How the brain stores long-term memory is a fundamental question in biology, with important clinical implications for neurology and psychiatry. Long-term increases in the strength of the synaptic connections between different networks of neurons are thought to be the physiological mechanism underlying memory storage. We have discovered the first molecular mechanism that maintains synaptic enhancement between these networks. This discovery was based upon experiments on the most widely studied form of synaptic plasticity in the brain, termed long-term potentiation (LTP). Although triggering LTP is very complex, the mechanism for maintaining LTP is relatively simple, involving a unique, persistently active kinase, called protein kinase Mzeta (PKMζ), a form of PKC discovered in the Sacktor lab. With Dr. Andre Fenton at Downstate, we were recently able to show that this mechanism not only maintains LTP, but underlies the persistence of long-term memory in the brain. As published in Science, inhibiting PKMζ with a drug caused the erasure of memories that had been learned a day, or even a month before. PKMζ inhibition did not damage the brain and, after the drug had been eliminated, new long-term memories could be learned and recalled. Thus PKMζ is the first functionally important memory storage molecule. In addition, work with Dr. Sue Mirra, Chair of Pathology at Downstate, showed that PKMζ is sequestered in the neurofibrillary tangles found in the brains of patients with Alzheimer's Disease. These results may be important toward understanding the memory loss that is the primary symptom of that disorder. As published in a second paper in Science, PKMζ has also been found to maintain long-term memories in the neocortex, the final repository for many types of memory. Therefore, PKMζ appears to be a general mechanism for long-term memory storage in the brain. The work on PKMζ and memory was recently highlighted as one of the ten “Breakthroughs of the Year 2006” by the editors of Science.
Sacktor, T. C., Olsten, P., Valsamis, H., Jiang, X., Naik, M., and Sublette, E. (1993). Persistent activation of the ζ isoform of protein kinase C in the maintenance of longterm potentiation. Proc. Natl. Acad. Sci. USA 90, 8342-8346.
Hrabetova, S., Serrano, P., Blace, N., Tse, H. W., Skifter, D. A., Jane, D. E., Monaghan, D. T., and Sacktor, T. C. (2000). Distinct NMDA receptor subpopulations contribute to the induction of LTP and LTD. J. Neurosci. 20, RC81.
Naik, M. U., Benedik, E., Hernandez, I., Hrabe, J., Osman, M.,Valsamis, M., Dow-Edwards, D., and Sacktor, T. C. (2000). Distribution of protein kinase MÉ and the complete protein kinase C isozyme family in rat brain. J. Comp. Neurol. 426, 243-258.
Drier, E. A., Tello, M. K., Cowan, M., Wu, P., Blace, N., Sacktor, T. C., and Yin, J. C. (2002). Memory enhancement and formation by atypical PKM activity in Drosophila melanogaster. Nat. Neurosci. 5, 316-324.
Ling, D. S., Benardo, L. S., Serrano, P. A., Blace, N., Kelly, M. T., Crary, J. F., and Sacktor, T. C. (2002). Protein kinase Mζ is necessary and sufficient for LTP maintenance. Nat. Neurosci. 5, 295-296.
Hernandez, A. I., Blace, N., Crary, J. F., Serrano, P.A., Leitges, M., Libien, J. M., Weinstein, G., Tcherapanov, A., and Sacktor, T. C. (2003). Protein kinase Mζ synthesis from a brain mRNA encoding an independent protein kinase Cζ catalytic domain. Implications for the molecular mechanism of memory. J. Biol. Chem. 278, 40305-40316.
Muslimov, I. A., Nimmrich, V., Hernandez, A. I., Tcherepanov, A., Sacktor, T. C., and Tiedge, H. (2004). Dendritic transport and localization of protein kinase Mζ mRNA: Implications for molecular memory consolidation. J. Biol. Chem. 279, 5261352622.
Pastalkova, E., Serrano, P., Pinkhasova, D., Wallace, E., Fenton, A. A., and Sacktor, T. C. (2006). Storage of spatial information by the maintenance mechanism of LTP. Science 313, 1141-1144.
Kelly M. T., Crary J. F., and Sacktor T. C. (2007). Regulation of protein kinase Mζ synthesis by multiple kinases in long-term potentiation. J. Neurosci. 27, 3439-3444.
Shema, R., Sacktor T. C., and Dudai Y. (2007). Rapid erasure of long-term memory associations in the cortex by an inhibitor of PKMζ. Science 317, 951-953.
Desingarao Jothianandan, Ph.D., Research Scientist
Peter Serrano, Ph.D., Research Assistant Professor
Rachna Sondhi, B.A., Graduate Student
Andrew Tcherepanov, M.S., Technician
Dezhi Tian, Ph.D., Postdoctoral Fellow
Yudong Yao, Ph.D., Postdoctoral Fellow
Grant reviewer for the NIH Learning and Memory Study Section, the Hartford Foundation, and Veterans Affairs.
Reviewer for various scientific journals.