Synaptic Plasticity in Cardiac Innervation and Its Potential Role in Atrial Fibrillation

Abstract

Synaptic plasticity is defined as the ability of synapses to change their strength of transmission. Plasticity of synaptic connections in the brain is a major focus of neuroscience research, as it is the primary mechanism underpinning learning and memory. Beyond the brain however, plasticity in peripheral neurons is less well understood, particularly in the neurons innervating the heart. The atria receive rich innervation from the autonomic branch of the peripheral nervous system. Sympathetic neurons are clustered in stellate and cervical ganglia alongside the spinal cord and extend fibers to the heart directly innervating the myocardium. These neurons are major drivers of hyperactive sympathetic activity observed in heart disease, ventricular arrhythmias, and sudden cardiac death. Both pre- and postsynaptic changes have been observed to occur at synapses formed by sympathetic ganglion neurons, suggesting that plasticity at sympathetic neuro-cardiac synapses is a major contributor to arrhythmias. Less is known about the plasticity in parasympathetic neurons located in clusters on the heart surface. These neuronal clusters, termed ganglionated plexi, or "little brains," can independently modulate neural control of the heart and stimulation that enhances their excitability can induce arrhythmia such as atrial fibrillation. The ability of these neurons to alter parasympathetic activity suggests that plasticity may indeed occur at the synapses formed on and by ganglionated plexi neurons. Such changes may not only fine-tune autonomic innervation of the heart, but could also be a source of maladaptive plasticity during atrial fibrillation.

Keywords: LTP; atria; atrial fibrillation; ganglionated plexi; innervation; synapse plasticity.

Figure 1

Structure of the intracardiac plexus and synaptic connections within: (A) Drawing of a posterior view of the human heart and major vessels showing the locations of posterior atrial ganglionated plexi (GP) and interconnecting nerves. This schematic representation of the plexus is derived from example reconstructions of acetylcholinesterase positive nerves and ganglia on the surface of juvenile atria (Pauza et al., 2000). Sympathovagal nerves enter the heart by coursing down the aorta and superior vena cava (SVC) to innervate the superior atrial GP. The locations of the pulmonary arteries (PA), left superior pulmonary vein (LSPV), left inferior pulmonary vein (LIPV), right superior pulmonary vein (RSPV), right inferior pulmonary vein (RIPV), left ventricle (LV), right ventricle (RV), and inferior vena cava (IVC) are shown. (B) Schematic representation of interconnectivity in cardiac ganglia showing types of synapses seen in electron microscopy studies (Shvalev and Sosunov, ; Armour et al., ; Pauziene and Pauza, 2003): (a) axo-dendritic synapse formed by adrenergic nerve terminal; (b) adrenergic varicosity without glial sheath; (c) axo-axonal synapses; (d) two axons forming axo-dendritic synapses on a single dendrite; (e) axo-dendritic synapse on dendritic spine; (f) cholinergic varicosity without glial sheath; (g) a single axon forming axo-dendritic synapses on two dendrites; (h) afferent nerve ending; (i) axo-dendritic synapse on small spine like protrusion from soma; (j) axo-somatic synapse; (k) contact of afferent nerve terminal with SIF cell; (l) efferent (soma-axonal) synapse made by SIF cell with cholinergic nerve terminal; (m) synapse formed between cholinergic nerve terminal and process of SIF cell; (n) afferent (axo-somatic) synapse made between SIF cell and cholinergic nerve terminal; (o) synapse formed between process of SIF cell and neuronal dendrite; (p) sensory neuron afferent nerve ending; (q) axo-dendritic synapse between neurons within the GP; (r) axo-dendritic synapse between sensory neuron and other neuronal types. Modified from Shvalev and Sosunov (1985).