| Several lines of investigation suggest that two neurotrophins, nerve growth factor (NGF) and neurotrophin-3 (NT3), are essential for the survival of sympathetic neurons both pre- and postnatally. Targeted disruption of NGF and NT3 genes provides a model system for the study of the dependence of sympathetic neurons on these neurotrophins in its physiological context. However, studies of the functional significance of the complete absence of NGF and NT3 genes are limited to the prenatal and early postnatal periods due to perinatal lethality of NGF and NT3 null mutant (−/−) mice. Heterozygous mutant (+/−) NGF- and NT3-deficient mice, in which a single allele of the NGF or NT3 genes has been inactivated, develop normally and survive through reproductive maturity. Therefore, NGF and NT3 +/− mice were utilized to investigate the dependence of cardiac sympathetic neurons on NGF and NT3 from birth through adulthood. Results from the first two studies demonstrated that numbers of left stellate ganglion (LSG) neurons were significantly reduced in adult NGF +/− mice and in newborn, weanling and adult NT3 +/− mice, relative to +/+ mice of either strain. Data from LSG analysis correlated with a significant reduction in cardiac norepinephrine concentrations that manifested by three weeks of age and were maintained in adult NGF and NT3 +/− mice. The third study addressed whether norepinephrine receptors in the heart, β-adrenergic receptors, were altered with respect to number in the hearts of adult NGF and NT3 +/− mice, relative to +/+ mice. Results from this study showed that densities of cardiac β-adrenergic receptors in NGF and NT3 +/− mice were reduced relative to +/+ mice of either strain. Thus, the density of cardiac β-adrenergic receptors is maintained in equilibrium with reduced cardiac sympathetic innervation present in adult NGF and NT3 +/− mice. The results of these studies demonstrate that two functional NGF and NT3 gene alleles are required for the proper postnatal development and maturation of cardiac sympathetic innervation and regulation of β-adrenergic receptor expression in the heart. NGF and NT3 +/− mice may serve as animal models of sympathetic impairment present in forms of human cardiovascular disease. |
