Long-term modifications in the efficiency of specific synapses are believed to contribute to the physiological basis of memory. A leading hypothesis for the molecular mechanism of this sustained modification is that the signal transduction events which modulate synaptic strength in the short-term can be extended into long-term changes. For example, a persistent activation of protein kinase C (PKC) may participate in the long-term increase in synaptic efficacy (long-term potentiation, LTP) that follows a high-frequency afferent stimulation at the Schaffer collateral/commissural-CA1 synapse in the hippocampus. Recent studies, however, have suggested that activity-dependent synaptic plasticity is complex. LTP appears to evolve through several temporal phases, which may have distinct, but perhaps related, molecular mechanisms. In addition, other patterns of afferent stimulation may produce either short-term potentiation (STP), lasting but a few minutes, or long-term depression (LTD) of synaptic transmission. Both the early induction and the later maintenance phases of LTP may involve PKC, a heterogeneous family of multiple isoforms, each with subtly different enzymatic characteristics. Our overall hypothesis is that the various types of synaptic plasticity may involve specific forms of PKC. In preliminary data, we show that in the induction phase of LTP in CA1 of rat hippocampal slices, multiple PKC isozymes translocate to membrane transiently. In addition to detecting 8 isoforms of PKC, we have identified in rat hippocampus the free, constitutively-active catalytic fragment, PKM, of a single isozyme, zeta (PKMzeta). We find that PKMzeta increases specifically in the maintenance phase of LTP, and decreases in LTD. The first specific aim of this proposal is the structural and biochemical characterization of PKMzeta, which appears to be selectively expressed in neural tissue.
Our second aim i s to analyze the stimulus dependency and temporal phases of the regulation of all the PKC isozymes and PKMzeta during synaptic plasticity. Finally, we plan to characterize the signal transduction pathways that regulate these persistent changes in PKC, particularly the bidirectional control of PKMzeta. We will examine the contributions of glutamate receptor subtypes, synaptic inhibition, and other second messenger pathways.
These specific aims are designed to characterize the molecular mechanisms of persistence of PKC, which are likely to prove important in understanding both the normal formation and clinical perturbations of memory.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29MH053576-04
Application #
2635509
Study Section
Neuropharmacology and Neurochemistry Review Committee (NPNC)
Project Start
1995-01-01
Project End
1999-12-31
Budget Start
1998-01-01
Budget End
1998-12-31
Support Year
4
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Suny Downstate Medical Center
Department
Physiology
Type
Schools of Medicine
DUNS #
068552207
City
Brooklyn
State
NY
Country
United States
Zip Code
11203
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Li, Yan-qin; Xue, Yan-xue; He, Ying-ying et al. (2011) Inhibition of PKMzeta in nucleus accumbens core abolishes long-term drug reward memory. J Neurosci 31:5436-46
Madronal, Noelia; Gruart, Agnes; Sacktor, Todd C et al. (2010) PKMzeta inhibition reverses learning-induced increases in hippocampal synaptic strength and memory during trace eyeblink conditioning. PLoS One 5:e10400
Heida, James G; Englot, Dario J; Sacktor, Todd C et al. (2009) Separating kindling and LTP: lessons from studies of PKM zeta in developing and adult rats. Neurosci Lett 453:229-32
Shema, Reut; Hazvi, Shoshi; Sacktor, Todd C et al. (2009) Boundary conditions for the maintenance of memory by PKMzeta in neocortex. Learn Mem 16:122-8