| In the central nervous system, chemical synapses are highly specialized junctions that are known to be critical for communication between neurons. The ability of synapses to change their physiological and structural properties, known as synaptic plasticity, is important for storing information in neural connections. Dendritic spines are small protrusions on dendrites where the majority of glutamatergic synapses form in the brain. In general, a dendritic spine has an enlarged head region that is connected to the dendritic shaft by a narrow neck. This geometry allows spines to function as individual biochemical compartments and control postsynaptic signaling events. Recent evidence indicates that structural remodeling of spines and the formation of new synaptic contacts may lead to long-term changes in synaptic function including long-term potentiation (LTP) and long-term depression (LTD). These forms of synaptic plasticity are believed to contribute to cognitive processes such as learning and memory. Interestingly, the actin cytoskeleton is enriched in dendritic spines and its turnover contributes to spine shape and motility. A variety of signaling proteins associate with the actin cytoskeleton and are likely critical for controlling the morphological plasticity of spines. However, the molecular mechanisms that regulate actin-based spine dynamics remain unclear. My studies revealed novel pathways downstream of the EphA class of receptor tyrosine kinases that are important for regulating spine plasticity. I showed that PLCgamma1 physically interacts with the EphA4 receptor tyrosine kinase and links EphA4 to the downstream actin depolymerizing/severing protein, cofilin. PLCgamma1 signaling is critical for maintaining spine morphology and PLC activity is required for spine retraction caused by ephrin ligand binding to EphA4. Remarkably, the amount of cofilin associated with the cell membrane is regulated by PLC and EphA4 activity. Furthermore, I found that ephrin binding to EphA receptors cause the dephosphorylation and activation of cofilin through the phosphatases slingshot (SSH) and calcineurin. Both of the phosphatases are needed for EphA-mediated reorganization of actin filaments and dendritic spine remodeling. These studies contribute new insight into the intricate signaling mechanisms downstream of EphA receptors that control the local remodeling of the actin cytoskeleton in dendritic spines and structural plasticity of excitatory synapses in the central nervous system. |
