TBS induced LTP magnitude is reduced after 2 hours in ArcKR compared to WT mice.
We observed that the magnitude of TBS (4 bursts as in (Kyrke-Smith et al. , 2021) induced LTP was significantly smaller in ArcKR mice versus WT mice 2 hours following induction. This was not a consequence of differences in synaptic activation, as there was no significant difference in the baseline fEPSP slope before the induction of LTP between the genotypes. The mechanism for this reduction in LTP magnitude is currently unclear. One potential mechanism is that peak accumulation of Arc (in response to the LTP induction stimulus) is larger, and will persist for a longer duration, in the ArcKR hippocampus and this may dampen down synaptic potentiation, potentially via increased AMPAR endocytosis. Recent findings have shown that Arc interacts and disperses the protein stargazin (Zhang et al. , 2015) , which is located at the postsynaptic density (PSD), away from the synapse (Chen et al. , 2022). Thus, it could be hypothesised that if ArcKR protein accumulates at the proximities of the PSD it may move stargazin-AMPAR complexes away from the PSD to be targeted for endocytosis (Chen et al. , 2022). This hypothesis, of ArcKR accumulation following LTP induction, is difficult to directly test, since only a small number of hippocampal synapses are potentiated during LTP induction and thus any changes in Arc expression would only occur in specific groups of neurons and probably be too small to measure, for example using western blotting techniques. More sensitive techniques such a the use of the Arc reporter mice could potentially be used to address this question (Eguchi & Yamaguchi, 2009)
Several studies have shown that disrupting LTP in the CA1 area of the hippocampus leads to deficiency in spatial learning (reviewed in (Lynch, 2004; Kandel et al. , 2014; Abraham et al. , 2019)). Thus, it may be predicted that spatial memories and learning would be disrupted in the ArcKR mouse. Previous experiments in younger animals showed no such deficits in the acquisition of spatial memories ((Wall et al. , 2018) but significant changes following the reversal learning task. This may not be the case in older mice, but this remains to be tested. This effect of ArcKR expression on LTP magnitude may at first appear contradictory to the results of (Kyrke-Smith et al. , 2021), who showed that deletion of Arc had no effect on LTP. However, it may be that WT levels of Arc have no effect on LTP, but if Arc expression is enhanced or Arc can accumulate at dendritic spines, it may then play a role in LTP.