Figure 6. The p38-MK2/3 cascade regulating actin rearrangement in DHPG-LTD.

(a,b) A schematic representation of the putative mechanism by which the p38-MK2/3 cascade regulates cofilin1 activity and GluA1 trafficking. (a) At non-stimulated dendritic spines of WT neurons levels of p38, MK2 and cofilin1 activity are low, and the balance between G- and F-actin is skewed towards F-actin; resulting in low levels of GluA1/2 endocytosis. By comparison, in spines of non-stimulated DKO neurons, where the p38-MK2 signalling cascade is blocked, there is a long lasting increase in basal cofilin1 activity levels, resulting in increased G-actin and abnormal spine morphology. Interestingly, the spines of MK2/3 DKO neurons, which display decreased head diameters and longer neck lengths, also have deficits in glutamatergic synaptic transmission. (b) Activation of mGluRs in WT spines induces an increase in p38 and MK2 activity, which correlates to an increase in cofilin1 activity and a shift in balance between G- and F-actin towards G-actin and increased endocytosis of GluA1 receptors. In DKO mice, the block of p38-MK2/3 cascade results in reduced cofilin1 activity and GluA1 endocytosis combined with deficits in mGluR-LTD.