Satellite glia have been proposed to be closest to astrocytes in the central nervous system (CNS) with respect to expression of machinery related to neurotransmitter uptake/turnover, inward-rectifying potassium channels, functional coupling via gap junctions, and close association with synapses ( Hanani and Spray, 2020 Hanani and Verkhratsky, 2021). Recent studies implicate sensory satellite glia in regulating chronic pain through modulating neuronal hyper-excitability ( Kim et al., 2016), and in promoting axon regeneration after peripheral nerve injury in vivo ( Avraham et al., 2020).

Satellite glia also envelop neuronal cell bodies in sensory ganglia in the peripheral nervous system (PNS) ( Hanani and Spray, 2020). Studies in sympathetic neuron–glia co-cultures have suggested roles for satellite glia in promoting dendrite growth, synapse formation, modulating extracellular ion and neurotransmitter concentrations, and regulating synaptic transmission ( Enes et al., 2020 Feldman-Goriachnik et al., 2018 Hanani, 2010 Tropea et al., 1988). This unique arrangement places satellite glial cells in an ideal position to be critical regulators of neuronal connectivity, synaptic transmission, and homeostasis. Multiple satellite glia surround a single neuron and are connected with each other, and with neurons, via gap junctions, with the number of glial cells per neuron being positively correlated to soma size ( Elfvin and Forsman, 1978 Hanani, 2010 Ledda et al., 2004). Like neurons, satellite glial cells are derived from multipotent neural crest precursors and form thin cytoplasmic sheaths around cell bodies, dendrites, and synapses of sympathetic neurons, with only 20 nm of space, the width of a synaptic cleft, between neuronal and glial membranes ( Elfvin and Forsman, 1978 Gabella et al., 1988 Hanani, 2010 Pannese, 1981). Satellite glia have been largely characterized by their distinctive location and morphology in peripheral ganglia ( Elfvin and Forsman, 1978 Gabella et al., 1988). Despite this intimate association, the functions of satellite glial cells in the sympathetic nervous system, particularly in vivo, are vastly understudied. Each neuron and associated glia are thought to form a discrete structural and functional unit ( Hanani, 2010). Satellite glia are the major glial cells in sympathetic ganglia ( Hanani, 2010 Mapps et al., 2021) and have a unique architecture in completely enveloping neuronal cell bodies ( Elfvin and Forsman, 1978 Gabella et al., 1988). Post-ganglionic neurons, which reside in sympathetic ganglia and project axons to innervate diverse peripheral organs and tissues, mediate key autonomic effects, including cardiac output, metabolism, and immune function ( Goldstein, 2013). The sympathetic nervous system prepares the body for ‘fight or flight’ responses and maintains homeostasis during daily activities such as exercise, digestion, or regulation of body temperature.

These findings highlight neuron–satellite glia as functional units in regulating sympathetic output, with implications for disorders linked to sympathetic hyper-activity such as cardiovascular disease and hypertension. Satellite glia-specific deletion of Kir4.1, an inward-rectifying potassium channel, largely recapitulates the cellular defects observed in glia-ablated mice, suggesting that satellite glia act in part via K +-dependent mechanisms. However, persisting neurons have elevated activity, and satellite glia-ablated mice show increased pupil dilation and heart rate, indicative of enhanced sympathetic tone. Adult ablation of satellite glia results in impaired mTOR signaling, soma atrophy, reduced noradrenergic enzymes, and loss of sympathetic neurons. Here, we show that satellite glia are critical for metabolism, survival, and activity of sympathetic neurons and modulate autonomic behaviors in mice. Despite this intimate association, the extent to which sympathetic functions are influenced by satellite glia in vivo remains unclear.

Satellite glia are the major glial cells in sympathetic ganglia, enveloping neuronal cell bodies.

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