Defining impaired neuronal architecture in the Snord116del mouse model for Prader-Willi Syndrome

Funding Summary

The cognitive challenges experienced by many individuals with PWS remains poorly understood. Pilot data obtained in the Wells laboratory indicates that loss of expression of PWS-region gene, Snord116, leads to reduced length and branching of a certain type of neuron in the cortex of the brain. In this project they will use specialized techniques to build on this preliminary finding in a mouse model of PWS. This project will begin to address a major deficit in our understanding of PWS, delineating the mechanisms of cognitive impairment, with the ultimate goal of identifying potential therapeutic strategies to improve cognition.

Dr. Theresa Strong, Director of Research Programs, shares details on this project in this short video clip. 

Watch the full webinar describing all 7 research projects funded in this grant cycle here. 

Lay Abstract

Many individuals with Prader-Willi syndrome (PWS) experience varying degrees of intellectual sluggishness and disturbed patterns of behaviour. Low IQ scores may be accompanied by under-attainment in numeracy, literacy and comprehension, with social interactions and awareness of social norms being either under-developed or lacking. The mechanisms underlying these deficits and their relationship with the range of genetic mutations giving rise to PWS remain poorly understood.
In broad developmental terms, behavioural dysfunction arises from a reduction in the number of nerve cells (neurons) in the brain or impairments in their electrical activity or their capacity to communicate with neighbouring neurons. Pilot data obtained in our laboratory indicates that loss of expression of Snord116, one of the genes in the PWS locus whose expression is commonly lost in PWS, results in a reduction in the branching and length of basal dendrites in pyramidal neurons in the cortex of 10-day old mice. Since these dendrites receive information from neighbouring cells in the cortex, this implies that the capacity of the pyramidal cells to integrate information correctly in order to direct appropriate behavioural responses is impaired. As this was recorded at the end of a critical period for the development of the cortex, these changes are likely to persist into adulthood.
In this project, we will establish whether the deficits we have seen in male mice are replicated in females and maintained with age. In addition, we will determine whether these changes arise from defects in the neurons themselves or from defects in the cells that they are attempting to connect with. This study is important as it will enable us to understand how the structure of these vital neurons develops in mice with PWS – information that is not possible to obtain in humans.
These findings will lead to a subsequent project in which we will characterize the electrical deficits in these cells and analyse behavioural tests specifically associated with the function of these neurons. We will then exploit our expertise to establish the role of a range of factors that regulate dendrite growth and whether treatment with these factors could rescue neuronal architecture and function and restore behaviour. Thus, we are beginning a program of research aimed at alleviating the cognitive impairment experienced by individuals with PWS.