Abstract
Protein synthesis-dependent, late long-term potentiation (LTP) and depression (LTD) at glutamatergic hippocampal synapses are well characterized examples of long-term synaptic plasticity. Persistent increased activity of protein kinase M ζ (PKMζ) is thought essential for maintaining LTP. Additional spatial and temporal features that govern LTP and LTD induction are embodied in the synaptic tagging and capture (STC) and cross capture hypotheses. Only synapses that have been “tagged” by a stimulus sufficient for LTP and learning can “capture” PKMζ. A model was developed to simulate the dynamics of key molecules required for LTP and LTD. The model concisely represents relationships between tagging, capture, LTD, and LTP maintenance. The model successfully simulated LTP maintained by persistent synaptic PKMζ, STC, LTD, and cross capture, and makes testable predictions concerning the dynamics of PKMζ. The maintenance of LTP, and consequently of at least some forms of long-term memory, is predicted to require continual positive feedback in which PKMζ enhances its own synthesis only at potentiated synapses. This feedback underlies bistability in the activity of PKMζ. Second, cross capture requires the induction of LTD to induce dendritic PKMζ synthesis, although this may require tagging of a nearby synapse for LTP. The model also simulates the effects of PKMζ inhibition, and makes additional predictions for the dynamics of CaM kinases. Experiments testing the above predictions would significantly advance the understanding of memory maintenance.
Highlights
Protein synthesis-dependent forms of long-term potentiation (LTP) and long-term depression (LTD) are the subject of intense study because they represent cellular mechanisms of longterm memory
How are the above processes integrated into a synapse that can express different forms of plasticity? To help in understanding the integrated function, we developed a computational model that describes some of the postsynaptic molecular cascades at hippocampal CA3–CA1 synapses
Synapses that have been ‘‘tagged’’ by a stimulus, such as stimuli needed for LTP and learning, can ‘‘capture’’ protein kinase M f (PKMf)
Summary
Protein synthesis-dependent forms of LTP and LTD (late LTP/ D, abbreviated LTP and LTD) are the subject of intense study because they represent cellular mechanisms of longterm memory. Some key mechanisms underlying the induction and maintenance of LTP and LTD are emerging. These include compartmentalization, within stimulated dendritic spines, of Ca2+ signals and of kinase activation [1,2], and synapse specificity of induction mediated by synaptic tagging and capture (STC). In STC [3,4], one synapse (S1) receives either a weak high-frequency tetanus (WTET) or a weak low-frequency stimulus (WLFS). Neither WTET nor WLFS induce LTP or LTD Such stimuli ‘‘tag’’ the activated synapse for subsequent plasticity. If activity in S1 closely precedes or follows a strong tetanus (STET) or strong low-frequency stimulus (SLFS) at a second synapse (S2), long-term changes occur at S1
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