Figure 7.

Proposed mechanism of TMAO induced synaptic plasticity deficits. Activation of PERK by TMAO leads to phosphorylation of eIF2α which can directly inhibit general protein synthesis (mRNA translation) or activate ATF4. ATF4 negatively regulates synaptic plasticity and memory by acting as a repressor of CRE-dependent transcription (CREB). Alternatively, ATF4 translocates to the nucleus and increases the expression of CHOP which promotes reactive oxygen species formation, inflammation, and apoptosis.