Molecular Mechanisms Underlying Memory Consolidation and its Possible Implications for Alzheimer Disease New Therapy

We are interested in understanding how memories are encoded and retained in the brain and use different methods to uncover the basic molecular and cellular mechanisms underlying learning. Following accumulation of basic science research and data,   we recently try to find new ways to enhance memory. Very little is known about drugs which can enhance the consolidation phase of memories in the cortex, the brain structure considered to store at least partially, long term memories. We tested the hypothesis that pharmacological and genetic manipulation of translation machinery, known to be involved in the molecular consolidation phase, enhances positive or negative forms of cortical dependent memories. We found that dephosphorylation (Ser51) of eIF2α specifically in the cortex is both correlated and necessary for normal memory consolidation. In order to reduce eIF2α phosphorylation and improve memory consolidation, we pharmacologically or genetically inhibited the different eIF2α kinases expressed in the brain. In addition, we tested the involvement of eIF2α pathway in mice models of aging and sporadic Alzheimer disease and found strong link between the two.

Relevant recent publications:

1. Costa-Mattioli M, Gobert D, Stern E, Gamache K, Colina R, Cuello C, Sossin W, Kaufman R, Pelletier J, Rosenblum K, Krnjević K, Lacaille JC, Nader K, Sonenberg N (2007). eIF2a phosphorylation regulates the switch from short to long-term synaptic plasticity and memory. Cell  6;129(1):195-206.  http://www.ncbi.nlm.nih.gov/pubmed/17418795
2. ApoE ε4 is associated with eIF2α phosphorylation and impaired learning in young mice (2013). Yifat Segev, Daniel M. Michaelson, Kobi Rosenblum Neurobiology of Aging. 

http://www.ncbi.nlm.nih.gov/pubmed/22883908

3. Blocking eIF2a kinase – PKR – Enhances Positive and Negative Forms of Cortex-Dependent Taste Memory (2013). Stern Elad, Chinnakkaruppan Adaikkan, David Orit ,Sonenberg Nahum and Rosenblum Kobi. Journal of Neuroscience (in press).