Identifying mechanisms ofsynapse maturation at neuronal subtype resolution

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Project Summary/Abstract The human brain function relies on the formation and maintenance of precise neural circuits among more than 100 subtypes of neurons. These circuits are mediated by synapses, the characteristics of which vary depending on neuronal subtype. Synaptic dysfunction plays a critical role in most, if not all, human brain disorders. Thus, understanding synaptic diversity and its developmental origin are crucial for us to understand how the brain functions and how it goes awry in mental disorders. During brain development, synapses undergo profound changes to become mature and fully functional. Maturation of glutamatergic synapses involves changes in the postsynaptic density (PSD), a highly sophisticated protein complex composed of >1,000 proteins. However, the compositional changes of the PSD in development were not well characterized. My preliminary data revealed the temporal dynamics of >1,000 PSD proteins during cerebral cortex development, providing initial insight into mechanisms of synapse maturation. Moreover, integrative analysis of the developing PSD proteome and single- cell RNA-seq data suggested that different neuronal subtypes undergo divergent synapse maturation processes. However, we know little about the compositional diversity of neuronal subtype-specific synapses or the different maturation processes they go through. In addition, synapse maturation, diversity, and specificity can be controlled by transcription, but the underlying gene regulatory programs remain elusive. This information is particularly relevant to mental disorders like autism spectrum disorder, in which genetic mutations converge on transcription regulation and synaptic transmission. Thus, the specific aims of this project first seek to uncover the compositional diversity of neuronal subtype-specific synapses in the developing cerebral cortex using a novel chemogenetic method (Aim 1, K99 phase). The second aim is to decode the disease-relevant gene regulatory mechanisms that generate this diversity by applying single-cell genomics and machine learning approaches (Aim 2, K99 phase). Finally, using the training, tools, and preliminary data from the K99 phase of my proposal, I will launch an independent research project that focuses on investigating the effects of neuronal activity on synapse maturation and plasticity at neuronal subtype resolution (R00 phase). Results from these studies will provide insights into synapse diversity, its regulatory mechanisms, and its dysregulation in autism. My long-term goal is to study the functional importance of synapse diversity on neural circuits and behaviors and develop targeted therapies to alleviate synaptic dysfunction in mental disorders in patients. Additional training obtained during this award in developmental neurobiology (with Dr. Arnold Kriegstein), synaptic biology (with Dr. Robert Edwards), chemogenetics (with Dr. Alice Ting), and advanced machine learning (with Dr. Jingjing Li), combined with my previous experience in rodent models, proteomics, and single-cell genomics will provide me with a solid foundation for an independent research career to achieve my goal.