Introduction: Prader–Willi syndrome (PWS) is a multisystemic disorder. Notably, many characteristic symptoms of PWS are correlated with locus coeruleus norepinephrine system (LC-NE) dysfunction, including arousal, learning, pain modulation, and stress-induced negative affective states. Electrophysiological experiments involving necdin-deficient mice, an established animal model of PWS, have revealed decreased spontaneous neuronal firing activity in the LC and impaired excitability. However, the behavioral phenotypes related to LC-NE dysfunction remain unexplored. Methods: Heterozygous necdin-deficient mice (B6.Cg-Ndn tm1ky) were bred from wild-type (WT) females to generate WT (+m/+p) and heterozygous (+m/−p) animals. We utilized this model to investigate if behavioral responses to acute restraint stress are dependent on the LC-NE system. Results: Using the open field test, we demonstrated defective stress-induced anxiety associated with LC dysfunction in necdin-deficient mice. Additionally, the plasma norepinephrine surge following exposure to acute restraint stress in necdin-deficient mice was impaired. Pretreatment with atomoxetine, a norepinephrine reuptake inhibitor, to enhance LC function, restored necdin-deficient mice to exert a normal response to acute restraint stress. Moreover, post-stress anxious responses in necdin-deficient and wildtype mice were reinstated and obstructed by augmenting or suppressing LC neuronal firing using chemogenetic approaches, respectively. Conclusions: These data strongly suggest that LC dysfunction is implicated in the pathogenesis of stress-related neuropsychiatric symptoms in PWS. Manipulation of LC activity may hold therapeutic potential for patients with PWS.

Li-Ping Tsai
Taipei Tzu Chi Hospital
Taiwan

Da-Zhong Lo
National Taiwan University
Taiwan

Rui-Ni Wu
Taipei Tzu Chi Hospital
Taiwan

Wei-Chen Hung
Taipei Tzu Chi Hospital
Taiwan

Wen-Sung Lai
National Taiwan University
Taiwan

Ming-Yuan Min
National Taiwan University
Taiwan

Shi-Bing Wong
Taipei Tzu Chi Hospital
Taiwan