Satellite Glial Cells Drive Homeostatic Synaptic Structural Plasticity in Sympathetic Neurons

Sympathetic neuronal (SN) activity critically regulates the development and function of peripheral organs and tissues. Activity-dependent plasticity has been shown to modulate SN output, suggesting that compensatory forms of plasticity could contribute to maintaining stability of sympathetic circuits. Early SN hyperactivity drives the development of hypertension in humans and in the spontaneously hypertensive rat (SHR). In this study we used chemogenetic and pharmacological approaches, and took advantage of the enhanced activity of SHR SNs, to examine how long-term changes in activity impact synaptic properties in neonatal SN cultures. We showed that bidirectional changes in SN activity result in compensatory shifts in synaptic density that counteract long-term activity manipulations. These changes were mediated by satellite glial cells (SGCs), a non-neuronal cell in the sympathetic ganglia that has been shown to influence cholinergic synaptic sites during development. In the absence of SGCs there was no induction of homeostatic plasticity. Further, direct chemogenetic activation of SGCs was sufficient to drive compensatory plasticity, while glial inhibition blocked SN plasticity. We found that SGCs respond to cholinergic signaling by downregulating the expression of the synaptic regulators NGF and TNF, suggesting that neurons and glia interact to stabilize sympathetic output during long-term changes in circuit activity. Finally, we investigated whether these plasticity mechanisms are present in neonatal SHR SNs. We demonstrated that SHR SNs have an attenuated response to glia, both during synapse formation and activity-dependent plasticity. Taken together, this work outlines a novel homeostatic activity-dependent plasticity mechanism in the peripheral nervous system.