Part I: Trans-synaptic interaction of PTPRD is critical for synaptic developmentFormation of the synapse is arguably the most important event in brain development. Many pre- and post-synaptic proteins have been discovered and studied, but who’s who in the criticality of roles is as of yet unclear. Among the more renown candidates of synaptic formation are the axon-guidance LAR-RPTPs, of which PTPRD is a member. Here we study in depth the synaptic role of PTPRD, where we show that PTPRD is present in the excitatory presynapse and that deletion of PTPRD results in significant electrophysiological and structural impairments of PTPRD-rich brain regions such as the SLM of the hippocampus. These impairments are accompanied by major biochemical changes of, among others, IL1ApL1’s phosphorylation state in two novel residues. The synaptic changes seen in KO mice largely translate to severe disruptions in behavior, which clearly segregates into excitatory and inhibitory circuits as defined by EMX1-cre and Viaat-cre, but not CamKIIalpha-cre, conditional deletion. Of the many behavioral changes, whole KO and EMX1-cre KO mice both displayed increased activity during the first 6 hours of the inactive phase, and reduction of NREM sleep duration along with significant decrease in delta band power. These result, ranging from structural to behavioral, all suggest a criticality of PTPRD in the development of the synapse.
Part II: Sexually dimorphic behavior, neuronal activity, and gene expression in Chd8-mutant miceAutism spectrum disorders (ASDs) are four times more common in males than in females, but the underlying mechanisms are poorly understood. Here we report sexually dimorphic changes in mice carrying a heterozygous mutation in Chd8 ($Chd8^{+/N2373K}$) identified in human CHD8 (Asn2373LysfsX2), a strong ASD-risk gene encoding a chromatin remodeler. Notably, whereas male mutant mice display a range of abnormal behaviors during pup, juvenile, and adult stages, including enhanced mother-seeking ultrasonic vocalization, enhanced attachment to reunited mothers, and isolation-induced self-grooming, female counterparts do not. This behavioral divergence is associated with sexually dimorphic changes in neuronal activity, synaptic transmission, and transcriptomic pro-files. Specifically, female mice display suppressed baseline neuronal excitation, enhanced inhibitory synaptic transmission and neuronal firing, and increased expression of genes associated with extracellular vesicles and the extracellular matrix. These results suggest that a human CHD8 mutation leads to sexually dimorphic changes ranging from transcription to behavior in $Chd8^{+/N2373K}$ mice.