Neural mechanisms underlying sleep disturbances in Syngap1+/- mutant mice

  • Awarded: 2018
  • Award Type: Pilot
  • Award #: 572595

Many children with autism spectrum disorder (ASD) suffer from sleep disturbances such as difficulties in falling asleep, staying asleep or waking up early. Sleep disturbances are associated with the severity of ASD core symptoms such as difficulties with social skills, hyperactivity and stereotypical behaviors. This suggests that sleep problems and core symptoms of ASD are related, and that understanding circuit and molecular mechanisms underlying sleep disorders in children with ASD may help to elucidate the underlying etiology of ASD.

The preoptic area (POA) of the hypothalamus is crucial for sleep generation. Shinjae Chung previously showed that GABAergic neurons in the POA projecting to the tuberomammillary nucleus are sleep active and sleep promoting1. This discovery serves as a valuable entry point for exploring sleep-circuit dysfunctions in mouse models of ASD.

In the current project, Chung and Ted Abel aim to unravel changes in the activity and molecular signature of POA sleep neurons that underlie sleep disturbances. To do so, they plan to study the Syngap1 mutant mouse model of ASD. Syngap1 mutant mice exhibit sleep deficits, suggesting that they may be a useful model for investigating potential mechanisms underlying sleep and activity issues found in individuals with ASD. In vivo electrophysiology and deep brain calcium imaging will be used to record the activity of POA sleep neurons in this mouse model with the goal of understanding how the neural dynamics of sleep neurons are altered during sleep and whether changes in their activity are correlated with sleep disturbances and related psychopathology.

Furthermore, they plan to determine whether restoring the activity of sleep neurons in Syngap1 mutant mice by pharmacogenetic or optogenetic manipulation counteracts sleep disturbances and related psychopathology. To comprehensively unravel any changes in the molecular signature of sleep neurons, they will also generate transcriptional profiles from sleep neurons in Syngap1 mutant and wildtype mice. Their transcriptional profiles will be compared to unravel differentially regulated genes that may contribute to sleep disturbances.

This approach is unique in its use of cutting-edge techniques, enabling an unprecedented level of genetic, anatomical and temporal precision to uncover changes in neural circuits and molecular mechanisms that causally underlie sleep disturbances in ASD. Such findings are expected to inform efforts to develop novel therapeutic interventions to alleviate sleep issues and related symptoms of ASD.


1.Chung S. et al. Nature 545, 477-481 (2017) PubMed
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