Funding Research for Treatments and a Cure

To what extent are striatal deficits underlying clinical features of Angelman syndrome?
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Dr. Ype Elgersma Dr. Ype Elgersma Erasmus Medical Centre, Rotterdam
2019

To what extent are striatal deficits underlying clinical features of Angelman syndrome?

It remains unclear which brain areas (and hence which cellular changes) directly contribute to phenotypes of AS. Knowledge of the critically affected brain areas is important for two reasons: 1) it will help us to identify the most relevant mechanisms that underlie AS (which is important for drug development), and 2) it will help us to understand why the success of UBE3A gene-reinstatement strategies appear to be sensitive to age at treatment onset.

Recent MRI studies revealed that individuals with AS show morphological deficits in striatum, a brain area involved in motor learning, speech, emotional modulation and cognitive function. Notably, AS mice also show behavioral impairments which are known to be dependent on striatal activity. 

This study will attempt to answer these questions: 

  1. To what extent does loss of UBE3 in striatal MSNs contribute to the behavioral deficits as observed in AS mice?
  2. What is the temporal profile of the electrophysiological changes in striatal MSNs? 
  3. Does the critical period for reversal of striatal electrophysiological deficits overlap with the critical period of the behavioral deficits in the AS mouse model?

Uncovering the functional changes that underlie the behavioral phenotypes as well as understanding the basis for the critical period for therapeutic intervention, is essential for understanding the pathophysiology in AS and for the development of successful treatments.