FIGURE 9.

The impact of HSV-1 neuronal infection at the dendritic spine level. Diagram of the HSV-1-induced phenotype in cortical neurons at 1, 4, 8 and 18 hpi. Changes in shape and structure both in somata and dendrites are shown. Early in infection, 1 hpi CREB is activated (pS133) by p38 MAPK (Hargett et al., 2005) instead of Erk. From 1 hpi there is a progressive decrease of PSD-95, Drebrin and CaMKIIβ along the infection kinetics (upper panel zoom dendrites), most likely due to VHS viral protein in charge of downregulating the host cell mRNAs (Brunella Taddeo et al., 2007). From 4 hpi there is a notorious increase of Arc expression (shown as red color), reaching its highest level at 8 hpi. At this time, CREB activation is downregulated, most likely due to the inhibitory phosphorylation of GSK3 at S129. The viral kinase Us3 phosphorylates GSK3 at inhibitory residue (S9) (Wagner and Smiley, 2009), thus promoting Arc accumulation (Gozdz et al., 2017) (first dashed red arrow). Then, at 18 hpi, the Us3 effect is abolished and GSK3 is activated due to the rising levels of intracellular calcium (Piacentini et al., 2011). The activation of GSK3 promotes Arc degradation at late infection (18 hpi) (second dashed red arrow), this rapid turnover of Arc expression is accompanied by high S206 phosphorylation levels, which could have an impact on protein localization.