From Synapses to Circuits, Astrocytes Regulate Behavior

Abstract

Astrocytes are non-neuronal cells that regulate synapses, neuronal circuits, and behavior. Astrocytes ensheath neuronal synapses to form the tripartite synapse where astrocytes influence synapse formation, function, and plasticity. Beyond the synapse, recent research has revealed that astrocyte influences on the nervous system extend to the modulation of neuronal circuitry and behavior. Here we review recent findings on the active role of astrocytes in behavioral modulation with a focus on in vivo studies, primarily in mice. Using tools to acutely manipulate astrocytes, such as optogenetics or chemogenetics, studies reviewed here have demonstrated a causal role for astrocytes in sleep, memory, sensorimotor behaviors, feeding, fear, anxiety, and cognitive processes like attention and behavioral flexibility. Current tools and future directions for astrocyte-specific manipulation, including methods for probing astrocyte heterogeneity, are discussed. Understanding the contribution of astrocytes to neuronal circuit activity and organismal behavior will be critical toward understanding how nervous system function gives rise to behavior.

Keywords: GPCR; astrocyte; behavior; chemogenetic; optogenetic.

FIGURE 1

Astrocyte G-protein coupled receptor (GPCR) signaling. (A) A major communication pathway from neurons to astrocytes occurs through GPCRs expressed by astrocytes. (B) (1) Activation of astrocyte GPCRs (magenta) activate alpha subunits Gαq, Gαi, or Gαs. (2) Tools for astrocyte manipulation target these pathways. (3) Following Gq GPCR activation, the phospholipase C (PLC)/inositol 1,4,5-triphosphate (IP3) pathway and ITPR2 receptor activation induces release of calcium (Ca²⁺, yellow) from the endoplasmic reticulum (ER, white). All three G protein signaling pathways are known to increase calcium in astrocytes though the intracellular signaling pathways are not fully resolved (question mark). (4) Additional sources of calcium include calcium influx through ionotropic glutamate receptors α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA) and N-methyl-d-aspartate receptor (NMDA); transient receptor potential (TRP) channels; store-operated calcium channels (SOC); and reversed operation of the Na⁺/Ca²⁺ exchanger (not shown). (5) Calcium is also released from mitochondria.

FIGURE 2

Current and future tools for the study of astrocytes. (A) Current tools employ Aldh1ll1, GFAP, or GfaABC1D promoters to specifically target astrocytes. Acute manipulations including chemo- or optogenetic approaches and bidirectional increase or decrease of calcium activity, in soma or processes, are used to probe causal relationships between astrocytes and behavior. (B) Future research may identify new genetic markers for astrocytes, strategies for subtype specific manipulation, manipulations that target additional endogenous signaling pathways, and may detect astrocyte released factors with neurochemical sensors.

FIGURE 3

Summary. Astrocyte activity influences synaptic plasticity, neuronal network activity, and organismal behavior. LTP, long term potentiation.; LTD, long term potentiation.