title: Deletion of neurturin impairs development of cholinergic nerves and heart rate control in postnatal mouse hearts.
abstract: The neurotrophic factor neurturin is required for normal cholinergic innervation of adult mouse heart and bradycardic responses to vagal stimulation. Our goals were to determine effects of neurturin deletion on development of cardiac chronotropic and dromotropic functions, vagal baroreflex response, and cholinergic nerve density in nodal regions of postnatal mice. Experiments were performed on postnatal C57BL/6 wild-type (WT) and neurturin knockout (KO) mice. Serial electrocardiograms were recorded noninvasively from conscious pups using an ECGenie apparatus. Mice were treated with atenolol to evaluate and block sympathetic effects on heart rate (HR) and phenylephrine (PE) to stimulate the baroreflex. Immunohistochemistry was used to label cholinergic nerves in paraffin sections. WT and KO mice showed similar age-dependent increases in HR and decreases in PR interval between postnatal days (P) 2.5 and 21. Treatment with atenolol reduced HR significantly in WT and KO pups at P7.5. PE caused a reflex bradycardia that was significantly smaller in KO pups. Cholinergic nerve density was significantly less in nodal regions of P7.5 KO mice. We conclude that cholinergic nerves have minimal influence on developmental changes in HR and PR, QRS, and QTc intervals in mouse pups. However, cholinergic nerves mediate reflex bradycardia by 1 week postnatally. Deletion of neurturin impairs cholinergic innervation of the heart and the vagal efferent component of the baroreflex early during postnatal development.
authors.affiliation: Department of Biomedical Sciences, East Tennessee State University, Johnson City, Tennessee.
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Downs
authors.affiliation: Department of Biomedical Sciences, East Tennessee State University, Johnson City, Tennessee.
authors.forename: Hawa B
authors.initials: HB
authors.lastname: Jalloh
authors.affiliation: Department of Biomedical Sciences, East Tennessee State University, Johnson City, Tennessee.
authors.forename: Kayla J
authors.initials: KJ
authors.lastname: Prater
authors.affiliation: Department of Biomedical Sciences, East Tennessee State University, Johnson City, Tennessee.
authors.forename: Santiago P
authors.initials: SP
authors.lastname: Fregoso
authors.affiliation: Department of Biomedical Sciences, East Tennessee State University, Johnson City, Tennessee.
authors.forename: Cherie E
authors.initials: CE
authors.lastname: Bond
authors.affiliation: Mouse Specifics, Inc., Framingham, Massachusetts.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Hampton
authors.affiliation: Department of Biomedical Sciences, East Tennessee State University, Johnson City, Tennessee Center of Excellence in Inflammation, Infectious Disease and Immunity, Quillen College of Medicine East Tennessee State University, Johnson City, Tennessee hoover@etsu.edu.
authors.forename: Donald B
authors.initials: DB
authors.lastname: Hoover
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D017704:Baroreflex / Q000502:physiology*; D059329:Cholinergic Neurons / Q000502:physiology*; D017353:Gene Deletion; D006321:Heart / Q000254:growth & development* / Q000294:innervation*; D006339:Heart Rate / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051101:Neurturin / Q000172:deficiency*
chemical_list: D051101:Neurturin; C495056:Nrtn protein, mouse
keywords: Autonomic development; Baroreflex; cholinergic nerves; heart rate; neurotrophic factor