{Reference Type}: Journal Article
{Title}: RIPK1 activation in Mecp2-deficient microglia promotes inflammation and glutamate release in RTT.
{Author}: Cao Z;Min X;Xie X;Huang M;Liu Y;Sun W;Xu G;He M;He K;Li Y;Yuan J;
{Journal}: Proc Natl Acad Sci U S A
{Volume}: 121
{Issue}: 6
{Year}: 2024 Feb 6
{Factor}: 12.779
{DOI}: 10.1073/pnas.2320383121
{Abstract}: Rett syndrome (RTT) is a devastating neurodevelopmental disorder primarily caused by mutations in the methyl-CpG binding protein 2 (Mecp2) gene. Here, we found that inhibition of Receptor-Interacting Serine/Threonine-Protein Kinase 1 (RIPK1) kinase ameliorated progression of motor dysfunction after onset and prolonged the survival of Mecp2-null mice. Microglia were activated early in myeloid Mecp2-deficient mice, which was inhibited upon inactivation of RIPK1 kinase. RIPK1 inhibition in Mecp2-deficient microglia reduced oxidative stress, cytokines production and induction of SLC7A11, SLC38A1, and GLS, which mediate the release of glutamate. Mecp2-deficient microglia release high levels of glutamate to impair glutamate-mediated excitatory neurotransmission and promote increased levels of GluA1 and GluA2/3 proteins in vivo, which was reduced upon RIPK1 inhibition. Thus, activation of RIPK1 kinase in Mecp2-deficient microglia may be involved both in the onset and progression of RTT.