavioral implications. We observed: 1)THC increases astrocytic calcium activity; 2)THC induces glutamate release in NAc in wildtype, but not Astrop38α; 3)NAc astrocytes are involved in learning; 4)Removal of p38αMAPK in NAc astrocytes restores THC-related impairments. Altogether, our results reveal astrocytes as critical elements for the maintenance of glutamate signaling, with a significant role in drug-use-related alterations.

Switching behavior of the gamma power in the neuronal network modulated by the astrocytes

Understanding the dynamical neural gamma oscillation during brain state switch has been accepted as a critical step to explain attention and related human behaviors. Recent experimental studies have found a specific pulse of gamma power traces, coexisting with a pulse of functional magnetic resonance imaging with energy consumption by utilizing intracranial electroencephalography and neuroimaging. This phenomenon implies that the gamma oscillation is crucial in the success of the attention switching process after the attention task termination. However, until now no experimental evidence exists that explains how this type of gamma oscillation occurs and participates in the attention switching process. In this paper, the neuron-astrocyte-capillary network model was established, by utilizing the mathematical models of neurons and astrocytes that could explain the micro-scale behavior of neurons and investigated the formation process of this type of gamma oscillation. Our simulation results showed that the astrocyte calcium activity was pivotal in the occurrence of gamma oscillation after the attention task termination, and properly explained the underlying mechanisms of the dynamical switching of brain neuronal networks.

Neurovascular coupling mechanisms in health and neurovascular uncoupling in Alzheimer's disease.

To match the metabolic demands of the brain, mechanisms have evolved to couple neuronal activity to vasodilation, thus increasing local cerebral blood flow and delivery of oxygen and glucose to active neurons. Rather than relying on metabolic feedback signals such as the consumption of oxygen or glucose, the main signalling pathways rely on the release of vasoactive molecules by neurons and astrocytes, which act on contractile cells. Vascular smooth muscle cells and pericytes are the contractile cells associated with arterioles and capillaries, respectively, which relax and induce vasodilation.Much progress has been made in understanding the complex signalling pathways of neurovascular coupling, but issues such as the contributions of capillary pericytes and astrocyte calcium signal remain contentious. Study of neurovascular coupling mechanisms is especially important as cerebral blood flow dysregulation is a prominent feature of Alzheimer’s disease. In this article we will discuss developments and controversies in the understanding of neurovascular coupling and finish by discussing current knowledge concerning neurovascular uncoupling in Alzheimer’s disease.

Analytical Needs for Machine Learning‐based Image Analysis of Brainstem Astrocyte Cell Function

Reactive astrogliosis represents a neuropathogical finding in most brain diseases across the lifespan. Despite its near ubiquitous presence in CNS pathologies, the consequences of reactive astrogliosis on cell function are poorly characterized. We address the capability gap within the glial biology community by applying machine learning image segmentation and multivariate analyses to understand the consequences of gliosis on astrocyte cell function. We utilized live cell imaging of astrocytic intracellular calcium transients as a measure of physiological responses to external stimuli (i.e., exposure to lipopolysaccharide and/or hypoxic (100% N2) gas challenges). After obtaining 300 GBytes of live cell imaging footage, we developed an efficient, unbiased image segmentation workflow to capture astrocytes during physiological challenges. In contrast to prior methodologies which extracted only mean fluorescence intensity of segmented objects, we utilized pixel textures and fluorescent propagation in our analysis. Following the recommendations set forth by the recent consensus statement (Escartin et al., 2021), we performed multivariate and clustering analyses to identify distinct groups based on intracellular calcium transients waveforms under physiological challenges. These analyses reveal a diversity of cellular processes amongst brainstem astrocytes.

Inositol‐requiring enzyme 1 alpha (IRE1α) regulates astrocyte metabolic and inflammatory phenotypes: Implications in (METH)amphetamine use disorder and HIV‐associated neurocognitive disorders

