Synaptic plasticity at the interface of health and disease: New insights on the role of endoplasmic reticulum intracellular calcium stores

Work from the past 40years has unraveled a wealth of information on the cellular and molecular mechanisms underlying synaptic plasticity and their relevance in physiological brain function. At the same time, it has been recognized that a broad range of neurological diseases may be accompanied by severe alterations in synaptic plasticity, i.e., 'maladaptive synaptic plasticity', which could initiate and sustain the remodeling of neuronal networks under pathological conditions. Nonetheless, our current knowledge on the specific contribution and interaction of distinct forms of synaptic plasticity (including metaplasticity and homeostatic plasticity) in the context of pathological brain states remains limited. This review focuses on recent experimental evidence, which highlights the fundamental role of endoplasmic reticulum-mediated Ca²⁺ signals in modulating the duration, direction, extent and type of synaptic plasticity. We discuss the possibility that intracellular Ca²⁺ stores may regulate synaptic plasticity and hence behavioral and cognitive functions at the interface between physiology and pathology.