Satellite Glial Cells Drive Homeostatic Synaptic Structural Plasticity in Sympathetic Neurons

Abstract

Sympathetic neuronal (SN) activity critically regulates the development and function of peripheral organs and tissues. The demonstration of activity-dependent modulation of SN output suggests that compensatory forms of plasticity could contribute to maintaining the stability of sympathetic circuits. Such plasticity mechanisms could act to restrain SN hyperactivity, a key driver of hypertension in humans and in the spontaneously hypertensive rat (SHR). In this study we examined how long-term changes in activity impact synaptic properties in postnatal sympathetic neuron cultures using chemogenetic and pharmacological manipulations and by examining the effects of enhanced activity of SHR neurons. We showed that bidirectional changes in neuronal activity resulted in homeostatic shifts in synaptic density to counteract long-term activity manipulations. In the absence of sympathetic satellite glial cells (SGCs) there was no synaptic compensation in the cultures. Direct chemogenetic activation of SGCs was sufficient to drive a decrease in synaptic sites and neuronal activity, while glial inhibition blocked activity-dependent synaptic compensation, demonstrating a role for the SGCs in homeostatic regulation of synaptic properties. We found that the SGCs responded to cholinergic signaling by downregulating the expression of the synaptic regulators NGF and TNF, suggesting that reciprocal signaling between SNs and SGCs acts to stabilize sympathetic output during long-term changes in circuit activity. Finally, we showed that these plasticity mechanisms are disrupted in postnatal SHR neurons, with an attenuated neuronal response to glia signaling during synapse formation and activity-dependent plasticity. Taken together, this work describes a new homeostatic activity-dependent plasticity mechanism in the peripheral nervous system.