LAUSR

We have previously shown that treatment with a mGluR5 positive allosteric modulator (PAM) is neuroprotective after experimental traumatic brain injury (TBI), limiting post‐traumatic neuroinflammation by reducing pro‐inflammatory microglial activation and promoting anti‐inflammatory and neuroprotective responses. However, the specific molecular mechanisms governing this anti‐inflammatory shift in microglia remain unknown. Here we show that the mGluR5 PAM, VU0360172 (VuPAM), regulates microglial inflammatory responses through activation of Akt, resulting in the inhibition of GSK‐3β. GSK‐3β regulates the phosphorylation of CREB, thereby controlling the expression of inflammation‐related genes and microglial plasticity. The anti‐inflammatory action of VuPAM in microglia is reversed by inhibiting Akt/GSK‐3β/CREB signaling. Using a well‐characterized TBI model and CX3CR1gfp/+ mice to visualize microglia in vivo, we demonstrate that VuPAM enhances Akt/GSK‐3β/CREB signaling in the injured cortex, as well as anti‐inflammatory microglial markers. Furthermore, in situ analysis revealed that GFP + microglia in the cortex of VuPAM‐treated TBI mice co‐express pCREB and the anti‐inflammatory microglial phenotype marker YM1. Taken together, our data show that VuPAM decreases pro‐inflammatory microglial activation by modulating Akt/GSK‐3β/CREB signaling. These findings serve to clarify the potential neuroprotective mechanisms of mGluR5 PAM treatment after TBI, and suggest novel therapeutic targets for post‐traumatic neuroinflammation.