Cdk5-dependent phosphorylation of liprinα1 mediates neuronal activity-dependent synapse development

The experience-dependent modulation of brain circuitry depends on dynamic changes in synaptic connections that are guided by neuronal activity. In particular, postsynaptic maturation requires changes in dendritic spine morphology, the targeting of postsynaptic proteins, and the insertion of synaptic neurotransmitter receptors. Thus, it is critical to understand how neuronal activity controls postsynaptic maturation. Here we report that the scaffold protein liprin alpha 1 and its phosphorylation by cyclin-dependent kinase 5 (Cdk5) are critical for the maturation of excitatory synapses through regulation of the synaptic localization of the major postsynaptic organizer postsynaptic density (PSD)-95. Whereas Cdk5 phosphorylates liprin alpha 1 at Thr701, this phosphorylation decreases in neurons in response to neuronal activity. Blockade of liprin alpha 1 phosphorylation enhances the structural and functional maturation of excitatory synapses. Nanoscale superresolution imaging reveals that inhibition of liprin alpha 1 phosphorylation increases the colocalization of liprin alpha 1 with PSD-95. Furthermore, disruption of liprin alpha 1 phosphorylation by a small interfering peptide, siLIP, promotes the synaptic localization of PSD-95 and enhances synaptic strength in vivo. Our findings collectively demonstrate that the Cdk5-dependent phosphorylation of liprin alpha 1 is important for the postsynaptic organization during activity-dependent synapse development.