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The Par3 polarity protein is critical for subcellular compartmentalization in different developmental processes. Variants of PARD3 , encoding PAR3, are associated with intelligence and neurodevelopmental disorders. However, the role of Par3 in glutamatergic synapse formation and cognitive functions in vivo remains unknown. Here, we show that forebrain-specific Par3 conditional knockout leads to increased long, thin dendritic spines in vivo . In addition, we observed a decrease in the amplitude of miniature excitatory postsynaptic currents. Surprisingly, loss of Par3 enhances hippocampal-dependent spatial learning and memory and repetitive behavior. Phosphoproteomic analysis revealed proteins regulating cytoskeletal dynamics are significantly dysregulated downstream of Par3. Mechanistically, we found Par3 deletion causes increased Rac1 activation and dysregulated microtubule dynamics through CAMSAP2. Together, our data reveal an unexpected role for Par3 as a molecular gatekeeper in regulating the pool of immature dendritic spines, a rate-limiting step of learning and memory, through modulating Rac1 activation and microtubule dynamics in vivo ., Competing Interests: The authors declare no competing interests., (© 2024 The Authors.)

Autism Spectrum Disorders (ASD) and schizophrenia are distinct neurodevelopmental disorders that share certain symptoms and genetic components. Both disorders show abnormalities in dendritic spines, which are the main sites of excitatory synaptic inputs. Recent studies have identified the synaptic scaffolding protein Shank3 as a leading candidate gene for both disorders. Mutations in the SHANK3 gene have been linked to both ASD and schizophrenia; however, how patient-derived mutations affect the structural plasticity of dendritic spines during brain development is unknown. Here we use live two photon in vivo imaging to examine dendritic spine structural plasticity in mice with SHANK3 mutations associated with ASD and schizophrenia. We identified shared and distinct phenotypes in dendritic spine morphogenesis and plasticity in the ASD-associated InsG3680 mutant mice and the schizophrenia-associated R1117X mutant mice. No significant changes in dendritic arborization were observed in either mutant, raising the possibility that synaptic dysregulation may be a key contributor to the behavioral defects previously reported in these mice. These findings shed light on how patient-linked mutations in SHANK3 affect dendritic spine dynamics in the developing brain, which provides insight into the synaptic basis for the distinct phenotypes observed in ASD and schizophrenia., (Copyright © 2023 IBRO. Published by Elsevier Ltd. All rights reserved.)