LIPID MODULATORS AND LONG TERM HIPPOCAMPAL SYNAPTIC PLASTICITY

Activity-dependent long-term potentiation (LTP) and long-term depression (LTD) of synaptic transmission in the mammalian hippocampus are among the best candidates for the cellular substrates of learning and memory. Although there is general agreement that induction of LTP and LTD requires an elevation of Ca2+ in the postsynaptic CA1 neuron, the precise role of downstream signaling pathways remains less certain. A number of second messenger systems have been proposed to contribute to LTP and LTD, including Ca2+, the gases LO and CO, cAMP, cGMP, and arachidonic acid (AA). In addition, metabotropic glutamate receptor (mGluR) activation has been implicated in both LTP and LTD. Much of the work on signaling mechanisms in LTP and LTD is controversial, in part, because of a lack of unified biochemical and physiological studies. Arachidonic acid (or its metabolites) was proposed to play a role in the induction of LTP because these lipids can acts as retrograde messengers which, when released postsynaptically can alter the function of a presynaptic cell. These lipids are also attractive candidates for signaling in the mGlur pathway, since activation of these receptors stimulate AA release and metabolism. It is our belief that progression in the study of the role of arachidonate metabolites in LTP and LTD requires a combination of sophisticated biochemical and electrophysiological approaches. We propose to perform such experiments in rat and mouse hippocampal slices and cultures, relying on our combined biochemical expertise in the analysis of arachidonate metabolites and experience in physiological recordings of unitary synaptic transmission between pairs of pre- and post synaptic hippocampal neurons. We propose top investigate the following: 1) What is the role of AA and its metabolites in the induction and expression of LTP? 2) What is the role of AA and its metabolites in the induction and expression of LTD? 3) Which subtypes of metabotropic glutamate receptors are involved in LTD? 4) Is LTP or LTD altered in genetically engineered mice deficient in either the 5- or 12-lipoxygenase pathway? A deeper understanding of these biochemical mechanisms will be important for our basic understanding of memory in the mammalian brain and for potential therapeutic targets in the treatment of memory disorders.