The precise regulation of synaptic plasticity is crucial for the proper functioning of the nervous system. For example, changes in the molecular composition of the postsynaptic region regulate synaptic plasticity, which underlies learning and memory. This change in the postsynaptic composition is suggested to be in part dependent on the phosphorylation of specific proteins by kinases such as the serine/threonine kinase cyclin-dependent kinase 5 (Cdk5). To better understand how Cdk5 regulates synaptic plasticity, it is important to identify new substrates of Cdk5 and characterize their functions. Liprinα1, a member of the Liprinα family, interacts with the LAR family of transmembrane protein tyrosine phosphatases, which are important for synapse maintenance. Our laboratory previ...[ Read more ]

The precise regulation of synaptic plasticity is crucial for the proper functioning of the nervous system. For example, changes in the molecular composition of the postsynaptic region regulate synaptic plasticity, which underlies learning and memory. This change in the postsynaptic composition is suggested to be in part dependent on the phosphorylation of specific proteins by kinases such as the serine/threonine kinase cyclin-dependent kinase 5 (Cdk5). To better understand how Cdk5 regulates synaptic plasticity, it is important to identify new substrates of Cdk5 and characterize their functions. Liprinα1, a member of the Liprinα family, interacts with the LAR family of transmembrane protein tyrosine phosphatases, which are important for synapse maintenance. Our laboratory previously found that liprinα1 is highly expressed in postsynaptic regions and can be phosphorylated by Cdk5. Liprinα1 knockdown in hippocampal neurons by shRNA significantly reduces dendrite number and dendritic spine protrusion density, which can be rescued by the overexpression of RNAi-resistant wild-type liprinα1. Importantly, liprinα1 phosphorylation dramatically reduces the density of spines and impairs their maturation. In the present study, to further elucidate the function of liprinα1 phosphorylation, a small interfering peptide that specifically blocks liprinα1 phosphorylation was designed. Blockade of liprinα1 phosphorylation by the small interfering peptide promoted spine morphogenesis and maturation. Moreover, blockade of liprinα1 phosphorylation strengthened the interaction between liprinα1 and PSD-95. Furthermore, treating acute mouse hippocampal slices with the interfering peptide enhanced synaptic plasticity as revealed by enhanced long-term potentiation. These findings collectively reveal an important role of the Cdk5-mediated phosphorylation of liprinα1 in hippocampal synaptic functions and plasticity.