Synapses are uniquely vulnerable to sleep loss during brain development while maturation confers resilience

Gay, S. M.; Chartampila, E.; Lord, J. S.; Grizzard, S.; Maisashvili, T.; Ye, M.; Barker, N. K.; Mordant, A. L.; Mills, C. A.; Herring, L. E.; Diering, G. H.

doi:10.1101/2023.11.06.565853

bioRxiv · 10.1101/2023.11.06.565853

Synapses are uniquely vulnerable to sleep loss during brain development while maturation confers resilience

Gay, S. M.·Chartampila, E.·Lord, J. S.·Grizzard, S.·Maisashvili, T.·Ye, M.·Barker, N. K.·Mordant, A. L.·Mills, C. A.·Herring, L. E.·Diering, G. H.

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Abstract

Sleep is an essential behavior that supports lifelong brain health and cognition. Neuronal synapses are a major target for restorative sleep function and a locus of dysfunction in response to sleep deprivation (SD). Synapse density is highly dynamic during development, becoming stabilized with maturation to adulthood, suggesting sleep exerts distinct synaptic functions between development and adulthood. Importantly, problems with sleep are common in neurodevelopmental disorders including autism spectrum disorder (ASD). Moreover, early life sleep disruption in animal models causes long lasting changes in adult behavior. Different plasticity engaged during sleep necessarily implies that developing and adult synapses will show differential vulnerability to SD. To investigate distinct sleep functions and mechanisms of vulnerability to SD across development, we systematically examined the behavioral and molecular responses to acute SD between juvenile (P21-28), adolescent (P42-49) and adult (P70-100) mice of both sexes. Compared to adults, juveniles lack robust adaptations to SD, precipitating cognitive deficits in the novel object recognition test. Subcellular fractionation, combined with proteome and phosphoproteome analysis revealed the developing synapse is profoundly vulnerable to SD, whereas adults exhibit comparative resilience. SD in juveniles, and not older mice, aberrantly drives induction of synapse potentiation, synaptogenesis, and expression of peri-neuronal nets. Our analysis further reveals the developing synapse as a convergent node between vulnerability to SD and ASD genetic risk. Together, our systematic analysis supports a distinct developmental function of sleep and reveals how sleep disruption impacts key aspects of brain development, providing mechanistic insights for ASD susceptibility. Significance StatementSleep is a fundamental pillar of lifelong health. Sleep disruption is commonly associated with neurodevelopmental conditions including autism spectrum disorder (ASD) and schizophrenia. Therefore, understanding the vulnerabilities associated with developmental sleep loss is an essential research question. Here we systemically examine the molecular and behavioral consequence of sleep deprivation (SD) in developing and adult mice. Compared to adults, developing mice show absent or blunted adaptive responses to SD, and heightened sensitivity to SD-induced cognitive deficits. Our molecular analysis indicates sleep plays an important role in key aspects of brain development including synaptogenesis, and that the effects of SD converge on nodes of genetic risk for ASD. This study provides new insights into the role of sleep in healthy brain development.

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Gay, S. M., Chartampila, E., Lord, J. S., Grizzard, S., Maisashvili, T., Ye, M., Barker, N. K., Mordant, A. L., Mills, C. A., Herring, L. E., Diering, G. H.. 2023-11-07. Synapses are uniquely vulnerable to sleep loss during brain development while maturation confers resilience. https://doi.org/10.1101/2023.11.06.565853

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