Long-term changes in synaptic strength are widely believed to underlie memory storage. Thus one approach to understanding memory storage is to investigate long-term synaptic plasticity, particularly a persistent synaptic enhancement induced by strong afferent stimulation, long-term potentiation (LTP). The mechanisms of LTP can be divided into 2 phases: induction, triggering the potentiation, and maintenance, sustaining the potentiation over time. Although inducing persistent LTP requires new protein synthesis and involves complex signaling mechanisms, the functionally important, newly synthesized proteins maintaining LTP, and whether they play similar roles in memory storage, had previously been unknown. Recently, we found that a constitutively active PKC isoform, PKMzeta (PKM6), is both necessary and sufficient for maintaining LTP. Produced from a PKM6 mRNA, PKM6 is the independent catalytic domain of PKC6, which, lacking an autoinhibitory regulatory domain, persistently phosphorylates without second messenger stimulation. Once synthesized in LTP induction, persistent PKM6 activity maintains synaptic potentiation because inhibiting PKM6 reverses established LTP, even when the inhibition begins hours after induction. Moreover, inhibiting PKM6 disrupts behavioral long-term memory retention, even days after learning, without affecting subsequent memory storage. Thus, the overall hypothesis of this application is that persistent increases in PKM6 at synapses may be a common molecular mechanism of information storage for both LTP maintenance and behavioral long-term memory. This application therefore focuses on the physiological mechanisms for initially encoding and persistently maintaining PKM6 at synapses.
Our first aim i s to examine the mechanisms of PKM6 synthesis in the phases of LTP, focusing on a positive feedback loop that might increase PKM6 levels through dendritic protein synthesis. Second is to examine changes in the distribution of PKM6 in neurons during LTP. We will examine if PKM6 activity maintains its targeting to spines by its autonomous activity and through the same trafficking mechanism by which the kinase also potentiates synaptic strength. Third, we will determine if these mechanisms of synthesis and synaptic compartmentalization are the same in behavioral memory storage. Preliminary data indicate that PKM6 in the hippocampus increases after learning and correlates with the extent of memory retention. Thus our 3 aims will provide fundamental new knowledge on how PKM6 maintains activity- dependent information within neurons, which might be a common mechanism for synaptic and behavioral memory storage that may be relevant to disorders of memory.

Public Health Relevance

How long-term memories are stored is a fundamental question in neuroscience with important clinical implications for neurology and psychiatry. Our laboratory has identified a molecular component of the storage mechanism of long-term memory, a protein kinase termed PKMzeta, by studying the maintenance mechanism of a persistent form of synaptic plasticity, long-term potentiation (LTP). This application focuses on the physiological mechanisms for initially encoding and persistently maintaining PKMzeta at synapses that might be common mechanisms for information storage during both LTP and long-term memory, and thus relevant to the pathophysiology of amnestic disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH053576-19
Application #
8383108
Study Section
Neurobiology of Learning and Memory Study Section (LAM)
Program Officer
Asanuma, Chiiko
Project Start
1995-01-01
Project End
2014-11-30
Budget Start
2012-12-01
Budget End
2013-11-30
Support Year
19
Fiscal Year
2013
Total Cost
$378,972
Indirect Cost
$141,372
Name
Suny Downstate Medical Center
Department
Physiology
Type
Schools of Medicine
DUNS #
040796328
City
Brooklyn
State
NY
Country
United States
Zip Code
11203
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Hernandez, A Ivan; Oxberry, William C; Crary, John F et al. (2014) Cellular and subcellular localization of PKMýý. Philos Trans R Soc Lond B Biol Sci 369:20130140
Eom, Taesun; Muslimov, Ilham A; Tsokas, Panayiotis et al. (2014) Neuronal BC RNAs cooperate with eIF4B to mediate activity-dependent translational control. J Cell Biol 207:237-52
Yao, Yudong; Shao, Charles; Jothianandan, Desingarao et al. (2013) Matching biochemical and functional efficacies confirm ZIP as a potent competitive inhibitor of PKMζ in neurons. Neuropharmacology 64:37-44
Vélez-Hernández, María E; Vázquez-Torres, Rafael; Velasquez-Martinez, Maria C et al. (2013) Inhibition of Protein kinase Mzeta (PKMζ) in the mesolimbic system alters cocaine sensitization in rats. J Drug Alcohol Res 2:235669
Sacktor, Todd Charlton (2012) Memory maintenance by PKMýý--an evolutionary perspective. Mol Brain 5:31
Shao, Charles Y; Sondhi, Rachna; van de Nes, Paula S et al. (2012) PKMζ is necessary and sufficient for synaptic clustering of PSD-95. Hippocampus 22:1501-7
Wang, Jun; Meng, Fanli; Cottrell, James E et al. (2012) Metabotropic actions of the volatile anaesthetic sevoflurane increase protein kinase M synthesis and induce immediate preconditioning protection of rat hippocampal slices. J Physiol 590:4093-107
Barry, Jeremy M; Rivard, Bruno; Fox, Steven E et al. (2012) Inhibition of protein kinase Mýý disrupts the stable spatial discharge of hippocampal place cells in a familiar environment. J Neurosci 32:13753-62

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