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.