Neuronal activity plays an essential role in guiding synapse development, which underlies the experience-dependent shaping of brain circuitry. Synapse development requires the concerted regulation of different types of synaptic components to drive specific functions. However, it is unclear how neuronal activity coordinates this process. Liprinα family proteins, originally identified as protein interactors of the receptor protein tyrosine phosphatase LAR (LAR-RPTP), are suggested to play important roles during dendrite development and synapse maintenance by mediating synaptic component assembly and cargo trafficking. Liprinα1 is further distinguished from other liprinα family members because of its activity-dependent regulation. However, liprinα1 regulation and function during activity-d...[ Read more ]

Neuronal activity plays an essential role in guiding synapse development, which underlies the experience-dependent shaping of brain circuitry. Synapse development requires the concerted regulation of different types of synaptic components to drive specific functions. However, it is unclear how neuronal activity coordinates this process. Liprinα family proteins, originally identified as protein interactors of the receptor protein tyrosine phosphatase LAR (LAR-RPTP), are suggested to play important roles during dendrite development and synapse maintenance by mediating synaptic component assembly and cargo trafficking. Liprinα1 is further distinguished from other liprinα family members because of its activity-dependent regulation. However, liprinα1 regulation and function during activity-dependent synapse development remain elusive. The present study found that in vivo, liprinα1 is highly expressed at postsynaptic regions and is a cyclin-dependent kinase 5 (Cdk5) substrate. Interestingly, liprinα1 phosphorylation in the mouse visual cortex declined during eye-opening which was blocked by dark rearing, suggesting its involvement in activity-dependent synapse development. Importantly, liprinα1 phosphorylation plays a negative role in both spine maturation and AMPA receptor surface expression. Disruption of liprinα1 phosphorylation facilitates dendritic spine growth and enhances synaptic plasticity. The underlying mechanism was further resolved by demonstrating the regulation of PSD-95 synaptic localization after modulating liprinα1 phosphorylation. The functional significance of liprinα1 was also examined in vivo, which showed impairment in spine morphogenesis and synaptic plasticity after loss of liprinα1. The results collectively reveal a novel mechanism of activity-dependent synapse development mediated by Cdk5-dependent liprinα1 phosphorylation.