Astrocyte-synapse Interactions Research Articles

A novel role for MLC1 in regulating astrocyte-synapse interactions.

Loss of function of the astrocyte membrane protein MLC1 is the primary genetic cause of the rare white matter disease Megalencephalic Leukoencephalopathy with subcortical Cysts (MLC), which is characterized by disrupted brain ion and water homeostasis. MLC1 is prominently present around fluid barriers in the brain, such as in astrocyte endfeet contacting blood vessels and in processes contacting the meninges. Whether the protein plays a role in other astrocyte domains is unknown. Here, we show that MLC1 is present in distal astrocyte processes, also known as perisynaptic astrocyte processes (PAPs) or astrocyte leaflets, which closely interact with excitatory synapses in the CA1 region of the hippocampus. We find that the PAP tip extending toward excitatory synapses is shortened in Mlc1-null mice. This affects glutamatergic synaptic transmission, resulting in a reduced rate of spontaneous release events and slower glutamate re-uptake under challenging conditions. Moreover, while PAPs in wildtype mice retract from the synapse upon fear conditioning, we reveal that this structural plasticity is disturbed in Mlc1-null mice, where PAPs are already shorter. Finally, Mlc1-null mice show reduced contextual fear memory. In conclusion, our study uncovers an unexpected role for the astrocyte protein MLC1 in regulating the structure of PAPs. Loss of MLC1 alters excitatory synaptic transmission, prevents normal PAP remodeling induced by fear conditioning and disrupts contextual fear memory expression. Thus, MLC1 is a new player in the regulation of astrocyte-synapse interactions.

Necl2/3-mediated mechanism for tripartite synapse formation.

Ramified, polarized protoplasmic astrocytes interact with synapses via perisynaptic astrocyte processes (PAPs) to form tripartite synapses. These astrocyte-synapse interactions mutually regulate their structures and functions. However, molecular mechanisms for tripartite synapse formation remain elusive. We developed an in vitro co-culture system for mouse astrocytes and neurons that induced astrocyte ramifications and PAP formation. Co-cultured neurons were required for astrocyte ramifications in a neuronal activity-dependent manner, and synaptically-released glutamate and activation of astrocytic mGluR5 metabotropic glutamate receptor were likely involved in astrocyte ramifications. Astrocytic Necl2 trans-interacted with axonal Necl3, inducing astrocyte-synapse interactions and astrocyte functional polarization by recruiting EAAT1/2 glutamate transporters and Kir4.1 K+ channel to the PAPs, without affecting astrocyte ramifications. This Necl2/3 trans-interaction increased functional synapse number. Thus, astrocytic Necl2, synaptically-released glutamate and axonal Necl3 cooperatively formed tripartite glutamatergic synapses in vitro. Studies on hippocampal mossy fiber synapses in Necl3 knockout and Necl2/3 double knockout mice confirmed these previously unreported mechanisms for astrocyte-synapse interactions and astrocyte functional polarization in vivo.

Electron microscopy analysis of astrocyte-synapse interactions shows altered dynamics in an Alzheimer's disease mouse model.

Astrocyte-synapse bi-directional communication is required for neuronal development and synaptic plasticity. Astrocytes structurally interact with synapses using their distal processes also known as leaflets or perisynaptic astrocytic processes (PAPs). We recently showed that these PAPs are retracted from hippocampal synapses, and involved in the consolidation of fear memory. However, whether astrocytic synaptic coverage is affected when memory is impaired is unknown. Here, we describe in detail an electron microscopy method that makes use of a large number of 2D images to investigate structural astrocyte-synapse interaction in paraformaldehyde fixed brain tissue of mice. We show that fear memory-induced synaptic activation reduces the interaction between the PAPs and the presynapse, but not the postsynapse, accompanied by retraction of the PAP tip from the synaptic cleft. Interestingly, this retraction is absent in the APP/PS1 mouse model of Alzheimer's disease, supporting the concept that alterations in astrocyte-synapse coverage contribute to memory processing.

Astrocyte-synapse interactions and cell adhesion molecules.

Astrocytes are increasingly gaining attention as a major player in regulating brain functions. Not only are astrocytes important for their supporting roles in maintaining optimal neuronal activity, they also dynamically interact with synapses through their highly ramified morphology to directly influence information processing by the neural circuits and the behaviours that depend on it. Here, we take a close look at astrocyte-synapse interactions involved in the coordination of synaptogenesis and astrocyte maturation in the developing brain through to the contribution of astrocytes in synaptic plasticity in the adult brain, and end with a perspective on astrocyte function in behaviours and diseases. In particular, we focus on the roles of synapse adhesion proteins. While cell adhesion proteins that form a bridge between the presynaptic and the postsynaptic compartments have been extensively studied, recent reports highlighting the striking participation of astrocytic cell adhesion proteins in synapse formation and function underscores the importance of reconsidering the conventional neurocentric view of synaptic adhesive interactions and the underlying logic.

Human Astrocytes Exhibit Tumor Microenvironment-, Age-, and Sex-Related Transcriptomic Signatures.