Human immunodeficiency virus 1 (HIV‐1) invades the central nervous system (CNS) early during infection and can persist in the CNS for life despite effective antiretroviral treatment. Infection and activation of residential glial cells leads to low viral replication and chronic inflammation, which damage neurons contributing to a spectrum of HIV‐associated neurocognitive disorders (HAND). Astrocytes are the most numerous glial cells in the CNS and provide essential support to neurons. During a neuropathological challenge, such as HIV‐1 infection, astrocytes can shift their neurotrophic functions to become neurotoxic and even serve as latent reservoirs for HIV‐1 infection. Notably, substance use disorders, including methamphetamine (METH) are disproportionately elevated among people living with HIV‐1. METH use can induce neurotoxic and neurodegenerative consequences, which can increase one’s risk and severity of HAND. Thus, a better understanding of HIV‐1 infection and METH exposure both alone and in combination on astrocyte function could help identify key cellular or molecular targets that can regulate astrocyte neuroprotective versus neurotoxic phenotypes to optimize astrocyte and neuronal coupling and combat CNS pathology.Direct contact sites between the endoplasmic reticulum (ER) and the mitochondria, termed mitochondria‐associated ER membranes (MAMs), are central hubs for regulating several cellular processes, including inflammation and mitochondrial function and dynamics. In fact, the transfer of calcium from the ER to mitochondria is essential for mitochondrial bioenergetics. Interestingly, increasing evidence supports that the three arms of the unfolded protein response (UPR) are key cell signaling messengers within the ER‐mitochondrial interface, beyond their classical ER stress functions. Briefly, protein kinase RNA‐like endoplasmic reticulum kinase (PERK) has been determined as a regulator for MAM tethering and mitochondrial morphology. Inositol‐requiring enzyme 1 alpha (IRE1α) is implicated in regulating MAM‐mediated calcium transfer. Activating transcription factor 6 (ATF6) is suspected to participate in MAM formation as it is known to mediate ER elongation and lipid homeostasis. However, these regulatory mechanisms have not yet been fully elucidated.Our studies specifically highlight IRE1α as a key regulator of astrocyte metabolic and inflammatory phenotypes. Using primary human astrocytes infected with pseudotyped HIV and/or exposed to low doses of METH for seven days, astrocytes have increased protein expression of select UPR/MAM mediators. Under the same paradigms, we see increased cytosolic calcium flux and mitochondrial oxygen consumption rate, which were associated with increased mitochondria calcium uptake. Manipulation of IRE1α using both pharmacological inhibitors and an overexpression plasmid, confirms IRE1α modulates astrocyte calcium signaling, metabolic activity, glutamate clearance, and cytokine release. These findings identify a novel target for regulating astrocyte metabolic and inflammatory phenotypes, which could help combat astrocyte‐mediated neurotoxicity and potentially promote a neurotrophic phenotype during CNS pathologies.

Bistability and Chaos Emergence in Spontaneous Dynamics of Astrocytic Calcium Concentration

In this work, we consider a mathematical model describing spontaneous calcium signaling in astrocytes. Based on biologically relevant principles, this model simulates experimentally observed calcium oscillations and can predict the emergence of complicated dynamics. Using analytical and numerical analysis, various attracting sets were found and investigated. Employing bifurcation theory analysis, we examined steady state solutions, bistability, simple and complicated periodic limit cycles and also chaotic attractors. We found that astrocytes possess a variety of complex dynamical modes, including chaos and multistability, that can further provide different modulations of neuronal circuits, enhancing their plasticity and flexibility.

Developmental neural activity requires neuron-astrocyte interactions.

Developmental neural activity is a common feature of neural circuit assembly. Although glia have established roles in synapse development, the contribution of neuron-glia interactions to developmental activity remains largely unexplored. Here we show that astrocytes are necessary for developmental activity during synaptogenesis in Drosophila. Using wide-field epifluorescence and two-photon imaging, we show that the glia of the central nervous system participate in developmental activity with type-specific patterns of intracellular calcium dynamics. Genetic ablation of astrocytes, but not of cortex or ensheathing glia, leads to severe attenuation of neuronal activity. Similarly, inhibition of neuronal activity results in the loss of astrocyte calcium dynamics. By altering these dynamics, we show that astrocytic calcium cycles can influence neuronal activity but are not necessary per se. Taken together, our results indicate that, in addition to their recognized role in the structural maturation of synapses, astrocytes are also necessary for the function of synapses during development.

Complementary encoding of spatial information in hippocampal astrocytes.

Calcium dynamics into astrocytes influence the activity of nearby neuronal structures. However, because previous reports show that astrocytic calcium signals largely mirror neighboring neuronal activity, current information coding models neglect astrocytes. Using simultaneous two-photon calcium imaging of astrocytes and neurons in the hippocampus of mice navigating a virtual environment, we demonstrate that astrocytic calcium signals encode (i.e., statistically reflect) spatial information that could not be explained by visual cue information. Calcium events carrying spatial information occurred in topographically organized astrocytic subregions. Importantly, astrocytes encoded spatial information that was complementary and synergistic to that carried by neurons, improving spatial position decoding when astrocytic signals were considered alongside neuronal ones. These results suggest that the complementary place dependence of localized astrocytic calcium signals may regulate clusters of nearby synapses, enabling dynamic, context-dependent variations in population coding within brain circuits.