Grant: Project Grant

Intellectual disability (ID) is characterized by poor general mental capacity, such as learning, reasoning and problem solving, and is caused by disruptions in the proper development of the brain. Severe ID is almost always accompanied by other neurological challenges including epilepsy, speech defects and autism. There is a clear genetic component to ID, and patients with ID often have mutations in genes that code for proteins that control the structure of the nerve cell (neuron), the formation of synapses (connections between neurons where information is exchanged), or the formation and breakdown of synapse proteins. Studies have clearly demonstrated that even minor disruptions in synapse structure and function can give rise to mild to severe changes in intellectual abilities. There is growing evidence that a chemical process called 'palmitoylation', in which palmitic acid is attached to proteins, may play a central role in the proper development and functioning of synapses. Indeed, approximately 41% of all known synaptic proteins can be palmitoylated. Mutations in enzymes that mediate palmitoylation, called DHHC proteins, have been linked to a number of neurodevelopmental disorders including schizophrenia, autism, and ID. Interestingly, nearly 2% of all patients who have ID linked to the X chromosome, have mutations in DHHC9 (one of 23 known DHHC enzymes). The large majority of patients with DHHC9 mutations also have epilepsy, underscoring a link between, ID and epilepsy. In this proposal we will: 1) evaluate the role of DHHC9 in controlling the proper formation of neuronal connections; 2) identify all synaptic proteins that can be modified by DHHC9 and the ones that are specifically modified by this enzyme during a learning event; and 3) determine whether reintroducing DHHC9 into the brains of adult mice that lack this enzyme can rescue some of the structural and behavioral deficits seen in these animals.