Arc expression regulates long-term potentiation magnitude and
metaplasticity in area CA1 of the hippocampus in ArcKR mice.
Abstract
Expression of the immediate early gene Arc/Arg3.1 (Arc), a key mediator
of synaptic plasticity, is enhanced by neural activity and then reduced
by proteasome-dependent degradation. We have previously shown that
disruption of Arc degradation, in an Arc knock-in mouse (ArcKR), where
the predominant Arc ubiquitination sites were mutated, reduced the
threshold to induce, and also enhanced, the strength of Group I
metabotropic glutamate receptor-mediated long-term depression
(DHPG-LTD). Here we have investigated if ArcKR expression changes
long-term potentiation (LTP) in CA1 area of the hippocampus. As
previously reported, there was no change in basal synaptic transmission
at Schaffer collateral/commissural-CA1 (SC-CA1) synapses in ArcKR versus
wild-type (WT) mice. There was however a significant increase in the
amplitude of synaptically-induced (with low frequency paired-pulse
stimulation) LTD in ArcKR mice. Theta burst stimulation-evoked LTP at
SC-CA1 synapses was significantly reduced in ArcKR versus WT mice (after
2 hours). Group 1 mGluR priming of LTP was abolished in ArckR mice,
which could also potentially contribute to a depression of LTP. Although
high frequency-stimulation (HFS)-induced LTP was not significantly
different in ArcKR compared to WT mice (after 1 hour) there was a
phenotype in environmentally enriched mice, with the ratio of LTP to
short-term potentiation (STP) significantly reduced in ArcKR mice. These
findings support the hypothesis that Arc ubiquitination supports the
induction and expression of LTP, likely via limiting Arc-dependent
removal of AMPA receptors at synapses.