Autonomic cardiac innervation: development and adult plasticity

Abstract

Autonomic cardiac neurons have a common origin in the neural crest but undergo distinct developmental differentiation as they mature toward their adult phenotype. Progenitor cells respond to repulsive cues during migration, followed by differentiation cues from paracrine sources that promote neurochemistry and differentiation. When autonomic axons start to innervate cardiac tissue, neurotrophic factors from vascular tissue are essential for maintenance of neurons before they reach their targets, upon which target-derived trophic factors take over final maturation, synaptic strength and postnatal survival. Although target-derived neurotrophins have a central role to play in development, alternative sources of neurotrophins may also modulate innervation. Both developing and adult sympathetic neurons express proNGF, and adult parasympathetic cardiac ganglion neurons also synthesize and release NGF. The physiological function of these "non-classical" cardiac sources of neurotrophins remains to be determined, especially in relation to autocrine/paracrine sustenance during development. Cardiac autonomic nerves are closely spatially associated in cardiac plexuses, ganglia and pacemaker regions and so are sensitive to release of neurotransmitter, neuropeptides and trophic factors from adjacent nerves. As such, in many cardiac pathologies, it is an imbalance within the two arms of the autonomic system that is critical for disease progression. Although this crosstalk between sympathetic and parasympathetic nerves has been well established for adult nerves, it is unclear whether a degree of paracrine regulation occurs across the autonomic limbs during development. Aberrant nerve remodeling is a common occurrence in many adult cardiovascular pathologies, and the mechanisms regulating outgrowth or denervation are disparate. However, autonomic neurons display considerable plasticity in this regard with neurotrophins and inflammatory cytokines having a central regulatory function, including in possible neurotransmitter changes. Certainly, neurotrophins and cytokines regulate transcriptional factors in adult autonomic neurons that have vital differentiation roles in development. Particularly for parasympathetic cardiac ganglion neurons, additional examinations of developmental regulatory mechanisms will potentially aid in understanding attenuated parasympathetic function in a number of conditions, including heart failure.

Keywords: autonomic; development; heart; neuroplasticity; neurotrophins.

Figure 1. Sympathetic stellate ganglion; most cardiac-projecting neurons have their origins in this ganglion. Developmental profile with immunohistochemistry for the noradrenergic marker tyrosine hydroxylase (TH; green) in sheep. Sheep sympathetic neurons express TH by E100 with more prominent expression by E129; staining is localized in neuronal cytoplasm (white arrowheads) and within nerve bundles and fibers (gray arrowheads) at all ages examined (Jonker S., Louey S., Moses M., Macek A., Giraud G., Thornburg K., Hasan W.; unpublished data). Scale bar in C is 200 υm.

Figure 2. Parasympathetic cardiac ganglion. Immunohistochemical staining in an adult rat cardiac ganglion for cholinergic marker vesicular acetylcholine transporter (VAChT; red) and catecholaminergic marker tyrosine hydroxylase (TH; green). Neurons stain in the soma for VAChT (white arrowhead) and also receive input from cholinergic pre-ganglionic terminals (small varicosities around cell bodies). Small intensely fluorescent (SIF; gray arrows) cells are catecholaminergic and believed to function as inter-neurons; here SIF cells make contact with each other and with a cholinergic neuron (Moses M., Macek A. Hasan W.; unpublished data). Scale bar is 50 υm.