Loss of the polarity protein Par3 promotes dendritic spine neoteny and enhances learning and memory

The Par3 polarity protein is critical for subcellular compartmentalization in different developmental processes. Variants of PARD3, which encodes 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 conditional knockout of Par3 leads to an increase in long, thin dendritic spines without significantly impacting mushroom spines in vivo. In addition, we observed a decrease in the amplitude of miniature excitatory postsynaptic currents. Surprisingly, loss of Par3 in vivo enhances hippocampal- dependent spatial learning. Phosphoproteomic analysis revealed proteins regulating cytoskeletal dynamics are significantly dysregulated downstream of Par3. Mechanistically, we found Par3 deletion causes increased activation of the Rac1 pathway. 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 in vivo.