Precise development of synapses, the contacting sites between neurons, is an indispensable event for proper neural wiring and neurotransmission. The dysfunction of synapses could lead to deficits in learning and memory in a range of neurological diseases, such as Alzheimer’s disease. Synapse development is tightly linked to the morphological changes of the tiny protrusions found along neuronal dendrites—dendritic spines. Eph receptors, including EphAs and EphBs, belong to the largest family of receptor tyrosine kinases and play vital roles in synapse development. Our lab has previously reported that a serine/threonine kinase cyclin-dependent kinase 5 (Cdk5) regulates the EphA4-dependent synaptic maintenance. Therefore, it is of particular interest to investigate whether and how...[ Read more ]

Precise development of synapses, the contacting sites between neurons, is an indispensable event for proper neural wiring and neurotransmission. The dysfunction of synapses could lead to deficits in learning and memory in a range of neurological diseases, such as Alzheimer’s disease. Synapse development is tightly linked to the morphological changes of the tiny protrusions found along neuronal dendrites—dendritic spines. Eph receptors, including EphAs and EphBs, belong to the largest family of receptor tyrosine kinases and play vital roles in synapse development. Our lab has previously reported that a serine/threonine kinase cyclin-dependent kinase 5 (Cdk5) regulates the EphA4-dependent synaptic maintenance. Therefore, it is of particular interest to investigate whether and how Cdk5 and its activator p35 regulate EphB-mediated synapse formation.

In this study, we discovered a novel function of EphB in mature neurons on regulating an important excitatory neurotransmitter receptor—the AMPA receptor (AMPAR). In particular, EphB activation not only augments the phosphorylation, surface expression and synaptic recruitment of the GluA1 subunit of AMPAR, but also exhibits functional enhancement on AMPAR-mediated neurotransmission. In addition, we found that Cdk5/p35 interacts with EphB2 receptor in a ligand-dependent manner. Moreover, EphB also enhances Cdk5 activation through the tyrosine phosphorylation of Cdk5. Intriguingly, Cdk5/p35 indeed mediates a variety of EphB-dependent processes. Firstly, the knockdown of p35 abolished the robust concomitant increases in both mature dendritic spines and functional synapses induced by EphB activation. More importantly, Cdk5/p35 is also imperative for the EphB-mediated regulations on AMPAR. Despite the exact mechanisms requires further investigations, these data collectively suggest the critical roles of Cdk5/p35 in EphB-mediated synapse development and trafficking of postsynaptic proteins.