Developmental Trajectory of Sleep Disturbances in a Shank3 Mouse Model
We focused our studies on SHANK3, a high confidence ASD gene candidate. Individuals with Phelan-McDermid Syndrome (PMS) carry deletions in chromosome 22q13.3, a region that includes SHANK3. Approximately 85% of PMS individuals have an ASD diagnosis and about half report chronic sleep problems, but the link between SHANK3 mutations and poor sleep is not understood. Sleep is a homeostatic process, in that sleep need accumulates with time awake and discharges during sleep. Typically, insufficient sleep (high sleep need) increases drive to fall asleep, but in ASD insufficient sleep and problems falling asleep co-occur. During development, both sleep need and the brain’s response to sleep loss change significantly. We hypothesize that loss of SHANK3 during development disconnects sleep need from sleep initiation, leading to problems falling and staying asleep.
Objectives: Determine the developmental emergence of sleep problems in Phelan-McDermid syndrome, and in Shank3 mutant mice.
Methods: In this study, we used questionnaire data to guide our studies in mouse models to understand how sleep problems develop in ASD. We obtained sleep questionnaire data from PMS individuals with SHANK3 mutations from the PMS Foundation International Registry. Sleep loss in mice and humans elicits specific changes in electroencephalographic (EEG) activity patterns that can be used to track sleep need. In Shank3ΔC and control mice, we collected EEG and electromyographic (EMG) data to determine sleep-wake patterns, and used sleep-deprivation to induce periods of high sleep need.
Results: We find that SHANK3 mutations are associated with sleep disturbances in both humans and mice. Children with PMS develop sleep problems between 5-12 years of age, including problems falling asleep, repeated awakening, and reduced sleep time. Similarly, we find that adult Shank3ΔC mutant mice have reduced sleep time, delayed sleep initiation following sleep deprivation, and reduced low-frequency EEG activity in non-rapid eye movement (NREM) sleep relative to littermate control mice. We find that adult responses to sleep deprivation emerge during adolescence in mice. Prior to this transition, low-frequency EEG activity during NREM sleep is normal in juvenile Shank3ΔC mice.
Conclusions: We show that sleep problems in PMS individuals emerge during early childhood. Sleep problems in Shank3ΔC mice also change across development. Adult Shank3ΔC mutant mice sleep less but have difficulty falling asleep following sleep deprivation. Changes in NREM EEG activity in Shank3ΔC mice are present in adults but not juveniles, suggesting that they are the result of abnormal post-natal development. Overall, our study shows that SHANK3 is an important modulator of sleep during development.