The role of astrocyte structural plasticity in regulating neural circuit function and behavior

Abstract

Brain circuits undergo substantial structural changes during development, driven by the formation, stabilization, and elimination of synapses. Synaptic connections continue to undergo experience-dependent structural rearrangements throughout life, which are postulated to underlie learning and memory. Astrocytes, a major glial cell type in the brain, are physically in contact with synaptic circuits through their structural ensheathment of synapses. Astrocytes strongly contribute to the remodeling of synaptic structures in healthy and diseased central nervous systems by regulating synaptic connectivity and behaviors. However, whether structural plasticity of astrocytes is involved in their critical functions at the synapse is unknown. This review will discuss the emerging evidence linking astrocytic structural plasticity to synaptic circuit remodeling and regulation of behaviors. Moreover, we will survey possible molecular and cellular mechanisms regulating the structural plasticity of astrocytes and their non-cell-autonomous effects on neuronal plasticity. Finally, we will discuss how astrocyte morphological changes in different physiological states and disease conditions contribute to neuronal circuit function and dysfunction.

Keywords: astrocytes; behavior; perisynaptic astrocyte processes; physiological states; synapses.

FIGURE 1

Sensory experience‐dependent astrocyte plasticity. (A) Sensory experience such as whisker stimulation and visual experience after eye‐opening drives cortical astrocyte hypertrophy and increase astrocyte process elaboration. (B) The activation GPCRs induces the release of Ca²⁺ in PAPs from intracellular stores such as the ER and mitochondria. Increased Ca²⁺ activity can trigger phosphorylation events that cause cytoskeletal reorganization and facilitate PAP elongation and withdrawal. PAP withdrawal may enhance the spillover of neurotransmitters such as glutamate, which may activate nearby synapses to promote LTP induction. Based on Bernardinelli, Randall, et al. (2014) and Perez‐Alvarez et al. (2014)

FIGURE 2

A possible link between astrocyte structural plasticity and GPCR activation during learning and memory formation. (A) Astrocytes processes may regulate neurotransmitter diffusion within the extracellular space through synapse coverage. By ensheathing synapses, astrocyte processes may prevent glutamate spillover and prevent trans‐synaptic activation, which could facilitate LTP (Henneberger et al., ; Herde et al., ; Ventura & Harris, ; Zheng et al., 2008). (B) During fear conditioning studies in which mice learn to associate a tone with a foot shock, activated GPCRs have different effects on memory formation. Gq enhances, and Gs impairs the formation of recent memories. However, the activation of Gi reduces remote memory recall (Adamsky et al., ; Kol et al., ; Orr et al., 2015).

FIGURE 3

PAP plasticity during the sleep–wake cycle. Astrocyte processes are closer to the synaptic cleft during wake and sleep deprivation. In addition to increased synaptic contact, PAPs in chronic sleep‐restricted mice also increase their coverage of the neuropil (Not shown). In contrast, PAPs make less contact with the synaptic cleft during sleep (Bellesi et al., 2015). This is proposed to play a role in increased glutamate spillover during sleep. The resulting trans‐synaptic activation may play a role in the synchronization that is important for generating slow‐wave oscillations required for sleep and cognition.

FIGURE 4

Injury and disease change astrocyte morphology. In a healthy brain, astrocytes extend their processes but maintain non‐overlapping domains. In contrast, astrocytes undergo astrogliosis during injury, which is characterized by hypertrophy and the formation of glia‐scar around the site of injury to protect healthy tissues around the injury site (Bush et al., ; Faulkner et al., 2004). Astrocytes have increased and thicker primary processes in chronic disease but still maintain their domains. However, the non‐overlapping domain structure is disrupted in epileptic brains (Oberheim et al., 2008).