Journal
JOURNAL OF NEUROCHEMISTRY
Volume 156, Issue 2, Pages 225-248Publisher
WILEY
DOI: 10.1111/jnc.14954
Keywords
Akt/GSK-3 beta/CREB signaling; anti-inflammatory; metabotropic glutamate receptor 5; microglia; positive allosteric modulator; traumatic brain injury
Categories
Funding
- National Institute of Neurological Disorders and Stroke [R01NS037313, R01NS082308, R01NS096002]
- Science Foundation Ireland [17/FRL/4860]
- National Institutes of Health
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Research shows that mGluR5 PAM treatment post-TBI reduces pro-inflammatory microglial activation by modulating Akt/GSK-3 beta/CREB signaling, enhancing anti-inflammatory markers and promoting neuroprotection.
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-3 beta. GSK-3 beta 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-3 beta/CREB signaling. Using a well-characterized TBI model and CX3CR1(gfp/+) mice to visualize microglia in vivo, we demonstrate that VuPAM enhances Akt/GSK-3 beta/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-3 beta/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.
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