ASTROCYTES

Physiology of astroglia

Alexej Verkhratsky

Faculty of Life Sciences, The University of Manchester, UK

Abstract:

The integration and information processing in the brain occurs though close interactions of two cellular circuits represented by neuronal networks embedded into internally connected astroglial syncytia. Our understanding of glial function changed dramatically over last two decades. This change concerns the whole concept of how the brain is organized, and how the development, life and death of neural circuits are controlled. There is compelling evidence demonstrating that these are the astrocytes that are creating the compartmentalization in the CNS, and these are the astrocytes that are able to integrate neurons, synapses, and brain capillaries into individual and relatively independent units. Astroglial syncytia allow intercellular communication routes, which permit translocation of ions, metabolic factors and second messengers. The resulting potential for parallel processing and integration is significant and might easily be larger, but also fuzzier, than the binary coded electrical communication within the neuronal networks. The neuronal-glial circuitry endowed with distinct signalling cascades, form a "diffuse nervous net" suggested by Golgi, where millions of synapses belonging to very different neurons are integrated first into neuronal-glial-vascular units and then into more complex structures connected through glial syncytia. These many levels of integration, both morphological and functional, presented by neuronal-glial circuitry ensure the spatial and temporal multiplication of brain cognitive power. 

Astrocyte heterogeneity at single cell level – physiological and developmental implications

Mykhailo Batiuk

École Polytechnique Fédérale de Lausanne, Switzerland 

Abstract:

Astrocytes, one of the major cell types in the CNS, perform a variety of roles crucial for brain physiology, neuronal function, and synaptic transmission. Despite multiple functions, morphological variability, and distinct anatomical locations, decades-long assumptions stated that astrocytes are generally homogeneous cells. Although, this notion was often questioned in recent years. 
To investigate the true extent of astrocyte molecular diversity across forebrain regions, we used single-cell RNA sequencing. Our analysis identified five transcriptionally distinct astrocyte subtypes in adult mouse cortex and hippocampus. In situ validation of our data revealed distinct spatial positioning of defined subtypes, reflecting the distribution of morphologically and physiologically distinct astrocyte populations. Our findings revealed the complexity of astrocyte heterogeneity and hinted towards developmental and tissue micro-environment factors as possible bases of astrocyte heterogeneity.

Adaptable astroglial control of excitatory inter-synaptic crosstalk in the brain

Dmitri Rusakov

UCL Queen Square Institute of Neurology, University College London, UK

Abstract:

Extrasynaptic actions of the excitatory neurotransmitter glutamate are limited by high-affinity transporters expressed by perisynaptic astroglia. This helps maintain point-to-point transmission in excitatory circuits. Memory formation in the brain is associated with synaptic remodelling, but whether and how this affects perisynaptic astroglial processes (PAPs) and therefore extrasynaptic glutamate actions is poorly understood. We used a battery of advanced imaging methods, in situ and in vivo, to find that a classical synaptic memory mechanism, long-term potentiation (LTP), triggers withdrawal of PAPs from potentiated synapses. Optical glutamate sensors combined with patch-clamp and super-resolved 3D molecular localisation reveal that LTP induction in ex vivo brain slices thus prompts spatial retreat of astroglial glutamate transporters, boosting glutamate spillover and NMDA receptor-mediated inter-synaptic cross-talk. The LTP-triggered PAP withdrawal involves astroglial NKCC1 transporters and the actin-controlling protein cofilin but does not depend on major Ca2+-dependent cascades in astrocytes. We combine targeted viral transduction with multiplexed imaging in vivo to document a similar phenomenon under the physiological LTP paradigm (rhythmic whisker stimulation) in the intact brain. Our results thus uncover a mechanism by which a memory trace at one synapse could alter signal handling in multiple neighboring connections by engaging use-dependent plasticity of local astroglia.

Functional Roles of Astrocyte Calcium Elevations in the Basolateral Amygdala

Olena Bukalo

National Institute on Alcohol Abuse and Alcoholism, NIH, USA

Abstract:

The ability to retrieve associations between environmental stimuli and previously encountered threat represents a fundamental form of memory crucial to survival. Recent studies suggest astrocytes support fear memory by modulating memory-encoding neural circuits and neuronal engrams in cortical and limbic regions. However, the precise mechanisms by which this occurs remain unknown. We monitored and manipulated astrocyte activity in vivo with fiber photometry in the basolateral amygdala (BLA), a brain region critical to the formation, retrieval, and extinction of fear memories. First, our data demonstrate that population BLA astrocyte Ca2+ activity signals the retrieval of a cued threat memory then tracks the extinction-induced shift from a high to low fear state and subsequent return of high fear during context-driven renewal. Next, we found that genetic manipulations aimed to reduce Ca2+ activity in astrocytes impair formation/retrieval of fear memory. To further dissociate the significance of astrocytic Ca2+ signaling in fear memory, we employed a chemogenetic manipulation by expressing viral constructs for hM3D(Gq)- or hM4D(Gi)--coupled DREADD in BLA astrocytes. Systemic injection of the inert ligand clozapine n-oxide (CNO), prior to extinction training, have an opposite effect on freezing behavior. We found that freezing levels were markedly lower in hM3D-, but higher in hM4D-expressing animals as compared to mice expressing control viral construct, during early extinction trials, consistent with an impairment or improvement in fear memory retrieval. Using in vivo fiber photometry Ca2+ imaging during CNO application, we observed a different dynamic of Ca2+ signal in astrocytes in hM3D- and hM4D-expressing animals. Altogether, our data suggests that Ca2+ responses in astrocytes are not only tightly correlated with fear state, but also that BLA astrocyte Ca2+ activity is necessary for fear memory retrieval. Future studies will investigate how astrocytes are implicated in shaping neuronal networks in the amygdala during fear memory acquisition and retrieval.