| The functional role of integrins in the central nervous system (CNS) has focused on their involvement in development, including processes such as cell migration, differentiation, and the control of neurite outgrowth. The role of integrins in the adult nervous system has long thought to be a static one involved in simply anchoring cells to the extracellular matrix and to adjacent cells. We hypothesize that integrins play a much more dynamic role in the mature CNS and that they are active modifiers of neuronal function. There is increasing evidence implicating integrin involvement in mechanisms of synaptic plasticity, such as Long Term Potentiation (LTP), although little is know about the molecular pathways underlying these actions. The research in this dissertation, definitively demonstrates that integrins are expressed, and more specifically are concentrated, at synapses. They are exclusively expressed at excitatory synapses and excluded from inhibitory synapses. Integrin ligation at the synapse increases fast, excitatory synaptic responses by activating CaMKII and modifying the AMPA-type glutamate receptor. Additionally, synaptic integrin binding to ligand peptides and the native α5β1 ligand fibronectin, results in the activation of intracellular signaling molecules such as focal adhesion kinase (FAK), proline-rich tyrosine kinase 2 (Pyk2), and Src family kinases (SFK). Importantly, this integrin signaling pathway activation results in downstream Src family kinase sensitive modification of the NMDA receptor. Therefore, we have shown that synaptic integrin ligation results in an intracellular signaling response that can increase fast, excitatory transmission by modifying AMPA and NMDA subtype glutamate receptors that mediate synaptic transmission and plasticity. |
