? Regulation of the strength of synaptic transmission is postulated to play a critical role in processing and storage of information in the brain. Structural and functional modifications of the synapse contribute to changes in strength of transmission. However, the biochemical mechanisms that regulate synaptic plasticity remain poorly understood. Various growth factors have been shown to influence synaptic structure and function, but many of the downstream effects of the signals they induce have not been identified. Our long-term objective is to understand the molecular signals initiated by growth factors at synapses, and identify how these signals regulate synaptic structure as it relates to learning and memory. We have strong Preliminary Data that demonstrates that the receptor protein tyrosine kinase Met and its ligand, hepatocyte growth factor (HGF), are clustered at excitatory synapses in hippocampal neurons. We demonstrate that neuronal activity leads to release of HGF and activation of Met. Met is known to influence many aspects of cellular morphology, and we show that exogenous HGF increases the clustering of presynaptic and postsynaptic proteins at synapses, increases the expression of synaptic proteins, and initiates acute and long-term changes in neurons. This proposal represents an initial step in characterizing the regulation of synaptic biochemistry by hepatocyte growth factor and Met. In the first aim, the subcellular location of Met and HGF will be identified to determine whether these signaling molecules operate at the presynaptic or postsynaptic membrane, and whether HGF is located in vesicles that undergo regulated secretion. In the second aim, the secretion of HGF in response to pharmacological activation of synaptic activity will be quantified and mechanisms regulating its release will be identified.
The third aim i s to test the acute effects of HGF on synapses with the use of live-cell imaging and biochemical studies. In the fourth aim, the signaling pathways initiated by HGF and Met to regulate glutamate receptor trafficking will be identified. These studies will provide the basis for further studies on the mechanisms by which Met regulates synaptic structure. ? ?
| Lim, Chol Seung; Walikonis, Randall S (2008) Hepatocyte growth factor and c-Met promote dendritic maturation during hippocampal neuron differentiation via the Akt pathway. Cell Signal 20:825-35 |
| Tyndall, Stephanie J; Walikonis, Randall S (2007) Signaling by hepatocyte growth factor in neurons is induced by pharmacological stimulation of synaptic activity. Synapse 61:199-204 |
| Tyndall, Stephanie J; Patel, Sandip J; Walikonis, Randall S (2007) Hepatocyte growth factor-induced enhancement of dendritic branching is blocked by inhibitors of N-methyl-D-aspartate receptors and calcium/calmodulin-dependent kinases. J Neurosci Res 85:2343-51 |
| Tyndall, Stephanie J; Walikonis, Randall S (2006) The receptor tyrosine kinase Met and its ligand hepatocyte growth factor are clustered at excitatory synapses and can enhance clustering of synaptic proteins. Cell Cycle 5:1560-8 |
