PROJECT SUMMARY Proper brain development requires precise dosages of genes critical for synapse formation. Alterations of gene dosage through loss-of-function mutations, such as genomic deletions, or gain of function mutations, such as genomic duplications, result in approximately 50% change in protein content. This often has devastating consequences for brain development and function. In one example, dominant, loss-of-function mutations in the post-synaptic scaffolding protein encoded by the SHANK3 gene causes a severe neurodevelopmental disorder, Phelan-McDermid syndrome. Individuals with Phelan-McDermid syndrome have moderate to severe intellectual disability with developmental delays often noted in the first two years of life. There are currently no targeted therapies for this disorder. This proposal aims to investigate SHANK3’s post-translational regulation to add fundamental knowledge of synaptic development and physiology and develop treatment avenues for individuals with SHANK3 mutations. In this proposal, a combination of biochemistry, behavior and neurophysiology will be utilized to address the following: 1. Determine if in vivo inhibition of ERK2 rescues molecular and behavioral abnormalities due to SHANK3 haploinsufficiency. 2. Determine the impact of Casein Kinase inhibition on SHANK3 stability and function and 3. Identify the proteasomal elements which regulate SHANK3 stability. The impact of this work will be to understand the dynamic regulation of SHANK3 through post-translational mechanisms, develop pre-clinical insight into therapeutic treatment avenues for Phelan-McDermid syndrome and develop a molecular approach for identifying personalized therapies for neurodevelopmental disorders due to mutations in dosage sensitive genes.