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. 2020 Dec 16:14:569349.
doi: 10.3389/fncom.2020.569349. eCollection 2020.

Comparing Theories for the Maintenance of Late LTP and Long-Term Memory: Computational Analysis of the Roles of Kinase Feedback Pathways and Synaptic Reactivation

Paul Smolen  1 , Douglas A Baxter  1   2 , John H Byrne  1
Affiliations

Comparing Theories for the Maintenance of Late LTP and Long-Term Memory: Computational Analysis of the Roles of Kinase Feedback Pathways and Synaptic Reactivation

Paul Smolen et al. Front Comput Neurosci. .

Abstract

A fundamental neuroscience question is how memories are maintained from days to a lifetime, given turnover of proteins that underlie expression of long-term synaptic potentiation (LTP) or "tag" synapses as eligible for LTP. A likely solution relies on synaptic positive feedback loops, prominently including persistent activation of Ca2+/calmodulin kinase II (CaMKII) and self-activated synthesis of protein kinase M ζ (PKMζ). Data also suggest positive feedback based on recurrent synaptic reactivation within neuron assemblies, or engrams, is necessary to maintain memories. The relative importance of these mechanisms is controversial. To explore the likelihood that each mechanism is necessary or sufficient to maintain memory, we simulated maintenance of LTP with a simplified model incorporating persistent kinase activation, synaptic tagging, and preferential reactivation of strong synapses, and analyzed implications of recent data. We simulated three model variants, each maintaining LTP with one feedback loop: autonomous, self-activated PKMζ synthesis (model variant I); self-activated CamKII (model variant II); and recurrent reactivation of strengthened synapses (model variant III). Variant I predicts that, for successful maintenance of LTP, either 1) PKMζ contributes to synaptic tagging, or 2) a low constitutive tag level persists during maintenance independent of PKMζ, or 3) maintenance of LTP is independent of tagging. Variant II maintains LTP and suggests persistent CaMKII activation could maintain PKMζ activity, a feedforward interaction not previously considered. However, we note data challenging the CaMKII feedback loop. In Variant III synaptic reactivation drives, and thus predicts, recurrent or persistent activation of CamKII and other necessary kinases, plausibly contributing to persistent elevation of PKMζ levels. Reactivation is thus predicted to sustain recurrent rounds of synaptic tagging and incorporation of plasticity-related proteins. We also suggest (model variant IV) that synaptic reactivation and autonomous kinase activation could synergistically maintain LTP. We propose experiments that could discriminate these maintenance mechanisms.

Keywords: computational; engram; long-term potentiation; memory; model; replay.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Model for maintenance of LTP. Three model variants contrast positive feedback loops mediated by CaMKII, PKMζ and synaptic reactivation. Stimuli activate CaMKII, PKA, Raf, and ERK. CaMKII, ERK, and PKA phosphorylate a synaptic tag. CaMKII, and ERK also converge (dashed box and arrow) to induce translation of PKMζ. Production of plasticity-related protein (PRP) is necessary to maintain LTP. TAG, PRP, and PKMζ converge to increase synaptic weight W. The feedback loops are: (1) PKMζ can enhance its own translation and thus activity. For this model variant, two cases are simulated: (a) PKMζ contributes to increasing W, but not to maintaining TAG, and (b) PKMζ also contributes to maintaining an elevated level of TAG (dashed arrow). (2) Active CaMKII can reinforce and maintain its own activity. (3) Ongoing synaptic reactivation. An increase in W enhances the amplitude of spontaneous LTP-reinforcing stimuli. Only for potentiated W is the stimulus amplitude sufficient to significantly reactivate downstream signaling pathways.
Figure 2
Figure 2
Simulated LTP, without and with positive feedback based on sustained PKMζ activity. (A1) A three-tetanus stimulus induces peaks of CaMKII activity and elevates activities of PKA and ERK. Without positive feedback, kinase activities return to basal with the slowest variable, ERK, elevated for ~1.5 h. (A2) Increased kinase activities activate TAG and PKMζ. LTP decays over h. (B1) With persistent PKMζ activation, a tetanic stimulus leads to only temporary activation of CaMKII, ERK, and PKA. (B2) Enhancement by PKMζ of its own synthesis and activity leads to bistability and a state switch for PKMζ. But TAG is not persistently elevated and LTP is not maintained. (C1,C2) If PKMζ is assumed to increase the level of TAG, then stimulus-induced persistent PKMζ activation leads to elevation of TAG and maintenance of LTP. In Figures 2–5, time courses of some variables are vertically scaled for ease of visualization. Scaling factors are given in Methods.
Figure 3
Figure 3
Simulated LTP with positive feedback based on sustained CaMKII activity or on synaptic reactivation. (A1,A2) LTP maintenance due to autoactivation of CaMKII. (B1,B2) Maintenance due to positive feedback in which a strengthened synapse undergoes reactivation events, with each event reinforcing LTP. In both these model variants, PKMζ does not act to increase the level of TAG.
Figure 4
Figure 4
Simulated effects of PKMζ inhibition on LTP maintenance. (A) When LTP is maintained by CaMKII activation, only a temporary reduction in synaptic weight occurs. TAG does not depend on PKMζ and remains elevated. Thus, following PKMζ inhibition, TAG and PKMζ can again cooperate to increase W, restoring LTP. (B) With positive feedback based on reactivation of strong synapses, a decrease in W, induced by PKMζ inhibition, decreases amplitudes of reactivation stimuli and activation of CaMKII and other kinases, decreasing TAG. Long-lasting inhibition of PKMζ (90% inhibition for 50 h) decreases W below a threshold, such that the bistable system transitions to the basal state with low W, PKMζ, and TAG. In this model variant, one slow time constant is assumed to describe synaptic weight decay. Because of this slow time constant, the inhibition duration required to decrease W below threshold is ~ 2 d.
Figure 5
Figure 5
Maintenance of L-LTP by mutual reinforcement of self-sustaining PKMζ activity and synaptic reactivation. (A1,A2) Tetanic stimulus induces kinase activation, synaptic tagging, and persistent increase in W. After W increases, reactivation leads to recurrent increases in CaMKII, ERK, and PKA activities in (A1), and TAG in (A2), but these variables remain well below peak values during LTP induction. Starting at t = 33 h (black horizontal bar), PKMζ positive feedback is switched off by setting the parameter kPKM to zero. Despite continued synaptic reactivation, PKMζ and W decline to basal levels. (B) LTP is induced and maintained with the same parameters as in (A), with only the random timing of reactivation events differing. Starting at t = 33 h (black horizontal bar), reactivation is switched off, while PKMζ positive feedback remains on. PKMζ and W decline slowly to basal levels.
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