title: Calcium dysregulation and neuroinflammation: discrete and integrated mechanisms for age-related synaptic dysfunction.
abstract: Some of the best biomarkers of age-related cognitive decline are closely linked to synaptic function and plasticity. This review highlights several age-related synaptic alterations as they relate to Ca(2+) dyshomeostasis, through elevation of intracellular Ca(2+), and neuroinflammation, through production of pro-inflammatory cytokines including interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α). Though distinct in many ways, Ca(2+) and neuroinflammatory signaling mechanisms exhibit extensive cross-talk and bidirectional interactions. For instance, cytokine production in glial cells is strongly dependent on the Ca(2+) dependent protein phosphatase calcineurin, which shows elevated activity in animal models of aging and disease. In turn, pro-inflammatory cytokines, such as TNF, can augment the expression/activity of L-type voltage sensitive Ca(2+) channels in neurons, leading to Ca(2+) dysregulation, hyperactive calcineurin activity, and synaptic depression. Thus, in addition to discussing unique contributions of Ca(2+) dyshomeostasis and neuroinflammation, this review emphasizes how these processes interact to hasten age-related synaptic changes.
authors.affiliation: Department of Physiology, University of Kentucky College of Medicine, Lexington, KY 40536, USA; Spinal Cord and Brain Injury Research Center, University of Kentucky College of Medicine, Lexington, KY 40536, USA. Electronic address: diana.mathis@uky.edu.
authors.forename: Diana M
authors.initials: DM
authors.lastname: Sama
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Norris
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D002118:Calcium / Q000502:physiology*; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism*; D017774:Long-Term Potentiation / Q000502:physiology; D036881:Long-Term Synaptic Depression / Q000502:physiology; D009473:Neuronal Plasticity / Q000502:physiology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology; D013569:Synapses / Q000502:physiology*
chemical_list: D018836:Inflammation Mediators; D002118:Calcium
keywords: Aging; Ca(2+); Cytokine; Neuroinflammation; Plasticity; Synapse