Grant: CIHR Fellowship

Neuropsychiatric diseases, such as schizophrenia (SCZ) and autism spectrum disorder (ASD), are a huge burden on society. As such, the investigation of the biological causes is urgently needed. The current knowledge regarding the biological mechanism behind neuropsychiatric diseases is still limited but it has been proposed to have a strong genetic component. Unfortunately, the functional consequences of these gene mutations remain elusive. Recent genetic findings indicate the mutations of synaptic proteins, such as Neurexin (NRXN) and MAM Domain Containing Glycosylphosphatidylinositol Anchor (MDGA), are frequently associated with ASD and SCZ. I hypothesize that the mutations of NRXN and MDGA that have been identified in SCZ or ASD patients can disrupt their protein function and result in impaired neuronal function. I will express the ASD/SCZ-related NRXN and MDGA mutations in cultured neurons and probe their effects on neuronal structure and function. Moreover, I will apply in vivo imaging and electrophysiological recording techniques to systematically investigate alterations in brain activity and sensory processing in a novel SCZ-related knockout mouse line (MDGA1 KO). I hypothesize that as it results in excessive inhibition, MDGA1 KO could lead to decreased spontaneous activity and dampened sensory responses in the cortex, as well as altered cortical connectivity and laminar signal processing. This study will be a novel functional assessment of human ASD and SCZ-related gene mutations in neurons. The candidates with significant effects could be targeted for developing diagnosis and therapies for ASD and SCZ. The in vivo imaging and electrophysiological results can fill the gap between the results from brain slice electrophysiology and behavior tests, and connect brain imaging results from animal models of neuropsychiatric diseases with the ones from human patients.