Sleep-dependent synapse remodeling during development and in a mouse model of Rett syndrome
- Awarded: 2018
- Award Type: Bridge to Independence
- Award #: 385188
Although sleep is essential for optimal brain function, the mechanisms by which sleep supports cognitive functions are not fully understood. Many neurodevelopmental disorders, including Rett syndrome and autism spectrum disorders (ASDs), are associated with sleep disturbances.
Graham Diering hypothesizes that sleep disruption early in life may negatively affect normal brain development and contribute to risk for ASD and intellectual disability. It is possible that early life interventions that are able to correct sleep disruption will have lasting effects on brain function as individuals mature through sensitive periods of development.
In this project, Diering will use biochemistry and proteomics to examine changes in synapse composition and signaling during sleep, specifically focusing on synaptic signaling and metabolic pathways1. One pathway previously identified involves the group I metabotropic glutamate receptors mGluR1/5, which undergo wake/sleep remodeling dependent on the immediate early gene Homer1a; this pathway has also been implicated in ASD.
Sleep-dependent synaptic remodeling changes from early life through to adulthood will be studied in mice. In addition, Diering will also test the role of sleep disruption in the progression of Rett syndrome using an MeCP2 knock-out mouse model.
The overall goal of this project is to shed light on the normal processes of sleep and to examine possible sources of sleep disruption in Rett syndrome. With detailed knowledge of the mechanisms underlying the restorative functions of sleep, new therapies could be developed to restore sleep in individuals with neurodevelopmental disorders, thus improving the quality of life for affected individuals and their families.