Evidence suggests that integrins may be critical to the establishment and maintenance of neuronal networks. Integrins are involved in the directed migration of both neurons and their processes, and a number of studies suggest they are also involved in the stabilization of synapses. The ability of integrins to play a role in neural networking is understandably influenced by the nature and availability of integrin binding ligands. These ligands include cell surface receptors, soluble molecules such as the semaphorins, and select proteins of the extracellular matrix (ECM). Recent studies have shown that both neural networking and the availability of integrin binding ligands may be altered in the setting of central nervous system (CNS) inflammation. For example, in simian immunodeficiency virus encephalitis (SIVE), synaptic damage and loss of perineuronal matrix has been demonstrated. Similarly, in human immunodeficiency dementia, a loss of dendritic arbor has been observed. And with respect to changes that may occur in development, in utero infection with cytomegalovirus has been linked to disrupted cortical organization. While multiple mechanisms are likely to contribute to disordered neural networking in the context of inflammation, matrix metalloproteinase (MMP) mediated changes in integrin function are likely to play an important role. MMPs degrade constituents of the ECM that are known to interact with integrins, and select MMPs have also been shown to directly associate with cell surface integrins. In the present proposal, we outline plans to test the hypothesis that MMPs will interfere with neuronal migration and with the formation or maintenance of synapses. We will also test the hypothesis that such effects are dependent on neuronal integrins. The results of our studies should improve our understanding of those CNS inflammatory diseases that are characterized by elevated levels of MMPs. ? ? ?
