Endoplasmic Reticulum in Metaplasticity: From Information Processing to Synaptic Proteostasis

The ER (endoplasmic reticulum) is a Ca2+ reservoir and the unique protein-synthesizing machinery which is distributed throughout the neuron and composed of multiple different structural domains. One such domain is called EMC (endoplasmic reticulum membrane protein complex), pleiotropic nature in cellular functions. The ER/EMC position inside the neurons unmasks its contribution to synaptic plasticity via regulating various cellular processes from protein synthesis to Ca2+ signaling. Since presynaptic Ca2+ channels and postsynaptic ionotropic receptors are organized into the nanodomains, thus ER can be a crucial player in establishing TMNCs (transsynaptic molecular nanocolumns) to shape efficient neural communications. This review hypothesized that ER is not only involved in stress-mediated neurodegeneration but also axon regrowth, remyelination, neurotransmitter switching, information processing, and regulation of pre- and post-synaptic functions. Thus ER might not only be a protein-synthesizing and quality control machinery but also orchestrates plasticity of plasticity (metaplasticity) within the neuron to execute higher-order brain functions and neural repair.