Communication Dans Un Congrès Année : 2025

Modelling human REM sleep Behavior Disorder (RBD), a prodromal marker of synucleinopathies, using genetic tools in wild-type mice

Résumé

The sudden loss of tone in the skeletal muscles is a key physiological feature characterizing the transition from slow wave sleep to rapid eye movement (REM) sleep. According to convergent experimental data, atonia is thought to result from the activation at REM sleep onset of glutamate neurons within the dorsal pons, forming the so-called sublaterodorsal nucleus (SLD). Once recruited, they may generate REM sleep atonia by exciting, via descending pathways onto the ventromedial medulla (vmM), a contingent of reticular GABA/glycine inhibitory pre-motoneurons. REM sleep atonia can be lost as reported in patients with REM sleep behavior disorder (RBD). RBD is a parasomnia prodromal of synucleinopathies as Parkinson's Disease characterized by large, uncontrolled and violent movements with vocalization, often decoded as the visual reflection of their ongoing inner dreaming activity. Of pathophysiological interest, motor signs mimicking RBD has been reported in rats endowed with genetically induced damage to glutamate SLD neurons, without alteration of REM sleep microarchitecture as reported in RBD patients. This suggests that these pontine neurons may rather generate atonia during REM sleep than the state itself. We here tried to challenge these functional data with pertinent genetic and molecular tools allowing in mice a selective elimination of SLD to vmM projecting neurons. For that goal, we combined bilateral infusions of retro-AAVs carrying cre-recombinase in vmM and cre-dependent AAVs carrying diphtheria toxin A in SLD in wildtype mice prepared for polysomnography. Within 5-10 days post-surgery, all treated mice depicted a loss of muscle atonia concomitant to abnormal occurrence of violent and uncontrolled motor events during each REM sleep episode, without affecting locomotor activity during wakefulness. Further, REM sleep ultradian rhythm appeared severely disturbed with an increased number of shorten bouts, resulting in significant increased daily amounts. Brain histological analysis confirmed large neuronal loss in SLD areas, and unexpectedly in few SLD efferents as vmM. Our ongoing experiments highly suggest that erasing SLD to vmM projecting neurons is sufficient to recapitulate RBD features supporting the direct role of this unique brainstem pathway in REM sleep atonia and providing a convenient murine preclinical model of RBD. However, the unexpected increase of REM sleep quantities in treated mice requires further investigation to be explained.

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Dates et versions

hal-05119309 , version 1 (20-06-2025)

Identifiants

  • HAL Id : hal-05119309 , version 1

Citer

Blandine Duval, Sébastien Arthaud, Justin Malcey, Amarine Chancel, Luppi Pierre-Hervé, et al.. Modelling human REM sleep Behavior Disorder (RBD), a prodromal marker of synucleinopathies, using genetic tools in wild-type mice. Neurofrance 2025, Société Française des Neurosciences (SDN), May 2025, Montpellier, France. ⟨hal-05119309⟩
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