Cellular and molecular mechanisms of hippocampus-dependent long -term memory

Sonja Blum, The University of Texas Graduate School of Biomedical Sciences at Houston


The hippocampus is a brain structure involved in the formation of new memories. The cellular and molecular mechanisms of hippocampus-dependent memory formation have been intensely studied, and growth factor signaling has emerged as an essential component of this process. Growth factors activate three major intracellular signaling pathways: extracellular signal-regulated kinase (ERK), phosphoinositide-3 (PI-3) kinase, and phospholipase C gamma 1 (PLCγ1). Activation of these pathways can alter gene expression and protein synthesis, which are required for long-term memory formation. Whereas the roles of ERK and PI-3 kinase in hippocampus-dependent memory have been investigated, the role of PLCγ1 is unknown. As there is no isoform specific pharmacological inhibitor of PLCγ1, a PLCγ1 binding peptide sequence mimicking an activated growth factor receptor was used to interfere with PLCγ1 signaling. The peptide was made cell-permeable by addition of the TAT-HIV cell transduction domain. Using behavioral training in the Morris water maze, a hippocampus-dependent task, and targeted intra-hippocampal administration of the peptide, the influence of PLCγ1 inhibition on long-term spatial memory was assessed. The results demonstrate that interference with the PLCγ1 cascade significantly impairs long-term memory, without affecting acquisition of the task. It is thought that the hippocampus plays only a transient role in memory formation, and after a time, memories may become hippocampus-independent. The neocortex is thought to support the storage of remote memories, but the cellular and molecular mechanisms of neocortical memory storage are largely unknown. We used trace fear conditioning, a hippocampus-dependent task which also requires the integrity of the medial prefrontal cortex (mPFC), to examine if remote memory requires plasticity in this neocortical region from the time of training. Training in trace fear conditioning results in an increase in activity of ERK within the mPFC, similar to observations in the hippocampus. Remote memory was impaired by intra-mPFC inhibition of training-induced ERK activation. In addition, post-training inhibition of protein synthesis in the mPFC, impaired remote memory tested 30 days later. These results demonstrate that long-term trace fear memory is stored in the mPFC from the time of training, and that this storage is required for recall of both recent and remote memory.

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Recommended Citation

Blum, Sonja, "Cellular and molecular mechanisms of hippocampus-dependent long -term memory" (2005). Texas Medical Center Dissertations (via ProQuest). AAI3209525.