PROJECT SUMMARY CASK encodes the synaptic protein calcium/calmodulin-dependent serine protein kinase and is one of the five most common X-linked genes with de novo variants in developmental disorders. Loss-of-function variants in CASK result in a heterogeneous syndrome collectively known as CASK-related disorders (CRDs) with hallmark symptoms including intellectual disability (ID) and epilepsy. These patients, like many other children with rare neurodevelopmental disorders (NDDs), are clinically underserved without pharmacotherapies for ID and with increased resistance to anti-seizure medications. There is a critical need to understand the neuronal mechanisms of CRDs to identify targets for therapeutics to address this gap. While mouse models of CRDs have epilepsy, they have not yet been investigated for cognitive deficits, despite ID being the most penetrant symptom in patients. Conditional Cask KO in inhibitory neurons has recapitulated epileptic phenotypes with preliminary data suggesting altered synaptic function. Thus, the central hypothesis is that Cask dysfunction in inhibitory neurons causes both cognitive deficits and epilepsy due to impaired synaptic transmission. This will be studied through genetic manipulations in combination with various techniques. Aim 1 will test the mouse model for cognitive deficits and determine the contribution of inhibitory neuron specific Cask KO to the phenotype; Aim 2 will investigate changes in inhibitory neuron pre-synaptic output via paired whole-cell patch clamp; and Aim 3 will determine inhibitory neuron post-synaptic input changes via ex vivo whole-cell patch clamp and how these changes translate into in vivo neuronal activity via two-photon Ca2+ imaging. The overall goal of this project uses mouse models to determine how the loss of Cask in inhibitory neurons alters synaptic function to result in disease pathogenesis and is designed to prepare the applicant for a career as a pediatric neurologist specializing in treating patients with and studying NDDs. This project furthers the applicant’s long-term goal of understanding cortical interneuron development and homeostasis and how perturbations result in NDDs, with the end goal of developing novel therapeutics. The Xue lab has a strong track-record of successful MSTP trainees and conducts impactful research using mouse models of human NDDs to discover neuronal mechanisms that contribute to disease. Furthermore, the collaborative training environment of both Baylor College of Medicine and the Jan and Dan Duncan Neurologic Research Institute provide state-of-the-art technology cores, experts in the field of NDDs, and a central location in the Texas Medical Center that will facilitate the success of the project and training of the applicant. The proposed research is expected to elucidate how inhibitory neuron dysfunction contributes to cognitive deficits and epilepsy in mouse models of CASK-related disorders and the concomitant synaptic input and output c...