Firing activity of locus coeruleus noradrenergic neurons decreases in necdin-deficient mice, an animal model of Prader–Willi syndrome

Abstract

<jats:title>Abstract</jats:title> <jats:p>Background: Prader–Willi syndrome (PWS) is a neurodevelopmental disorder characterized by multiple respiratory, cognitive, endocrine, and behavioral symptoms, such as central apnea, intellectual disabilities, exaggerated stress responses, and temper tantrums. The locus coeruleus noradrenergic system (LC-NE) modulates a diverse range of behaviors, including arousal, learning, pain modulation, and stress-induced negative affective states, which are possibly correlated with the pathogenesis of PWS phenotypes. Therefore, we evaluated the LC-NE neuronal activity of necdin-deficient mice, an animal model of PWS.Methods: Heterozygous necdin-deficient mice (B6.Cg-Ndn<jats:sup>tm1ky</jats:sup>) were bred from wild-type (WT) females to generate WT (+m/+p) and heterozygotes (+m/−p) animals, which were examined of LC-NE neuronal activity, developmental reflexes and plethysmography.Results: On slice electrophysiology, LC-NE neurons of <jats:italic>Ndn</jats:italic><jats:sup><jats:italic>tm1ky</jats:italic></jats:sup> mice with necdin deficiency showed significantly decreased spontaneous activities and impaired excitability, which was mediated by enhanced A-type voltage-dependent potassium currents. <jats:italic>Ndn</jats:italic><jats:sup><jats:italic>tm1ky</jats:italic></jats:sup><jats:italic> </jats:italic>mice also exhibited the neonatal phenotypes of PWS, such as hypotonia and blunt respiratory responses to hypercapnia.Conclusions: LC-NE neuronal firing activity decreased in necdin-deficient mice, suggesting that LC, the primary source of norepinephrine in the central nervous system, is possibly involved in PWS pathogenesis.</jats:p>