Homeostatic Plasticity and Maturation of Excitability During Embryonic Development of the Sympathetic Nervous System

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Project Summary: The sympathetic nervous system (SNS) provides direct output onto target organs in the periphery, effecting autonomic functions such as heart rate and vasoconstriction. Diseases of the SNS are often associated with hyperexcitability, such as in the case of hypertension. It is still unclear why these disease states occur. We predict that it may be due, in part, to changes in excitability that are achieved through mechanisms of homeostatic plasticity. This form of plasticity can include changes in postsynaptic receptor accumulation and ion channel conductance, which both work to homeostatically regulate patterns of firing rate activity or synaptic efficacy in response to alterations in activity in a circuit. Homeostatic mechanisms are most robustly expressed during early development of a circuit. However, we predict that inducing these homeostatic changes in excitability during early development may result in long term consequences in the excitability of the circuit, potentially leaving the SNS vulnerable to maladaptive hyperexcitability. These mechanisms have never before been demonstrated in the SNS. Our lab has ample experience demonstrating homeostatic plasticity in chick embryo spinal motoneurons, which arise from a progenitor cell population that also gives rise to sympathetic preganglionic neurons (SPNs) in the spinal cord. The SPNs are also active during bouts of spinal cord spontaneous network activity, just like their motoneuron counterparts. Therefore, we expect to see evidence of homeostatic plasticity in these cells as well. Furthermore, we expect that these plasticity mechanisms may exist during a critical period that exists during early development of the circuit, much like that of the visual system. The central hypotheses of this study are 1) that cells in the SNS will exhibit mechanisms of homeostatic plasticity, 2) that this homeostatic adjustment is governed by critical periods, and 3) that sympathetic ganglion neurons (SGNs), which receive input from the SPNs and project directly onto target tissue, will show a permanently altered sympathetic tone or output following an early homeostatic perturbation that exists in the critical period for this form of plasticity. For these aims, the chick embryo provides an excellent model for embryonic development with incredible accessibility for observation and manipulation, without the confounds of maternal behavior. These results have never before been demonstrated and may have implications for long-term health and prevalent human disease states.