Impairment of neuronal morphology and function in SNORD116 Prader-Willi syndrome mice

Funding Summary

Data from the first year of this project that in the postnatal period mice that lack Snord116 (Snord116del) have dramatic changes in neuronal morphology in both the cortex and hippocampus, brain regions that are essential for cognitive function. In the second phase of this project, we will characterize the electrical activity and functional circuitry of these neurons and conduct a detailed assessment of morphological impairment in adulthood. We will also determine the impact of these cortical and hippocampal deficits on cognitive flexibility in the context of reversal learning behavior. This project will begin to address a major deficit in our understanding of PWS, enabling us to understand how the structure and function of these vital neurons are impaired in this mouse model.

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

 

Lay Abstract

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 under-developed or lacking. The mechanisms underlying these deficits and their relationship with the range of genetic mutations giving rise to PWS are poorly understood. In broad developmental terms, behavioural dysfunction arises from changes in the morphology of nerve cells (neurons) in the brain, and/or impairments in their electrical activity or their capacity to communicate with neighbouring neurons. Snord116 is a gene whose expression is commonly lost in PWS. Data obtained in the first phase of this project indicate that in the postnatal period mice that lack Snord116 (Snord116del) have dramatic changes in neuronal morphology in both the cortex and hippocampus, brain regions that are essential for cognitive function. However, the morphologies deficits observed in these two regions are markedly different. Cortical neurons from Snord116del mice have shorter, less branched basal processes (which receive incoming information), whereas the apical projections (which convey information to neighboring neurons) are unaffected. Conversely in the hippocampus the apical processes are less complex and project over a shorter distance. Since these deficits occur at a crucial stage in brain development, they are likely to persist into adulthood and could have a dramatic impact upon cognitive performance. In the second phase of this project, we will characterize the electrical activity and functional circuitry of these neurons and conduct a detailed assessment of morphological impairment in adulthood. We will also determine the impact of these cortical and hippocampal deficits on cognitive flexibility in the context of reversal learning behaviour. In addition, having now established a method to grow cortical neurons in culture, we will determine whether the morphological deficits in cortical neurons from Snord116del mice are intrinsic to the neurons themselves or dependent upon their developmental environment and whether these alterations can be reversed through the application of neuronal growth factors. This ground-breaking project will begin to address a major deficit in our understanding of PWS, enabling us to understand how the structure and function of these vital neurons are impaired in this mouse model – information that is not possible to obtain in humans. These findings will lead to a subsequent larger project in which we will characterise whether we can rescue neuronal architecture in Snord116del mice and restore cognitive behaviour. Thus, we are beginning a program of research aimed at alleviating the cognitive impairment that represents such a distressing aspect of human PWS.

Funded Year:

2022

Awarded to:

Timothy Wells, Ph.D.

Amount:

$162,000

Institution:

Cardiff University

Researcher:

Timothy Wells, PhD

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