Abstract
Sympathetic neurons (SNs) directly innervate peripheral target organs and tissues, providing the final peripheral sympathetic output that impacts their development and function. Although this output is essential under normal conditions, chronic elevations in sympathetic drive are causally linked to cardiovascular diseases such as hypertension, as seen in the spontaneously hypertensive rat (SHR). The SHR is a widely used model of neurogenic hypertension in which increased SN activity precedes and drives the pathological onset of high blood pressure. In work that I contributed to, our lab established that neonatal SHR SNs develop increased synaptic structural and functional properties when cultured in isolation, suggesting that increased SN output to targets is already present during neonatal development (Appendix). This study left unresolved why SHR animals do not develop hypertension despite the SNs output being enhanced. One possibility is that activity-dependent homeostatic plasticity mechanisms within the sympathetic circuit constrain excessive output. To investigate this, I first used a pharmacological and chemogenetic approach to chronically manipulate the activity of cultured SNs from rat superior cervical ganglia. I present evidence that chronic activation of SNs induces a homeostatic shift in the number of cholinergic synapses formed within the network and that the presence of satellite glial cells (SGCs) is important for induction of this plasticity. I next asked if directly activating SGCs was sufficient to induce plasticity. I found that directly activating SGCs decreased the number of synapses on SNs, and that SGCs were downregulating known release factors of synaptic structural and functional properties. Given that our lab has shown that SGCs promote cholinergic synapse formation and SN survival in NGF-depleted conditions, I next asked if SGCs are downregulating expression of NGF and if treatment of NGF impacts synaptic number. Indeed, I observed a downregulation in NGF upon SGC stimulation and that NGF can induce alterations in the number of SN synapses. Since SHR SNs are intrinsically more active, I next asked if SHR SGCs formed less synapses than the less active normotensive strains. I found that SHR neonatal SNs develop less synapses in vivo and in vitro and that they are unable to homeostatically maintain the number of cholinergic synapses upon further stimulation, suggesting that disruptions to SHR SGCs signaling might contribute to disease development. In chapter 3, I present preliminary data that supports this by showing that these mechanisms are disrupted in SHR SGCs, but their passive functions remain intact. Lastly, I present preliminary evidence that additional homeostatic plasticity mechanisms may act to remodel dendritic and axonal properties of neurons, suggesting that multiple neuronal properties are being adjusted to constrain aberrant changes in activity. Overall, this work highlights the importance of maintaining sympathetic neuronal output to the periphery and suggests that disruptions to this balance may underlie disease.