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

Abstract

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 tm1ky ) 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 Ndn tm1ky mice with necdin deficiency showed significantly decreased spontaneous activities and impaired excitability, which was mediated by enhanced A-type voltage-dependent potassium currents. Ndn tm1ky 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. BackgroundPrader-Willi syndrome (PWS) is a neurodevelopmental disorder characterized by multiple endocrine, metabolic, respiratory, cognitive, and behavioral/psychiatric symptoms. Affected infants uniformly have significant hypotonia, feeding difficulties, central apneas, and failure to thrive, followed by excessive appetite in later infancy or early childhood with gradual development of obesity, short stature, intellectual disabilities, and behavioral problems (1, 2). Although PWS is well-known as a genetic obesity syndrome, care for patients with PWS poses significant challenges and burden to caregivers and to the society predominantly because of their neurodevelopmental disabilities (3-6).The exaggerated stress responses and temper tantrums were the symptoms that most affected the

Necdin: A purposive integrator of molecular interaction networks for mammalian neuron vitality

“…In the midbrain of Ndn‐null mice (Ndn tm1Ky ), the number of dopaminergic neurons is reduced at the substantia nigra in late adulthood (Hasegawa et al., 2016). In the locus coeruleus, spontaneous electrophysiological activity of noradrenergic neurons is significantly reduced in Ndn‐null mice (Ndn tm1Ky ) (Wu et al., 2020). In the cerebellum of Ndn‐null mice (Ndn tm1Ky ), apoptotic cell populations in the external and internal granule layers are significantly increased (Kurita et al., 2006).…”

“…Ndn‐null mice show skin picking and improved performance in the Morris water maze test, indicating increased spatial learning and memory (Muscatelli et al., 2000). Furthermore, Ndn‐null mice exhibit phenotypes that are largely explained by neuronal abnormalities: increased pentylenetetrazole (PTZ)‐induced seizure susceptibilities due to reduced populations of cortical GABAergic inhibitory neurons (Kuwajima et al., 2010), low body temperatures due to central hypothyroidism caused by functional abnormalities of the hypothalamic neurons (Hasegawa et al., 2012), increased pain thresholds due to reduced sensory neuron populations in the DRG (Kuwako et al., 2005), abnormal circadian rhythm‐related behaviors caused by abnormal clock gene expression in neurons at the hypothalamic suprachiasmatic nucleus (Lu et al., 2020), transient hypotonia (Wu et al., 2020) and blunt respiratory responses to hypercapnia due to abnormal activities of locus coeruleus neurons (Wu et al., 2020). Although mutant mice (Ndn tm1Ky ) exhibit no apparent abnormalities in food‐related behaviors such as hyperphagia, adipose tissues in Ndn‐null mice are markedly enlarged owing to preadipocyte hyperproliferation when fed with high calorie diets during juvenile and adult periods (Fujiwara et al., 2012).…”