Synaptic Dysfunctions May be Linked to Sleep Issues in Patients with Neurodevelopmental Disorders, Review Finds

The close relationship between synaptic maturation and sleep may be the reason why many children with neurodevelopmental disorders (NDDs), including Angelman syndrome, experience sleep problems, a review study has found.

The study, “Mechanisms of sleep and circadian ontogeny through the lens of neurodevelopmental disorders,” was published in the journal Neurobiology of Learning and Memory.

Sleep is a highly regulated behavior present in most animal species that is required for cognition in both adults and developing animals. Previous studies have shown that sleep quality has a significant impact on other complex behaviors, including learning, memory, and mood regulation.

“Sleep deprivation impairs the consolidation of learned tasks into long-term memories and has profound effects on neural mechanisms of synaptic plasticity,” the researchers wrote in the study. Synaptic plasticity refers to the ability of synapses — the junctions between two nerve cells that allow them to communicate — to strengthen or weaken over time.

“Many NDDs such as ASDs [autism spectrum disorders] result from abnormalities in synaptic physiology and development, which we hypothesize accounts for the incredibly high rates of sleep dysfunction in children with NDDs,” they said.

In this review study, these researchers from the Boston Children’s Hospital and Harvard School of Medicine gathered information on several NDDs, including tuberous sclerosis complex (TSC), fragile X syndrome (FXS), and Angelman syndrome (AS), that have been linked to both synaptic and sleep dysfunctions.

In Angelman syndrome, a rare neurodevelopmental disorder caused by the loss or malfunction of the maternal copy of the UBE3A gene that provides instructions for making the enzyme ubiquitin ligase E3A (UBE3A), studies have shown that UBE3A not only regulates the function of other proteins involved in synaptic plasticity (e.g., Homer1A), but also of proteins that control circadian rhythms and sleep patterns (e.g., BMAL1).

In the case of TSC — a disorder caused by genetic mutations in either the TSC1 or TSC2 gene, which provide instruction for making the proteins hamartin and tuberin — sleep interruptions, difficulty falling asleep, and waking up early are among the most common complaints.

One of the hypotheses to explain the prevalence of sleep problems in these patients might be that both hamartin and tuberin are necessary for the inhibition of the mTOR signaling pathway, which is a key regulator of cell metabolism, growth, proliferation and survival. When this pathway is overly active, it can have a negative impact on the circadian rhythm, which refers to a series of biological, mental and behavioral changes that depend on the day/night cycle.

“Abnormalities of sleep homeostasis [equilibrium] in TSC mouse models or in human patients have not been formally examined however, in light of the importance of mTOR signaling to sleep-dependent hippocampal plasticity, this could be a fruitful area of future study,” the researchers wrote.

For FXS, a disorder triggered by mutations in the FMR1 gene that provides instructions for making the fragile X mental retardation protein (FMRP), studies performed in mouse and fly models have shown that FMRP could be directly involved in the regulation of the circadian rhythm and sleep, independently of mTOR.

“Chronic treatment with the mTOR inhibitor rapamycin was unable to [restore normal sleep patterns] suggesting that mechanisms other than the modest increase in mTOR signaling observed in Fmr1 [mice] mutants, is responsible for complex behavioral phenotypes [symptoms shown]. Clearly, future studies are needed, but these studies place FMRP squarely at a nexus of translation [the process by which genetic information is transformed into proteins] control, synaptic physiology, and circadian rhythms,” the researchers wrote.

“The biological importance of sleep and circadian rhythms for the health and function of the developing brain are clear but we still do not have a deep understanding of the molecular mechanisms that are responsible for these associations,” the researchers wrote.

“Many key questions still remain. … Can sleep be used as a biomarker for NDDs? Can NDDs be used as biomarkers for sleep? Experiments that address these questions (and others) will address other fundamental questions in the nature of sleep and also shed light on how it contributes to complex disorders of the developing brain,” they concluded.