Grant: Project Grant

Neural hyperexcitability is a common feature of autism spectrum disorders (ASDs), a collection of neurodevelopmental disorders affecting 1 in 66 children in Canada. ASD is genetically heterogeneous, making it difficult to study the pathogenic mechanism. Smith-Magenis Syndrome (SMS) is a type of ASD caused by genetic deletions of chromosome 17p11.2. Importantly, the dosage-sensitive gene has been identified as Retinoic acid induced-1 (Rai1), a chromatin-binding protein. SMS patients exhibit prominent neurologic symptoms, including seizures, learning deficits, obesity, and autistic features. How Rai1 loss causes neuronal dysfunction is unknown. My recent work found that Rai1 regulates expression of ion channels and growth factors. Our preliminary data found that loss of Rai1 causes the over-excitation of several cell types in the brain, including hippocampal dentate gyrus granule cells (dGCs) that play an important role in epilepsy and cognitive function. We also found that Rai1 loss results in hyper-activation of a key pathway involved in regulating neuronal activity. Our collective work to date has led us to hypothesize that loss of Rai1 causes altered neuronal signaling pathways and ion channel expression, thus driving neuronal hyperexcitability and behavioral symptoms. Therefore, we will determine the mechanism by which Rai1 regulates neuronal excitability at molecular, cellular, and synaptic levels. We will also test if targeting the hyperactivated neuronal signaling pathway rescues hyperexcitability and SMS-like neurobehavioral phenotypes. The proposed studies will create new knowledge of how Rai1 regulates brain excitability and uncover potential therapeutic strategies for treating brain hyperexcitability and behavioral deficits in SMS.