Rosenblum Lab Molecular and Cellular Mechanisms Underlying Learning and Memory

    Cognitive enhancers

    We study molecular and cellular mechanisms underlying learning and memory, and recently, depression as well. Since the foundation of the lab, we have been studying the regulation of mRNA translation into protein as a major molecular mechanism underlying learning and memory. Over the years, we have focused on specific molecules that serve as key regulators of protein synthesis, and shown them to be potential targets for memory enhancement in health and disease (e.g., mild dementia, Alzheimer's disease).

    These molecules include the eukaryotic initiation factor 2α (eIF2α) and its kinases (enzymes regulating its phosphorylation levels, and thereby, its activity). eIF2α has four known kinases, all known to be functional in the brain.

    We have shown that eIF2α and at least two of its kinases, protein kinase R (PKR) and PKR-like endoplasmic reticulum kinase (PERK), play an essential role in learning and memory. For example, eIF2α+/S51A mice (genetic reduction of eIF2α phosphorylation) have enhanced synaptic plasticity and enhanced hippocampal- and cortical-dependent learning (Costa-Mattioli et al. 2007). Furthermore, we have shown that treatment with a protein kinase R (PKR) inhibitor (C16) (rats, WT mice) or genetic deletion of eIF2α kinase PKR (PKR KO mice) results in enhanced memory in the conditioned taste aversion  paradigm (associative learning) and the novel taste learning paradigm (both paradigms are cortical-dependent) (Stern et al. 2013). Moreover, phosphorylation of eIF2α is increased with age in rats and mice, and in the ApoE4 mouse model of sporadic Alzheimer's disease, phosphorylation levels of PKR and eIF2α are increased (Segev et al. 2013), and PKR inhibition rescues memory impairment, as shown in the contextual fear conditioning paradigm (hippocampal-dependent) (Segev et al. 2015). Our findings regarding PKR, as a potential target for memory enhancement in health and disease, have been granted a patent. Based on our findings regarding PKR and this patent, in 2015 we founded a start-up company (Protekt Therapeutics, part of the FuturX biotechnological incubator, Israel) aiming to develop PKR inhibitors, invested by Takeda Pharmaceuticals and Johnson & Johnson.

    References

    Adaikkan C, Taha E, Barrera I, David O, Rosenblum K. 2018. CaMKII and eEF2K pathways mediate the antidepressant action of ketamine. Biological Psychiatry .

    Costa-Mattioli M, Gobert D, Stern E, Gamache K, Colina R, Cuello C, Sossin W, Kaufman R, Pelletier J, Rosenblum K, Krnjevic K, Lacaille JC, Nader K, Sonenberg N. 2007. eIF2alpha phosphorylation bidirectionally regulates the switch from short- to long-term synaptic plasticity and memory. Cell 129: 195-206.

    Segev Y, Michaelson DM, Rosenblum K. 2013. ApoE epsilon4 is associated with eIF2alpha phosphorylation and impaired learning in young mice. Neurobiol Aging 34: 863-872.

    Segev Y, Barrera I, Ounallah-Saad H, Wibrand K, Sporild I, Livne A, Rosenberg T, David O, Mints M, Bramham CR, Rosenblum K. 2015. PKR inhibition rescues memory deficit and ATF4 overexpression in ApoE epsilon4 human replacement mice. J Neurosci 35: 12986-12993.

    Stern E, Chinnakkaruppan A, David O, Sonenberg N, Rosenblum K. 2013. Blocking the eIF2alpha kinase (PKR) enhances positive and negative forms of cortex-dependent taste memory. J Neurosci 33: 2517-2525.

     

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    © 2017 Sagol Department of Neurobiology, University of Haifa | Tel: +972-4-8280015 | Fax: +972-4-8240339 | Email: elkobi.a@gmail.com, Designed by: Shani Zylberman, Computing and Information Systems division