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A Trafficking Protein Regulates Distribution of Postsynaptic Scaffolding Proteins to the Distal Dendrites of CNS Excitatory Neurons
Chemical synapses are junctions between neurons that allow transmission of chemical signals. In the brain, dendritic spines are membrane protrusions emanating from dendritic shafts of excitatory neurons that form synapses with axonal terminals of another neuron and provide major sites for excitatory inputs. Postsynaptic scaffold proteins are crucial for the structural and functional integrity of dendritic spines. In highly polarized neurons, how these proteins that are synthesized in the cell body are properly distributed to the dendrites is largely unexplored.
SNX6 is a member of the sorting nexins, a protein family involved in protein sorting and trafficking. Previous studies showed that in cultured epithelial cells, SNX6 serves as adaptor for the molecular motor dynein‒dynactin in transport of vesicular cargoes from endosomes to the trans-Golgi network.
A recent study conducted by researchers at Dr. SHI Yun’s team from Nanjing University and Dr. LIU Jia-Jia’s Lab from the Institute of Genetics and Developmental Biology of Chinese Academy of Sciences demonstrated that ablation of SNX6 in the central nervous system (CNS) causes loss of the postsynaptic scaffold protein Homer1b/c from distal dendrites and defects in synaptic function of hippocampal CA1 pyramidal cells in mice. This work was published in eLife.
Knockout of Snx6 in mouse brain causes deficits in spatial learning and memory, a hippocampus-dependent higher brain function. At the cellular level, there is a decrease in the spine density of distal dendrites, and impairment in synaptic transmission mediated by the glutamate receptor AMPAR in hippocampal CA1 pyramidal neurons. SNX6 interacts with Homer1b/c, one of the most abundant postsynaptic scaffold proteins that plays important roles in not only the formation and stability of dendritic spines, but also regulation of AMPAR expression in the postsynaptic membrane. Ablation of SNX6 causes impairment in the motility of vesicles carrying Homer1b/c in the dendritic shaft, and a reduction in its distribution in dendrites distal to the cell body.
This work demonstrated a physiological function of SNX6 in the CNS. Moreover, the spatial memory deficits exhibited in Snx6 null mouse indicate that synaptic plasticity is impaired in knockout neurons. As synaptic plasticity is the molecular and cellular basis for learning and memory, these findings could provide a new path to investigate whether SNX6 mediates transport of plasticity-related proteins and how SNX6-mediated vesicular transport of synaptic proteins is regulated in response to synaptic activity and plasticity.
This work was supported by grants from the National Natural Science Foundation of China, Chinese Academy of Sciences and the Ministry of Science and Technology.
Niu, Y., Dai, Z., Liu, W., Zhang, C., Yang, Y., Guo, Z., Li, X., Xu, C., Huang, X., Wang, Y., Shi, Y. S., Liu, J-J. Ablation of SNX6 leads to defects in synaptic function of CA1 pyramidal neurons and spatial memory. eLife. 2017 Jan 30;6. pii: e20991. doi: 10.7554/eLife.20991. [Epub ahead of print]
Dr. LIU Jia-Jia