The cellar basis of memory is thought to lie in synaptic plasticity. Many neurons of the CNS, in response to relatively brief patterns of physiological stimulation, can reset the efficiency of synaptic transmission at individual synapses. Such synaptic plasticity is readily observed in brain regions that are concerned with memory, and shows many characteristics expected of a mechanism for the storage of memories, including persistence and synapse-specificity. A particularly interesting form of synaptic plasticity is long-term potentiation (LTP), which can last for months in the intact animal, and for many hours in the more accessible brain slice preparation. In this laboratory, we study the cellular processes that establish and maintain LTP in the rodent hippocampus. We expect our research to shed light on the mechanisms of normal memory formation, as well as those underlying pathological conditions associated with memory impairment (dementia) and overly-intense memories (post-traumatic stress disorder and drug addiction). Current projects include:

• The detailed analysis of the roles of signaling pathways in LTP induction. The conditioning stimulation that establishes LTP also produces a transient activation of multiple signaling pathways in the postsynaptic cell. Many of these pathways are required for the induction of LTP, as shown by the vulnerability of LTP to numerous enzyme inhibitors during this period. The identification of so many essential molecules (mainly protein kinases) indicates a high degree of interaction between the pathways, and poses the challenge of reconstructing the complex signaling network that establishes LTP. Particular features of this network that we study include a cyclic AMP-operated phosphatase gate that controls signal flow through the Ca 2+ /calmodulin kinase II (CaMKII) pathway (Blitzer et al., 1998), and a bimodal role of MAP kinase in the activation and synthesis of CaMKII (Giovannini et al., 2001).
• The identification of the cellular processes that maintain LTP. The signaling network that establishes LTP is not what maintains it. Following the induction phase when LTP is so vulnerable to protein kinase inhibitors, LTP enters a remarkably stable maintenance stage. What cellular activities are responsible for maintaining LTP for extended periods? Compared to the process of LTP induction, relatively little is known on this topic. However, one consistent finding is that LTP (and memory) cannot survive more than a few hours without protein synthesis. We are studying how protein synthesis is regulated during LTP, and have identified a translation control mechanism that is activated in the dendrites of neurons undergoing LTP. This is the mTOR pathway, which affects translation at the initiation step (Tsokas et al., Soc. for Neurosci. Abstr. 583.15, 2003). We are also studying a novel cellular process that may represent another strategy for the neuron to regulate protein synthesis in the dendrites: the activation of translationally repressed mRNAs in response to LTP-inducing stimulation. The control of translation within dendrites promises to help us understand how LTP can be both synapse-specific and dependent on protein synthesis.
• Exploring the contribution of LTP to opiate addiction. The process of drug addiction is thought to include a learning component, which may be particularly evident in the intense psychological need for the drug that is termed craving. A major cause of relapse during withdrawal, craving can persist for years after physiological dependence has been reversed. What is the physiological basis for such an aberrantly strong form of learning? In experiments done in rats in vivo, we are determining how opiate administration and withdrawal affects the strength of LTP. Our driving hypothesis is that LTP is facilitated by periods of withdrawal, due to opiate-induced sensitization of the ascending noradrenergic projection to the hippocampus and related changes in hippocampal cAMP levels. By opening the phosphatase gate (described above), high levels of postsynaptic cyclic AMP are expected to enhance LTP by boosting the CaMKII activity.