Elucidating the biological basis of learning and memory is a goal critical to our understanding of both brain and behavior. Whether the ultimate goal of such research is the development of artificial systems with brain-like capabilities, or gaining insight into the diseased brain, this basic knowledge is indespensible. The most popular and successful model of learning-related plasticity in the mammalian brain is called long-term potentiation (LTP). We have learned a great deal about the cellular and molecular mechanisms of LTP induction, but are still in the dark as to whether LTP (or something like it) is really responsible for learning and memory. One consistent finding across laboratories and procedures is that the calcium concentration within neurons activated by high-frequency stimulation must be elevated for LTP to occur. We are therefore focusing our research efforts on two calcium dependent enzymes which could be critical for learning and memory; nitric oxide synthase (NOS) and calcium/calmodulin dependent protein kinase II (CaMKII). Specifically, since these enzymes are both activated by the same signal, but perform very different functions, we are exploring the hypothesis that NO and CaMKII act synergistically within neurons during LTP. Using pharmacological and electrophysiological techniques in living brain slices taken from mice which carry targeted mutations to the gene that produces a CaMKII, we are examining the conditions under which inhibitors of NOS impair LTP in two brain regions strongly associated with learning and memory. The studies are elucidating not only the interaction of the two enzymes, but the generality of their function in different brain regions, and their role in a simple form of learning. In doing so, we will be able to focus on those cellular and molecular processes that are most important for mammalian learning and memory.
