Implication of locus coeruleus dysfunction in Prader-Willi syndrome: Insights from a mouse model

Area of Science:

• Neuroscience
• Genetics
• Pharmacology

Background:

• Prader-Willi syndrome (PWS) is a complex genetic disorder with multisystemic manifestations.
• Many PWS symptoms correlate with dysfunction in the locus coeruleus norepinephrine (LC-NE) system, affecting arousal, learning, and stress responses.
• While electrophysiological studies in PWS mouse models show LC dysfunction, behavioral phenotypes remain largely unexplored.

Purpose of the Study:

• To investigate the behavioral consequences of LC-NE system dysfunction in a mouse model of Prader-Willi syndrome.
• To explore the role of necdin deficiency in stress-induced anxiety and norepinephrine release.
• To assess the therapeutic potential of enhancing LC function in PWS.

Main Methods:

• Utilized heterozygous necdin-deficient mice (Ndn+/m/-p) and wild-type (WT) littermates.
• Assessed cognitive and motor functions using Y-maze, Rotarod, open field test (OFT), and elevated plus maze (EPM).
• Evaluated stress response via acute restraint stress, plasma norepinephrine levels, and chemogenetic manipulation of LC neuronal activity.
• Tested the efficacy of atomoxetine, a norepinephrine reuptake inhibitor.

Main Results:

• Ndn+/m/-p mice exhibited impaired visual-spatial memory, reduced social interaction, and deficits in motor coordination.
• While locomotion was similar to WT, Ndn+/m/-p mice showed reduced anxiety in baseline tests but impaired stress-induced anxiety.
• Acute restraint stress led to impaired norepinephrine surges in Ndn+/m/-p mice.
• Atomoxetine treatment and chemogenetic LC activation partially rescued the stress-induced anxiety phenotype.

Conclusions:

• LC-NE system dysfunction is implicated in the pathogenesis of stress-related neuropsychiatric symptoms in Prader-Willi syndrome.
• Targeting LC activity through pharmacological or genetic interventions may offer therapeutic benefits for PWS patients.
• This study provides a behavioral framework for understanding LC-NE dysfunction in PWS and its potential treatment avenues.