TY - JOUR
T1 - Cdk5-dependent phosphorylation of liprinα1 mediates neuronal activity-dependent synapse development
AU - Huang, Huiqian
AU - Lin, Xiaochen
AU - Liang, Zhuoyi
AU - Zhao, Teng
AU - Du, Shengwang
AU - Loy, Michael M. T.
AU - Lai, Kwok-On
AU - Fu, Amy K. Y.
AU - Ip, Nancy Y.
PY - 2017/8/15
Y1 - 2017/8/15
N2 - 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 liprinα1 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 liprinα1 at Thr701, this phosphorylation decreases in neurons in response to neuronal activity. Blockade of liprinα1 phosphorylation enhances the structural and functional maturation of excitatory synapses. Nanoscale superresolution imaging reveals that inhibition of liprinα1 phosphorylation increases the colocalization of liprinα1 with PSD-95. Furthermore, disruption of liprinα1 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 liprinα1 is important for the postsynaptic organization during activity-dependent synapse development.
AB - 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 liprinα1 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 liprinα1 at Thr701, this phosphorylation decreases in neurons in response to neuronal activity. Blockade of liprinα1 phosphorylation enhances the structural and functional maturation of excitatory synapses. Nanoscale superresolution imaging reveals that inhibition of liprinα1 phosphorylation increases the colocalization of liprinα1 with PSD-95. Furthermore, disruption of liprinα1 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 liprinα1 is important for the postsynaptic organization during activity-dependent synapse development.
KW - Cyclin-dependent kinase 5
KW - Neurodevelopmental disorders
KW - Neuronal activity
KW - PSD-95
KW - Synaptic plasticity
UR - http://www.scopus.com/inward/record.url?scp=85027416939&partnerID=8YFLogxK
UR - https://www.scopus.com/record/pubmetrics.uri?eid=2-s2.0-85027416939&origin=recordpage
U2 - 10.1073/pnas.1708240114
DO - 10.1073/pnas.1708240114
M3 - RGC 21 - Publication in refereed journal
C2 - 28760951
SN - 0027-8424
VL - 114
SP - E6992-E7001
JO - PNAS: Proceedings of the National Academy of Sciences of the United States of America
JF - PNAS: Proceedings of the National Academy of Sciences of the United States of America
IS - 33
ER -