Calcium's role as nuanced modulator of cellular physiology in the brain

Abstract

Neuroscientists studying normal brain aging, spinal cord injury, Alzheimer's disease (AD) and other neurodegenerative diseases have focused considerable effort on carefully characterizing intracellular perturbations in calcium dynamics or levels. At the cellular level, calcium is known for controlling life and death and orchestrating most events in between. For many years, intracellular calcium has been recognized as an essential ion associated with nearly all cellular functions from cell growth to degeneration. Often the emphasis is on the negative impact of calcium dysregulation and the typical worse-case-scenario leading inevitably to cell death. However, even high amplitude calcium transients, when executed acutely, can alter neuronal communication and synaptic strength in positive ways, without necessarily killing neurons. Here, we focus on the evidence that calcium has a subtle and distinctive role in shaping and controlling synaptic events that underpin neuronal communication and that these subtle changes in aging or AD may contribute to cognitive decline. We emphasize that calcium imaging in dendritic components is ultimately necessary to directly test for the presence of age- or disease-associated alterations during periods of synaptic activation.

Keywords: Afterhyperpolarization; Aging; Estrogen; Familial Alzheimer's disease; Insulin; Vitamin D.

Figure 1

Survey of the literature relating to calcium dysregulation in the brain. A PubMed search was performed with EndNote using the terms “calcium” and “brain” (A) or “calcium” and “brain” and “aging” (B), or “calcium” and “brain” and “Alzheimer’s disease” (C). The number of papers containing the combined keywords and an association with “cell death”, “physiology”, or “pathology” was obtained once every five years between the years 1970 and 2015 and was normalized to the total number of scientific publications that year. We then restricted the search to the past 30 years and collapsed the data across years and used the same search strategy. This time, we normalized the number of papers in cell death, physiology or pathology to the total number of papers within “calcium” and “brain” or “calcium” and “brain” and “aging”, or “calcium” and “brain” and “Alzheimer’s disease” is shown in (D). It is clear that a greater proportion of the literature focusing on calcium in the brain contains a majority of the work centered on physiological outcomes.