eIF2α phosphorylation status is a major switch of synaptic plasticity, dictating whether a given synapse undergoes long-term potentiation (LTP) or long-term depression (LTD). Suppression of eIF2α phosphorylation induces LTP by favouring new protein synthesis of ‘LTP proteins’. In contrast, increased levels of eIF2α phosphorylation drives the expression of LTD-specific proteins. Impairment of these synaptic changes triggers cognitive decline (highlighted in red), inherently associated with neurodegenerative disorders that bidirectionally affect levels of eIF2α phosphorylation.