Astrocytes are critical for the development and function of synapses. There are notable species differences between human astrocytes and commonly used animal models. Yet, it is unclear whether astrocytic genes involved in synaptic function are stable or exhibit dynamic changes associated with disease states and age in humans, which is a barrier in understanding human astrocyte biology and its potential involvement in neurologic diseases. To better understand the properties of human astrocytes, we acutely purified astrocytes from the cerebral cortices of over 40 humans across various ages, sexes, and disease states. We performed RNA sequencing to generate transcriptomic profiles of these astrocytes and identified genes associated with these biological variables. We found that human astrocytes in tumor-surrounding regions downregulate genes involved in synaptic function and sensing of signals in the microenvironment, suggesting involvement of peritumor astrocytes in tumor-associated neural circuit dysfunction. In aging, we also found downregulation of synaptic regulators and upregulation of markers of cytokine signaling, while in maturation we identified changes in ionic transport with implications for calcium signaling. In addition, we identified subtle sexual dimorphism in human cortical astrocytes, which has implications for observed sex differences across many neurologic disorders. Overall, genes involved in synaptic function exhibit dynamic changes in the peritumor microenvironment and aging. These data provide powerful new insights into human astrocyte biology in several biologically relevant states that will aid in generating novel testable hypotheses about homeostatic and reactive astrocytes in humans.SIGNIFICANCE STATEMENT Astrocytes are an abundant class of cells playing integral roles at synapses. Astrocyte dysfunction is implicated in a variety of human neurologic diseases. Yet our knowledge of astrocytes is largely based on mouse studies. Direct knowledge of human astrocyte biology remains limited. Here, we present transcriptomic profiles of human cortical astrocytes, and we identified molecular differences associated with age, sex, and disease state. We found that peritumor and aging astrocytes downregulate genes involved in astrocyte-synapse interactions. These data provide necessary insight into human astrocyte biology that will improve our understanding of human disease.

Cell adhesion molecules regulating astrocyte-neuron interactions.

A tripartite synapse comprises a neuronal presynaptic axon and a postsynaptic dendrite, which are closely ensheathed by a perisynaptic astrocyte process. Through their structural and functional association with thousands of neuronal synapses, astrocytes regulate synapse formation and function. Recent work revealed a diverse range of cell adhesion-based mechanisms that mediate astrocyte-synapse interactions at tripartite synapses. Here, we will review some of these findings unveiling a highly dynamic bidirectional signaling between astrocytes and synapses, which orchestrates astrocyte morphological maturation and synapse development. Moreover, we will discuss the roles of these newly discovered molecular pathways in brain physiology and function both in health and disease.

Astrocyte-Synapse Receptor Coupling in Tripartite Synapses: A Mechanism for Self-Observing Robots

A model of an intentional self-observing system is proposed based on the structure and functions of astrocyte-synapse interactions in tripartite synapses. Astrocyte-synapse interactions are cyclically organized and operate via feedforward and feedback mechanisms, formally described by proemial counting. Synaptic, extrasynaptic and astrocyte receptors are interpreted as places with the same or different quality of information processing described by the combinatorics of tritograms. It is hypothesized that receptors on the astrocytic membrane may embody intentional programs that select corresponding synaptic and extrasynaptic receptors for the formation of receptor-receptor complexes. Basically, the act of self-observation is generated if the actual environmental information is appropriate to the intended observation processed by receptor-receptor complexes. This mechanism is implemented for a robot brain enabling the robot to experience environmental information as “its own”. It is suggested that this mechanism enables the robot to generate matches and mismatches between intended observations and the observations in the environment, based on the cyclic organization of the mechanism. In exploring an unknown environment the robot may stepwise construct an observation space, stored in memory, commanded and controlled by the intentional self-observing system. Finally, the role of self-observation in machine consciousness is shortly discussed.

State-of-art modelling of inflammatory astrocyte-synapse interactions in injury and amyotrophic lateral sclerosis.

State-of-art modelling of inflammatory astrocyte-synapse interactions in injury and amyotrophic lateral sclerosis.

Role of astrocyte-synapse interactions in CNS disorders.

Astrocytes comprise half of the cells in the brain. Although astrocytes have traditionally been described as playing a supportive role for neurons, they have recently been recognized as active participants in the development and plasticity of dendritic spines and synapses. Astrocytes can eliminate dendritic spines, induce synapse formation, and regulate neurotransmission and plasticity. Dendritic spine and synapse impairments are features of many neurological disorders, including autism spectrum disorder, schizophrenia, and Alzheimer's disease. In this review we will present evidence from multiple neurological disorders demonstrating that changes in astrocyte-synapse interaction contribute to the pathologies. Genomic analysis has connected altered astrocytic gene expression with synaptic deficits in a number of neurological disorders. Alterations in astrocyte-secreted factors have been implicated in the neuronal morphology and synaptic changes seen in neurodevelopmental disorders, while alteration in astrocytic glutamate uptake is a core feature of multiple neurodegenerative disorders. This evidence clearly demonstrates that maintaining astrocyte-synapse interaction is crucial for normal central nervous system functioning. Obtaining a better understanding of the role of astrocytes at synapses in health and disease will provide a new avenue for future therapeutic targeting.

Glia and the Synapse: Plasticity and Disease

Glia and the Synapse: Plasticity and Disease

Computational quest for understanding the role of astrocyte signaling in synaptic transmission and plasticity

The complexity of the signaling network that underlies astrocyte-synapse interactions may seem discouraging when tackled from a theoretical perspective. Computational modeling is challenged by the fact that many details remain hitherto unknown and conventional approaches to describe synaptic function are unsuitable to explain experimental observations when astrocytic signaling is taken into account. Supported by experimental evidence is the possibility that astrocytes perform genuine information processing by means of their calcium signaling and are players in the physiological setting of the basal tone of synaptic transmission. Here we consider the plausibility of this scenario from a theoretical perspective, focusing on the modulation of synaptic release probability by the astrocyte and its implications on synaptic plasticity. The analysis of the signaling pathways underlying such modulation refines our notion of tripartite synapse and has profound implications on our understanding of brain function.