About two-thirds of children with autism spectrum disorder (ASD) experience severe sleep disturbances. Strikingly, these sleep problems are positively correlated with the severity of ASD symptoms such as deficits in social behaviors and cognition. Abnormalities in the prefrontal cortex (PFC) and its connectivity with downstream areas are known to directly contribute to behavioral challenges in ASD. However, to what extent prefrontal dysfunction also causes specific sleep problems in individuals with ASD and whether the resulting sleep disturbances directly contribute to deficits in cognition remain unclear.
Early studies on sleep in children with ASD found disruptions in rapid eye movement (REM) sleep, notably a reduction in the frequency of rapid eye movements, indicating disturbances in phasic REM sleep1–2. Phasic REM sleep is characterized by bursts of rapid eye movements and intensified hippocampal theta oscillations (phasic theta events), which facilitate memory consolidation.
Recently, Franz Weber and colleagues showed that the medial PFC (mPFC) in mice promotes phasic REM sleep, reflected in an increased frequency of phasic theta events and rapid eye movements, while inhibition suppresses phasic REM sleep3. Subsequent pilot studies in a mouse model of 16p11.2 deletional syndrome (16p11.2+/-) demonstrated that phasic theta events are reduced, suggesting a reduction of phasic REM sleep. Previous studies revealed that the mPFC in 16p11.2+/- mice is less excitable due to synaptic dysfunction and restoring its excitability in vivo reserved memory deficits4. However, whether hypo-activation of the mPFC in ASD disturbs phasic REM sleep and thereby impairs memory processing in 16p11.2+/- mice, and whether abnormalities in prefrontal activity can be measured by tracking rapid eye movements, remains unclear.
In the current project, Weber’s team firstly aims to test whether mPFC neurons are hypo-activated in 16p11.2+/- mice and whether the hypo-activity is reflected in a reduced frequency of rapid eye movements. These experiments will involve combining high-density in vivo recordings (using Neuropixels probes), optogenetic manipulation and pupillometry. Second, they plan to assess whether enhancing phasic theta events through activation of cortico-hypothalamic projections can rescue memory deficits in 16p11.2+/- mice.
Unraveling the neural correlates of phasic REM sleep disturbances in 16p11.2+/- mice will provide a proof-of-concept that rapid eye movement tracking during REM sleep could be used as a non-invasive biomarker to predict prefrontal dysfunction in individuals with 16p11.2 deletion syndrome and potentially other ASD subtypes. Furthermore, results from these studies are expected to identify cortico-hypothalamic projections as a potential target to reverse memory deficits caused by REM sleep disturbances in ASD.