Arc expression regulates long‐term potentiation magnitude and metaplasticity in area CA1 of the hippocampus in ArcKR mice

Abstract

AbstractExpression 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 the 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 (TBS)‐evoked LTP at SC‐CA1 synapses was significantly reduced in ArcKR versus WT mice (after 2 h). 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 with WT mice (after 1 h), 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.