Title

A role for hepatocyte growth factor and Met at excitatory synapses

Date of Completion

January 2005

Keywords

Biology, Neuroscience

Degree

Ph.D.

Abstract

Activity-dependent structural and functional modifications to synapses and dendrites provide a biological model of learning and memory. However, the full range of factors and mechanisms that may link synaptic activity to structural and functional changes of synapses and dendrites remains poorly understood. In this study we demonstrate that hepatocyte growth factor is expressed in hippocampal neurons and that Met, its receptor, is clustered at the postsynaptic density of excitatory synapses. In epithelial cells, HGF and Met regulate protein synthesis, facilitate organization of intracellular junctions, and alter cytoskeletal and therefore are good candidates for involvement in neural plasticity. We explore HGF expression and signaling in response to pharmacologically induced neural activity in cultured hippocampal neurons. These treatments induced increased levels of proteolytically activated HGF and induced HGF signaling. To examine the effects of HGF on synaptic signaling pathways and post synaptic and dendritic morphology, exogenous HGF was added to dissociated hippocampal neurons. HGF treatment rapidly increased synaptic and dendritic calcium levels and also induced acute phosphorylation of NR2B, CaMKII and NR1. Additionally, neurons treated with HGF had enhanced dendritic arbors compared to those treated with vehicle alone. Finally we explore the mechanisms involved in HGF induced structural modifications. Inhibition with the NMDA receptor inhibitor APV blocks the HGF induced changes in synaptic calcium levels and enhancements of dendritic arbor. These data strongly suggest that HGF signaling can be induced through neural activity and that HGF modifies dendritic structure through activation of the NMDA receptor. ^