title: Atypical PKCs in memory maintenance: the roles of feedback and redundancy.
abstract: Memories that last a lifetime are thought to be stored, at least in part, as persistent enhancement of the strength of particular synapses. The synaptic mechanism of these persistent changes, late long-term potentiation (L-LTP), depends on the state and number of specific synaptic proteins. Synaptic proteins, however, have limited dwell times due to molecular turnover and diffusion, leading to a fundamental question: how can this transient molecular machinery store memories lasting a lifetime? Because the persistent changes in efficacy are synapse-specific, the underlying molecular mechanisms must to a degree reside locally in synapses. Extensive experimental evidence points to atypical protein kinase C (aPKC) isoforms as key components involved in memory maintenance. Furthermore, it is evident that establishing long-term memory requires new protein synthesis. However, a comprehensive model has not been developed describing how these components work to preserve synaptic efficacies over time. We propose a molecular model that can account for key empirical properties of L-LTP, including its protein synthesis dependence, dependence on aPKCs, and synapse-specificity. Simulations and empirical data suggest that either of the two aPKC subtypes in hippocampal neurons, PKMζ and PKCι/λ, can maintain L-LTP, making the system more robust. Given genetic compensation at the level of synthesis of these PKC subtypes as in knockout mice, this system is able to maintain L-LTP and memory when one of the pathways is eliminated.
authors.affiliation: Department of Neurobiology and Anatomy, The University of Texas Medical School at Houston, Houston, Texas 77030, USA.
authors.forename: Sajiya J
authors.initials: SJ
authors.lastname: Jalil
authors.affiliation: Department of Physiology, Pharmacology, Anesthesiology, and Neurology, SUNY Downstate Medical Center, Brooklyn, New York 11203, USA.
authors.forename: Todd Charlton
authors.initials: TC
authors.lastname: Sacktor
authors.affiliation: Department of Neurobiology and Anatomy, The University of Texas Medical School at Houston, Houston, Texas 77030, USA Harel.Shouval@uth.tmc.edu.
authors.forename: Harel Z
authors.initials: HZ
authors.lastname: Shouval
mesh_terms: D000818:Animals; D003198:Computer Simulation; D025461:Feedback, Physiological / Q000502:physiology; D006624:Hippocampus / Q000502:physiology*; D007527:Isoenzymes; D007700:Kinetics; D017774:Long-Term Potentiation / Q000502:physiology*; D008568:Memory / Q000502:physiology*; D008958:Models, Molecular; D008959:Models, Neurological; D009474:Neurons / Q000502:physiology; D010766:Phosphorylation; D014176:Protein Biosynthesis; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D007527:Isoenzymes; D011493:Protein Kinase C