Fig. 4

Schematic representation for how mGluR5 antagonism modulates mTOR and CREB signaling in zQ175 mice. The pharmacological inhibition of mGluR5 with CTEP in zQ175 mice abolishes the enhanced signaling of mammalian target of rapamycin (mTOR) by reducing the phosphorylation of phosphoinositide-dependent kinase-1 (PDK1), Akt and mTOR. Reduced mTOR signaling was confirmed by a reduction in the phosphorylation of downstream p70S6K and was associated with decreased inhibitory phosphorylation of ULK1 at S757 leading to activation of autophagy. Activation of autophagy and reduction in mHTT load can facilitate the binding of phosphorylated cAMP response element-binding protein (CREB) activity to cAMP response element (CRE) in the nucleus. Activation of CREB-mediated gene expression of cFos and brain-derived neurotrophic factor (BDNF) synthesis can contribute to neuronal survival and reduced apoptosis in zQ175 mice