A multi-omic atlas of dendritic spine morphometry across postnatal development in neurotypical and ASD subjects (Multi-omic ASD)

About This Grant

Sensory processing alterations, motor stereotypies, and impaired social interactions are the core characteristics of autism spectrum disorder (ASD), implicating multiple cortical regions including the prefrontal cortex (PFC) and primary visual cortex (V1). Hundreds of ASD risk genes have been identified by unbiased genetic studies, many linked to synaptic protein networks. Bulk tissue and single nuclear RNAseq investigations of cortical regions in idiopathic ASD, conducted by us and others, further implicate synaptic protein networks as well as other processes that regulate synaptic strength and pruning: astrocytes and microglia. Interestingly, we observed larger transcriptional alterations in V1, which undergoes pruning earlier in postnatal development, compared to the PFC. Dendritic spine structure and function are critical for cortical processing. Spines are highly dynamic across postnatal neurodevelopment regulated locally by synaptic protein networks and externally by microglia and astrocytes through multiple interconnected mechanisms. Increased density of immature spines and/or synapses has been reported in three small cohort studies of cortical tissue from idiopathic ASD subjects. These cytoarchitectonic alterations are widely theorized to underly cortical processing impairments in ASD. However, despite the clear importance of spine dynamics in both neurotypical (NT) and ASD, spine maturation and its direct mediators have not been mapped in the human brain across typical or ASD postnatal development. Our preliminary investigations found robust alterations in the trajectory of V1 synaptosome protein levels across postnatal development in ASD. Here, we address this critical gap by interrogating the trajectories of synaptic protein network features (protein expression, synaptosome levels, and phosphorylation) (Aim 1); dendritic spine density and size in proximity to microglia and astrocytes (Aim 2) whose state is finely parsed by spatial transcriptomics in the same tissue section (Aim 3) across postnatal development and laminae in PFC and V1, two regions implicated in ASD but with distinct maturation rates and molecular pathologies. Findings will be mapped across all three data sets to generate an atlas of synaptic protein network features, spine maturation, and cellular (e.g. astrocyte and microglia) state across NT and ASD postnatal development in the PFC and V1 and made available via an interactive web portal as a resource of the field (Aim 4).