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

Haley, Maisy, Bertrand, Jeanri, Anderson, Vanessa Torrico, Fuad, Mukattar, Frenguelli, Bruno, Correa-Muller, Sonia A L ORCID: https://orcid.org/0000-0002-7434-1073 and Wall, Mark (2023) Arc expression regulates long-term potentiation magnitude and metaplasticity in area CA1 of the hippocampus in ArcKR mice. European Journal of Neuroscience, 58 (10). pp. 4166-4180. ISSN 0953-816X

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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.