For several years investigators have sought to link mechanisms of long term potentiation (LTP) to memory. These efforts have typically fallen short because they fail to address the issue of how treatments that influence the capacity for synaptic plasticity affect neural firing patterns related to perception, behavior, as well as cognition and memory. This proposal will address that issue by characterizing firing patterns of neurons in the hippocampus and cortical areas of normal mice and mice with deficient capacity for LTP. Our efforts will focus on N- Methyl-D-Aspartate (NMDA) receptor dependent LTP because NMDA receptors are believed critical to induction of an essential form of plasticity while not required for synaptic transmission that mediates information processing in the cortex and hippocampus. The proposed studies will compare the effects of D-2-amino-5-phosphonopentanoate (AP5), a selective blocker of NMDA dependent LTP, and genetic manipulations that inactivate isoforrns of calcium-calmoduline dependent kinase type 11 (CaMKII) and cyclic adenosine monophosphate (cAMP) responsive element binding protein (CREB), two molecules that are critical to the formation of lasting LTP. Our experimental designs will employ recently developed electrophysiological methods for recording the extracellular activity of multiple neurons simultaneously in behaving mice, and several behavioral techniques we have developed to study spatial and olfactory learning and memory. We will examine the extent to which hippocampal and cortical firing patterns not associated with new learning are maintained in animals with a compromised capacity for LTP, with the hypothesis that non-memory sensory and behavior related neural processing, as well as memory processing associated with short term recognition or working memory and that associated with previously well-learned memories, should be intact (sic). We will also characterize lasting changes in neural firing patterns associated with new learning, with the hypothesis that permanent learning-associated changes will be reduced or prevented in animals with compromised LTP capacity. These findings will provide a comprehensive characterization of the effects of drug and genetic manipulations of LTP on different types of sensory, behavioral, and memory related neural processing. The results will strongly test the view that drug and genetic manipulations of NMDA mediated synaptic plasticity selectively affect memory formation, adding useful evidence on the question of whether the form of LTP is essential for memory.
| Devito, Loren M; Eichenbaum, Howard (2011) Memory for the order of events in specific sequences: contributions of the hippocampus and medial prefrontal cortex. J Neurosci 31:3169-75 |
| DeVito, Loren M; Eichenbaum, Howard (2010) Distinct contributions of the hippocampus and medial prefrontal cortex to the ""what-where-when"" components of episodic-like memory in mice. Behav Brain Res 215:318-25 |
| Devito, Loren M; Kanter, Benjamin R; Eichenbaum, Howard (2010) The hippocampus contributes to memory expression during transitive inference in mice. Hippocampus 20:208-17 |
