Application) We will use a genetic approach to test a number of popular ideas about the mechanisms of synaptic plasticity, specifically the well-studied phenomenon of long term potentiation, LTP, and long term depression, LTD. The development of technology to induce null mutations in genes specifically in the CAI region and after completion of brain development has provided strong evidence that LTP is necessary for the development of spatial memory and a proper representation of space in the CA1 region of the hippocampus. Thus, there is mounting evidence that synaptic plasticity underlies memory and learning and other cognitive functions. Synaptic plasticity is likely to play an important role in the proper development of the brain and it is possible that aberrations in synaptic plasticity play a role in mental illnesses such as schizophrenia and depression. There is also growing experimental support for the idea that synaptic alterations underlie the long-term changes in brain function observed in animals and humans exposed to drugs of abuse and addiction. Understanding the mechanisms of synaptic plasticity at the detailed molecular level will lead to new tools to explore cognitive function at a higher level and to the development of better therapeutic drugs directed to relevant molecular targets. The experiments depend critically on mutant mice and genetic engineering technology generated at MIT in the Tonegawa laboratory. The new multiple recording methods developed in the Wilson laboratory at MIT are essential for the behavioral analysis of the mutant mice. The expertise and collaboration of Drs. Bear (Brown) and Lin (MIT) are vital for the efficient analysis of synaptic plasticity (LTP, LTD) in the mutant mice.
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