A Novel Mouse Model of Sympathoadrenal Catecholamine Deficiency by Ablation of the Tyrosine Hydroxylase Gene With Slc6a4-Cre.

Abstract

Catecholamines (CAs) play important roles not only in the central nervous system but also in the periphery. Tyrosine hydroxylase (TH) is the rate-limiting enzyme for CA synthesis and selective Th ablation in tissues of interest is useful to investigate the physiological function of locally produced CAs. Slc6a4 encodes serotonin transporter (SERT), a membrane transporter for serotonin reuptake, which is reported to be expressed in several peripheral tissues as well as serotonin-producing cells. Here, we report a novel Th conditional knockout mouse line generated by Slc6a4-Cre. The conditional knockout mice (cKO mice) exhibited predominant depletion of adrenaline in the adrenal glands, while noradrenaline contents were preserved at approximately 70% of control levels. TH expression was largely lost, although sparsely retained, in the adrenal medulla of cKO mice contrary to unaltered expression of TH in the brain. In addition to the adrenal gland, TH expression was lost in approximately 80% of sympathetic neurons in the superior mesenteric ganglion of cKO mice. Plasma noradrenaline levels were significantly reduced, although plasma dihydroxyphenylalanine (DOPA) levels were comparable to those of controls. Bradycardia and changes in heart rate variability in cKO mice suggested impaired sympathoadrenal catecholaminergic regulation of the heart. The present data highlight the value of these cKO mice as a useful tool for elucidating the properties of the sympathoadrenal catecholaminergic system independently of the brain noradrenergic system.