Environmental enrichment reveals deficits in LTP in ArcKR mice.
There is considerable evidence demonstrating that exposure to enriched or complex environments positively influences neuronal structure and (Rosenzweig & Bennett, 1996; Nithianantharajah & Hannan, 2006; Correa et al. , 2012; Privitera et al. , 2020; Cooper & Frenguelli, 2021). ((Privitera et al. , 2020) showed that LTP magnitude at SC-CA1 synapses was enhanced by enriched conditions compared to standard house wildtype mice, with no enrichment-induced increase in basal synaptic transmission. In these mice the basal expression of Arc was significantly reduced after prolonged enrichment (Privitera et al. , 2020). We also found that there were no significant changes in basal synaptic transmission in WT mice, comparing standard house to environmentally-enriched (compare Fig 1A and 4D). In contrast there does appear to be a reduction in synaptic strength for ArcKR mice upon enrichment which may reflect the persistence of Arc and the resultant AMPA receptor internalisation. When we examined LTP (measured after 1 hour) and STP (short term potentiation, 5 minutes after induction) we observed no significant difference in their amplitudes between environmentally-enriched ArcKR and WT mice. We did however observe a clear difference in the pattern of EPSP potentiation, with a difference in the decay of potentiation after LTP induction. In standard-housed conditions, the slope of fEPSPs remained enhanced to around the same degree as with short term potentiation (STP, LTP magnitude ~ 95 % of STP) for both WT and ArcKR mice. Whereas in environmentally-enriched mice, LTP decayed to ~ 78 % of the STP level after an hour in ArcKR mice. The ratio of LTP to STP was significantly different between the genotypes (unlike the absolute magnitude of LTP, which may not have reached significance due to the larger variation in magnitude between slices). Thus, environment enrichment reveals an effect of ArcKR expression on potentiation. Recent studies (reviewed in (France et al. , 2022) have investigated the processes underlying STP and LTP and have shown that it is possible to differentially regulate STP and LTP using NMDA subunit-specific positive allosteric modulators and antagonists. Thus, different NMDA receptors appear to contribute to these two processes. It is unclear why expression of ArcKR has no effect on STP and LTP in standard housed conditions, but it does in environment enriched conditions. It is possible that changes in NMDA receptor expression in environment enriched mice could be involved (Rampon et al. , 2000) but this needs to be further tested.