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M.S., Peking University - 2010
Thesis Advisor: Huaye Zhang, Ph.D.
Graduate Program in Neuroscience
Friday, March 6, 2015
Dendritic spines are specialized protrusions on neurons that receive most of the excitatory synaptic inputs in the mammalian brain. The morphogenesis and plasticity of spines are believed to play a key role in cognitive functions. The loss or alterations of spines are linked to many psychiatric and neurological diseases, such as autism spectrum disorders (ASD), schizophrenia and Alzheimer’s disease (AD).
The polarity protein partitioning defective1 (Par-1), also called microtubule-affinity regulating kinase (MARK), plays an essential role in many cellular contexts including embryogenesis, asymmetric cell division, directional migration, and epithelial morphogenesis. Despite its known importance in different cellular processes, the role of Par-1/MARK in neuronal morphogenesis is less well understood.
In this project, we found Par-1/MARK is required for normal spine morphogenesis in hippocampal neurons. In addition, we found that Par-1/MARK functions through phosphorylating the synaptic scaffolding protein PSD-95 at Ser561 in its GK domain. Furthermore, we found that Ser561 phosphorylation of PSD-95 is downstream of Par-1/MARK in regulating spine morphogenesis.
We then examined how Ser561 phosphorylation regulates PSD-95 function. We found that Ser561 phosphorylation promotes the intramolecular interaction between the GK domain and the adjacent SH3 domain, leading to a closed conformation of PSD-95. By contrast, a non-phosphorylatable S561A mutant show decreased SH3-GK interaction, causing PSD-95 to adopt an open conformation. This open conformation facilitates the interaction between PSD-95 and its binding partners and stabilizes it at the synapse. Moreover, we show that Ser561 phosphorylation is required for dendritic spine structural plasticity during long-term potentiation and long-term depression.
Finally, we found that Par-1b/MARK2 knockout mice showed impaired dendritic spine morphogenesis. Additionally, Par-1b/MARK2 knockout mice showed a decrease synaptic transmission with a decrease in mEPSC and VGLUT1 immunoreactivity. Moreover, we show that Par-1b/MARK2 knockout mice exhibit impaired social interaction and poor performance in learning and memory tests.
Together, our findings show an important role of Par-1/MARK in synaptogenesis and plasticity both in vitro and in vivo. In addition, our findings provide novel mechanistic insight into the regulation of PSD-95 in synaptic plasticity through a phosphorylation-mediated conformational switch.