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  • br Conclusions br Introduction Astrocytes contribute to

    2021-10-15


    Conclusions
    Introduction Astrocytes contribute to physiological dgat inhibitor function on many levels. They help maintain the physiological composition of the extracellular medium by, for instance, buffering potassium and uptake of neurotransmitters. They can also provide neurons with energy substrates. In addition, they can sense neuronal activity and modulate synaptic and neuronal function by reciprocal signalling (Perea et al., 2009, Rusakov et al., 2014) thus fundamentally shaping neuronal and network properties and behaviour. Most of these mechanisms, which enable astrocytes and neurons to interact, rely on diffusion of ions and signalling molecules between neurons and astrocytes through extracellular space. The signal exchange between astrocytes and neurons therefore depends on the distance between synaptic structures like spines and presynaptic boutons and astrocyte processes. As a consequence, changes in astrocyte morphology such as the withdrawal or outgrowth of astrocyte processes are expected to modify signal exchange between astrocytes and neurons. This dependence of astrocyte–neuron interactions on the spatial arrangement of astrocyte processes and neurons has been first demonstrated in the supraoptic nucleus. In this structure, the coverage of neurons and synaptic structures by astrocyte processes decreases during lactation (Theodosis and Poulain, 1993). This leads to reduced glutamate clearance at these synapses (Oliet et al., 2001) and to a reduction of N-methyl-d-aspartate receptor (NMDAR) dependent synaptic plasticity, because of reduced astrocytic supply of the NMDAR co-agonists d-serine (Panatier et al., 2006). These observations established that the geometric relationship between neurons and astrocytes determines the functional properties of synapses and thus the information exchange between neurons. They also imply that changes of astrocyte coverage of synapses and variable astrocyte coverage between synapses are functionally relevant. This is very likely to be the case in other brain regions. In the CA1 stratum radiatum of the hippocampus, electron microscopy studies have revealed that coverage of individual synapses varies considerably such that only ∼60% of excitatory synapses have astrocyte processes directly apposed (Ventura and Harris, 1999). In the molecular layer of the dentate gyrus, the diffusion weighted distance between spines and astrocyte processes is smaller at thin compared to thick spines (Medvedev et al., 2014). Thus, a variable coverage of synapses by astrocytes processes appears to be a general feature of brain architecture. Given the functional relevance of astrocyte coverage and astrocyte–neuron interaction, it is reasonable to expect that astrocyte coverage is a dynamically regulated parameter. Indeed, astrocyte processes are mobile and astrocyte–spine configurations can change within minutes (Haber et al., 2006). A particularly prominent trigger of hippocampal astrocyte morphology changes appears to be the induction of synaptic plasticity (Bernardinelli et al., 2014a; Henneberger et al., 2010, Perez-Alvarez et al., 2014, Wenzel et al., 1991). This is particularly interesting because it suggests that neuronal synaptic plasticity and astrocyte morphology changes are closely associated and that the experience-dependent change of astrocyte structure is an important modulator of astrocyte–neuron interactions. Probing and understanding this structure–function relationship requires knowledge of the signalling cascades that control astrocyte morphology. For example, establishing the causal contribution of plasticity-associated astrocyte morphology changes to behaviour would require the experimenter to be able to disrupt astrocyte restructuring in a cell-type specific and controlled manner. In neurons and many other cell types, small GTPases of the Rho family are heavily implicated in controlling morphology dynamically and detailed information is available for the pathways that regulate their activity. In contrast, the available information on Rho family GTPases and their functional significance in astrocytes appears to be somewhat limited. Therefore, our aim is to review known contributions of Rho family members to astrocyte morphology and to discuss tools and experimental approaches to study their functional significance. We will focus on Rho GTPases and refer the reader to excellent recent reviews that also discuss, for instance, the roles of astrocyte volume control and cell adhesion molecules for shaping the morphology of astrocytes and their perisynaptic processes (Bernardinelli et al., 2014b; Heller and Rusakov, 2015, Reichenbach et al., 2010).