Calcium dysregulation and neuroinflammation: discrete and integrated mechanisms for age-related synaptic dysfunction.

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.