Metaplasticity governs compartmentalization of synaptic tagging and capture through brain-derived neurotrophic factor (BDNF) and protein kinase Mζ (PKMζ)

Abstract

Activity-dependent synaptic plasticity is widely accepted to be the cellular correlate of learning and memory. It is believed that associativity between different synaptic inputs can transform short-lasting forms of synaptic plasticity (<3 h) to long-lasting ones. Synaptic tagging and capture (STC) might be able to explain this heterosynaptic support, because it distinguishes between local mechanisms of synaptic tags and cell-wide mechanisms responsible for the synthesis of plasticity-related proteins (PRPs). STC initiate storage processes only when the strength of the synaptic tag and the local concentration of essential proteins are above a certain plasticity threshold. We present evidence that priming stimulation through the activation of metabotropic glutamate receptors substantially increases the "range of threshold" for functional plasticity by producing protein kinase Mζ (PKMζ) as a PRP through local protein synthesis. In addition, our results implicate BDNF as a PRP which is mandatory for establishing cross-capture between synaptic strengthening and weakening, whereas the newly generated PKMζ specifically establishes synaptic tagging of long-term potentiation. Most intriguingly, we show here that STC are confined to specific dendritic compartments and that these compartments contain "synaptic clusters" with different plasticity thresholds. Our results suggest that within a dendritic compartment itself a homeostatic process exists to adjust plasticity thresholds. The range in which these clusters operate can be altered by processes of metaplasticity, which will operate on the cluster independently of other clusters at the same dendrite. These clusters will then prepare the synaptic network to form long-term memories.

Metaplasticity mechanisms restore plasticity and associativity in an animal model of Alzheimer’s disease

“…4 E and G, but it had no effect on the expression rate of PKMζ (group 5; no statistically significant decrease in the expression of PKMζ compared with group 3; Fig. 4I), similar to previous reports (17,27). The control peptide scr-ZIP had no effect on the function of PKMζ as shown in Fig.…”

“…This observation is in agreement with earlier findings that application of Aβ has no effect on hippocampal LTD (10)(11)(12). We have reported earlier that L-LTD can be maintained during PKMζ inhibition, as depressed synapses rely more on brain-derived neurotrophic factor (27,28). The absence of cross-capture in APP/PS1 mice is most likely a result of the lack of PRPs such as PKMζ as RyR priming and subsequent induction of L-LTD was able to reinstate crosscapture.…”

“…We have reported earlier that group 1 mGluR or RyR activation leads to the new synthesis of PKMζ in rat hippocampal slices (17,27). In this study, we estimated and compared the total PKMζ level in the hippocampal CA1 region of WT and APP/PS1 mice.…”

“…It was proposed earlier that prior activation of group I metabotropic glutamate receptors (mGluRs) or RyRs facilitates the subsequent LTP through local synthesis of PRPs (17,18,27). To elucidate whether this also happens in APP/PS1 mice, the protein synthesis inhibitor anisomycin (ANI; 25 μM) was coapplied during RYA priming.…”

“…In conventional STC, PKMζ is identified as the first LTP-specific PRP (17,27,28). To test whether a similar mechanism was also present during RyR-mediated metaplasticity in APP/PS1 mice, myr-ZIP was bath-applied 60 min after the induction of RYA-primed L-LTP until the end of the experiment.…”