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).