mGluR dependent priming is abolished in ArcKR mice.
One major difference in synaptic plasticity in hippocampal slices from ArcKR mice compared to slices from WT mice was the prevention of GI-mGluR-dependent facilitation of LTP. The behavioural role for the enhancement of LTP induction by low level mGluR activation is currently unclear, but its loss does not seem to affect the acquisition of spatial memories in young animals (Wall et al. , 2018). Corroborating this observation is the finding that although LTP and NMDA receptor-mediated LTD are intact at hippocampal SC-CA1 synapses in MAPK-activated protein kinase 2 (MK2) KO mice when compared to WT littermate mice, the mGluR-mediated priming of LTP is abolished. Similar to the cognitive dysfunction observed in ArcKR mice (Wall et al. , 2018), MK2 KO mice are able to learn a hippocampal-dependent spatial task (the Barnes maze), but showed marked deficits in performing the reversal version of the previous learned task (Priviteraet al. , 2019). These findings suggest that mGluR-mediated facilitation of LTP may be involved in the process of re-learning a previously learned task, and not in the initial learning of the task. However, this is difficult to test, as there are currently no methods to selectively block the priming of LTP in vivo without effecting other forms of plasticity.
It is currently unclear how the mGluR-dependent priming of LTP is abolished by the expression of ArcKR, which is relatively resistant to degradation (Wall et al. , 2018). Increased Arc protein expression facilitates AMPA receptor endocytosis, in particular the GluA1 subunit, following the induction of its expression with the mGluR-agonist DHPG (Waung et al. , 2008; Wall et al. , 2018). Endocytosis of AMPA-lacking GluA2 subunits, which are calcium permeable, would reduce synaptic strength and the probability of inducing potentiation. This hypothesis would support our observation that there is prolonged inhibition of basal transmission following the application of 20 µM DHPG in some slices obtained from ArcKR mice but not from WT mice (Figure 4D). Although this is consistent with our previous studies, where we found that a lower concentration of DHPG (50 µM) was sufficient to induce LTD in ArcKR mice (Wall et al. , 2018), we could not measure any significant differences in Arc protein expression levels induced by exposure to 20 µM DHPG (this may be because any increases are below the limits of detection).