The activity of many different types of molecules is required in specific neurons as animals learn and form new memories. Few of the many molecules involved have been identified and studied carefully to understand their specific roles in memory formation. The research proposed here is directed at understanding the roles for one class of cell adhesion receptors, the integrins, in synaptic and behavioral plasticity. Previous research has demonstrated an intriguing and novel relationship between the function of certain types of integrins and working memory. Mice deficient in integrin function in the adult forebrain will be tested in different types of working memory assays to gather a deeper knowledge of the extent and specificity of the working memory deficiency. The signal transduction pathway involving integrins will be dissected genetically to identify the ligands with which integrins interact for normal working memory, as well as the kinases that are downstream of integrins in working memory. Deeper insights into associated synaptic plasticity deficits will be gathered from electrophysiological studies of hippocampal neurons in integrin mutants and mutants of putative integrin ligands and downstream signaling kinases. The brain regions that require normal integrin function for normal working memory will be identified. Overall, these studies will contribute significantly to the goal of understanding the roles of integrins and other integrin signaling molecules in the processes underlying working memory, other forms of memory, and synaptic plasticity. Working memory is one type of memory that is known to be impaired in certain human conditions to include Alzheimer's disease, schizophrenia, and normal aging. This research will advance the understanding of the molecules and genes that are required for normal working memory. Insights for the improvement of the diagnosis and treatment of diseases of working memory may be gathered from these studies. ? ? ?
