Developing forebrain synapses are uniquely vulnerable to sleep loss
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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 Statement
Sleep 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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n adults, these proteins are almost entirely regulated as a function of wake sleep states, whereas in adolescents these proteins show a more complex pattern including circadian rhythm
This is so cool! It's valuable to highlight these changes, it helps me better interpret how changes in protein expression might be related to physiological and developmental changes.
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This suggests that SD in juveniles drives heightened neuronal activity that aberrantly stimulates synapse growth and potentiation
This hypothesis is really cool, and seems testable! Are there any available datasets from slice or in vivo elecrophysiology/calcium imaging where you could look for this? Alternatively, could you do histology with tissue you have from these experiments to look for aberrant synapse growth?
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fig. S2
I really appreciate you explaining the experimental design and how you drew your conclusions. However, I'm not sure I agree that the effects of circadian rhythm, sleep, wake, and sleep deprivation are dissociable based on your experiments. It seems to me that multiple mechanisms might result in the same change in protein expression (e.g. sleep deprivation and sleep both independently cause reduced protein expression) that would be interpreted as coming from a single source (e.g. circadian rhythm). It also seems to me that different mechanisms might interact with each other (e.g. protein expression is changed by the combination of wakefulness and circadian rhythm), which might remain true even for proteins you identify as influenced by a single regulation group. Finally, it seems to me that some of the comparisons using sleep …
fig. S2
I really appreciate you explaining the experimental design and how you drew your conclusions. However, I'm not sure I agree that the effects of circadian rhythm, sleep, wake, and sleep deprivation are dissociable based on your experiments. It seems to me that multiple mechanisms might result in the same change in protein expression (e.g. sleep deprivation and sleep both independently cause reduced protein expression) that would be interpreted as coming from a single source (e.g. circadian rhythm). It also seems to me that different mechanisms might interact with each other (e.g. protein expression is changed by the combination of wakefulness and circadian rhythm), which might remain true even for proteins you identify as influenced by a single regulation group. Finally, it seems to me that some of the comparisons using sleep deprivation treat it as a wakeful state when controlling for sleep/wake changes and circadian changes, while also identifying it as having separate physiological and molecular effects. Overall, I think the wealth of data you've generated is deeply valuable, but i'm not sure it can be used to isolate single regulatory mechanisms underlying synaptic changes as you suggest.
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4 mice pooled per sample
It would be helpful to include the total number of mice/samples tested.
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(D)
These examples of how you labeled proteins (circadian, sleep deprivation, sleep or combined) are very helpful! Although the categorizations make it easier to see global expression level changes between juveniles, adolescents and adults (Figure H-J), I imagine it is possible that the expression levels may differ for reasons other than the changed variable (sleep deprivation). How did you take that into account while assigning regulation groups?
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homeostatic scaling factor Homer1a and circadian clock component Per2
This is great developmental data, and I'd love to be able to compare across different ages easily. Could you also show the expression data without normalizing?
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a response that was also completely absent in juvenile mice
It seems like Homer1a expression shows much lower changes in expression during wake (as well as during sleep deprivation) in juvenile mice compared to older mice. Does this affect the interpretation of its role and response to sleep deprivation in juvenile mice?
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ark phase sleep rebound was completely absent
This is such an interesting observation! Is it possible that juveniles have another compensatory mechanism? For instance, it seems from the example traces that juveniles and adolescents showed some increased sleep in the light phase. Could you quantify this and compare it to the adults? Do light phase sleep increases explain the (modest) deficit recovery for juveniles you see in (Fig. 1D)?
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synapse proteome (Fig. 2) and phosphoproteome (Fig. 3
Will you make the raw data available in the future?
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