PROJECT 4 – SUMMARY Neurodevelopmental disorders (NDDs) are caused by abnormal development of molecular and synaptic networks in the brain and are characterized by developmental behavioral deficits with clear social and cognitive impairments. Approximately 15% of children in the United States ages 3 to 17 years are affected by NDDs which include autism spectrum disorders (ASD), attention-deficit hyperactivity disorder (ADHD), epilepsy, intellectual disability (ID), hearing impairments, visual/motor impairments, among others. Interestingly, NDDs, in particular ASD and ID, are also marked by a number of memory-related deficits, such as face identity recognition, working memory, and episodic memory. Nevertheless, the link between genes, memory phenotypes, and NDDs is poorly understood. This project focuses on the function of the NDD risk gene, IL1RAPL2, in human iPSC-derived excitatory neurons and in ASD-like and memory behaviors using a newly developed mouse model. We hypothesize that IL1RAPL2 plays a key role in neurodevelopmental disorders and memory phenotypes by regulating synapse development on cortical excitatory neurons. Aim 1 will take advantage of human IPSC- derived deep layer excitatory neurons with IL1RAPL2 loss-of-function (LoF) to understand its function in the transcriptomic landscapes, in regulation of dendritic arborization and spine density, and in neuronal excitability and synaptic transmission. Aim 2 will take advantage of a new mouse model with a global Il1rapl2 LoF to mimic LoF mutations in humans, that will enable an understanding of its role in NDDs and memory related behaviors. The NIH COBRE in Neurodevelopment and Its Disorders (CNDD) will provide an ideal environment, critical resources and Cores, and career development opportunities to enable the successful transition of Dr. Berto to an established, independent investigator at MUSC. Moreover, the proposed studies, and approaches employed, are important and highly relevant to the mission and theme of the CNDD, and the Project data will prepare Dr. Berto for a future competitive R01 application.