2. Synaptic plasticity and memory formation

Experience-dependent changes in synaptic transmission, i.e., synaptic plasticity, form the cellular basis of cognitive functions such as learning and memory. Synaptic plasticity impairment can be devastating and is believed to underlie various psychiatric disorders and neurodegenerative diseases. Using a combination of molecular, cellular, electrophysiological, and behavioral approaches, our laboratory aims to elucidate the signaling pathways that regulate synaptic function in the adult brain under normal and diseased conditions. In particular, we aim to determine how protein phosphorylation relays extracellular signals to modulate synapse formation, maturation, and plasticity.

The dendrites of excitatory neurons are covered by dendritic spines, which are specialized subcellular compartments containing excitatory synapses. Dendritic spines are highly dynamic; their turnover and morphology continue to be modulated through environmental input in the form of synaptic activity, which is central to memory formation and other adaptive changes of the brain. Our laboratory has unraveled a signaling pathway that underlies dendritic spine remodeling during memory formation, which involves cross-talk between the receptor tyrosine kinase (RTK) TrkB  and Cdk5. After binding to BDNF, TrkB is phosphorylated by Cdk5 at neuronal synapses, which then recruits the guanine nucleotide exchange factor Tiam1  and activates the Rho-GTPase Rac1. This promotes re-organization of the actin cytoskeleton that underlies dendritic spine enlargement in response to the neurotransmitter glutamate. Mice lacking this Cdk5-mediated phosphorylation of TrkB consequently exhibit impaired long-term potentiation in the hippocampus and spatial memory in the Morris water maze. To gain further insight into how Cdk5 regulates synaptic plasticity, we are using a proteomic approach to identify novel Cdk5 substrates at the synapse. We will subsequently characterize the consequences of protein knockdown by shRNA and co-expression of wild-type compared to phospho-deficient/mimetic mutants of these putative Cdk5 sunstrates on synaptic function.

 

Another kinase that plays crucial roles in synaptic plasticity and memory formation is PKA. We recently identified melanocortin-4 receptor (MC4R), the cognate receptor of the neuropeptide, α-MSH, as a key player in hippocampal synaptic plasticity in a PKA-dependent manner. MC4R activation enhances synaptic plasticity through the regulation of dendritic spine morphology and abundance of AMPA-subtype glutamate receptors. We are currently characterizing the role of MC4R in hippocampal-dependent learning and memory, and identifying novel MC4R agonists that may act as memory-enhancing agents.

In addition to understanding the mechanisms that underlie synapse potentiation, my laboratory also investigates how synaptic strength is weakened through the loss of dendritic spines and reduction of neurotransmitter receptors at the synapse. We identified EphA4 (an RTK) that negatively regulates excitatory neurotransmission via two mechanisms. EphA4 activation leads to the elimination of dendritic spines through Cdk5-dependent phosphorylation and activation of the Rho-GEF, ephexin1. Moreover, EphA4 triggers the ubiquitination of AMPA receptor subunit GluA1 through the E3 ubiquitin ligase anaphase-promoting complex, resulting in the proteasomal degradation of the ion channels. Loss of dendritic spines and impaired synaptic plasticity are observed in the early stages of Alzheimer's disease before extensive neuronal death. Given the association between impaired synaptic functions and aberrant Cdk5 activity in Alzheimer's disease, we hypothesize the EphA4–Cdk5 pathway is dysregulated in animal models of Alzheimer's disease. To this end, we have identified small molecule inhibitors of EphA4 from a knowledge-based drug discovery program to search for novel drug leads from traditional Chinese medicine. We are currently testing the abilities of these inhibitors to counteract the synaptic loss and impaired synaptic plasticity in various Alzheimer's disease models.

 Research Interests

 1. Neural Development and Circuit Assembly

 3. Drug Discovery

 
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