Heterogeneous ventricular sympathetic innervation, altered β-adrenergic receptor expression, and rhythm instability in mice lacking the p75 neurotrophin receptor

Abstract

Sympathetic nerves stimulate cardiac function through the release of norepinephrine and the activation of cardiac beta(1)-adrenergic receptors. The sympathetic innervation of the heart is sculpted during development by chemoattractive factors including nerve growth factor (NGF) and the chemorepulsive factor semaphorin 3a. NGF acts through the TrkA receptor and the p75 neurotrophin receptor (p75(NTR)) in sympathetic neurons. NGF stimulates sympathetic axon extension into the heart through TrkA, but p75(NTR) modulates multiple coreceptors that can either stimulate or inhibit axon outgrowth. In mice lacking p75(NTR), the sympathetic innervation density in target tissues ranges from denervation to hyperinnervation. Recent studies have revealed significant changes in the sympathetic innervation density of p75NTR-deficient (p75(NTR-/-)) atria between early postnatal development and adulthood. We examined the innervation of adult p75(NTR-/-) ventricles and discovered that the subendocardium of the p75(NTR-/-) left ventricle was essentially devoid of sympathetic nerve fibers, whereas the innervation density of the subepicardium was normal. This phenotype is similar to that seen in mice overexpressing semaphorin 3a, and we found that sympathetic axons lacking p75(NTR) are more sensitive to semaphorin 3a in vitro than control neurons. The lack of subendocardial innervation was associated with decreased dP/dt, altered cardiac beta(1)-adrenergic receptor expression and sensitivity, and a significant increase in spontaneous ventricular arrhythmias. The lack of p75(NTR) also resulted in increased tyrosine hydroxylase content in cardiac sympathetic neurons and elevated norepinephrine in the right ventricle, where innervation density was normal.

Structural neuroplasticity following T5 spinal cord transection: increased cardiac sympathetic innervation density and SPN arborization

“…Importantly, a gradient of chemoattractive and chemorepulsive factors, and accordingly, heterogeneity of sympathetic innervation density, exists across the ventricle with more sympathetic fibers in the subepicardium than in the subendocardium (27,68). This is an important consideration because heterogeneous sympathetic innervation density in the left ventricle increases the occurrence of ventricular arrhythmias (7,8,27,47,72). In the present study, there was no attempt to determine regional sympathetic innervation density, and this is a limitation to the study.…”

“…Tyrosine hydroxylase immunohistochemistry was used to determine sympathetic innervation density on the remaining LV free wall of Intact and T5X rats, because tyrosine hydroxylase is the rate-limiting enzyme in norepinephrine synthesis and is routinely used to determine cardiac sympathetic innervation density (20,47). Innervation density was expressed as the percent area of tyrosine hydroxylase-positive fibers.…”

Differential roles for cortical versus sub-cortical noradrenaline and modulation of impulsivity in the rat

“…Thresholding was based on the contrast in pixel intensity between specific staining and background and was consistent across brain regions. Threshold levels were checked by eye to ensure that fiber staining corresponded to the pixels selected by ImageJ (Lorentz et al 2010; Matragrano et al 2013). For each image, the area occupied by pixels with an intensity value above the background level was converted to mm 2 and averaged across the group.…”

Development, Maturation, and Transdifferentiation of Cardiac Sympathetic Nerves

“…73 Lorentz et al 74 found that the subendocardium innervation of adult p75 knockout ventricles was disrupted with the left ventricle essentially devoid of sympathetic nerve fibers, whereas innervation density of the subepicardium was normal. This neural patterning defect is similar to that seen in mice overexpressing Sema3a, such that the sympathetic axons lacking p75 are highly sensitive to Sema3a-mediated inhibition of neurite outgrowth.…”