THESIS
2012
xix, 154 p. : ill. (some col.) ; 30 cm
Abstract
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...[
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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.
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