The Astrocytic cAMP Pathway in Health and Disease

Abstract

Astrocytes are major glial cells that play critical roles in brain homeostasis. Abnormalities in astrocytic functions can lead to brain disorders. Astrocytes also respond to injury and disease through gliosis and immune activation, which can be both protective and detrimental. Thus, it is essential to elucidate the function of astrocytes in order to understand the physiology of the brain to develop therapeutic strategies against brain diseases. Cyclic adenosine monophosphate (cAMP) is a major second messenger that triggers various downstream cellular machinery in a wide variety of cells. The functions of astrocytes have also been suggested as being regulated by cAMP. Here, we summarize the possible roles of cAMP signaling in regulating the functions of astrocytes. Specifically, we introduce the ways in which cAMP pathways are involved in astrocyte functions, including (1) energy supply, (2) maintenance of the extracellular environment, (3) immune response, and (4) a potential role as a provider of trophic factors, and we discuss how these cAMP-regulated processes can affect brain functions in health and disease.

Mapping Phosphodiesterase 4D (PDE4D) in Macaque Dorsolateral Prefrontal Cortex: Postsynaptic Compartmentalization in Layer III Pyramidal Cell Circuits

“…For example, PDE4D had very focal expression in perisynaptic astrocytic processes immediately next to the synapse. PDE4D expression in this glial microdomain may regulate glutamate uptake from the synapse as has been reported in mouse cortex, where PDE4D regulates cAMP mediated trafficking of the excitatory amino acid transporters (EAAT) that control glutamate levels in the synapse (Hughes et al, 2004;Zhang et al, 2014;Sharma et al, 2015;Zhou et al, 2019).…”

Astrocytic cAMP modulates memory via synaptic plasticity

“…cAMP is constantly produced in astrocytes in vitro, as evidenced by the immediate decrease in cAMP levels following adenylyl cyclase blockade ( 11 ). Astrocytic cAMP pathways have also been confirmed in vivo via gene expression analyses ( 12 ). In addition, in vivo cAMP imaging has shown that the cAMP levels in cortical astrocytes increase in response to repeated sensory stimulation ( 13 ).…”

PDE inhibition in distinct cell types to reclaim the balance of synaptic plasticity

“…Treatment of astrocytes with 8-Br-cAMP, a cAMP analog, has been shown to decrease the levels of the pro-inflammatory cytokine TNFα 11 . TNFα stimulates C3 expression, facilitating complement-mediated synapse elimination, suggesting that astrocytic cAMP might attenuate inflammatory induced synaptic elimination 175 , 176 .…”