A Link between Glial Ca 2+ Signaling and Hypoxia in Aging?

Most neuroscientists now acknowledge that there is more to the brain than neurons. A flurry of studies in the past decade have documented the importance of glia in complex processes that were previously believed to be strictly neuronal. ¹ The majority of these studies have pointed to a key role of astrocytic Ca²⁺ signaling in the modulation of synaptic transmission. In fact, Ca²⁺ signaling in electrically silent astrocytes can in many ways be compared with electrical excitability in neurons: Astrocytes integrate multiple inputs into dynamic Ca²⁺ signals and in turn modulate the activity of surrounding neurons. Perhaps, the most interesting discovery is that astrocytic Ca²⁺ signaling appears to be intimately involved in neural homeostatic regulation. For example, Ca²⁺ signaling in brain stem astrocytes may help to control breathing: A reduction in extracellular pH leads to astrocytic Ca²⁺-dependent ATP release. ATP binds to purinergic (ATP) receptors on neighboring respiratory neurons, depolarizing them and resulting in an increase in respiration. ²

Cerebellar Bergman glial cells, a special type of astrocyte, display a unique type of slowly and radially propagating Ca²⁺ signaling that is inhibited by purinergic receptor antagonists.^3,4 In the present issue of JCBFM, Mathiesen et al use two-photon in vivo imaging to study the occurrence of spontaneous Ca²⁺ waves in Bergman glial cells in the aging brain. ⁵ The authors found that spontaneous glial Ca²⁺ waves in the cerebellum become more frequent in an aged cohort of mice, and that this potentiation of Ca²⁺ signaling is correlated with a reduction in tissue partial pressure of oxygen. Using induced hypoxia and exogenous ATP application, additional data were collected to show that glial Ca²⁺ signaling and hypoxia are related to one another. This is an intriguing set of observations as glial Ca²⁺ signaling appears to drive a number of adaptive responses to hypoxia, including increases in local blood flow and changes in Purkinje cell bistability.^4,6,7

The present study by Mathiesen et al raises a number of provocative questions. Perhaps, the most important is whether reduced tissue oxygen or increased glial Ca²⁺ signaling is the driving factor of functional decline in the aging brain. The authors show that in the young brain, the interaction can go either way. ATP-evoked glial signaling drives a reduction in tissue oxygen, while inducing tissue hypoxia by altering the breathing mixture can increase glial Ca²⁺ signaling. Which of these factors come first in the aged brain? If tissue oxygenation in the aged brain is normalized, does the animal regain ‘young’ patterns of glial Ca²⁺ signaling? Conversely, if spontaneous glial signaling is normalized in the aged brain, will tissue oxygen levels rebound? The authors also note that similar increases in spontaneous glial Ca²⁺ events are observed in the awake state compared with the anesthetized brain.^8,9 Do the present age-related increases in spontaneous Ca²⁺ events reflect an extension of the ‘awake’ level of glial signaling into the anesthetized state, or is an even greater increase in astrocytic Ca²⁺ signaling observed in the aged awake brain?

Astrocytes play a critical role in maintaining essential homeostasis within brain tissue, including modulating neuronal activity and coupling neuronal activation to local changes in blood flow. ¹⁰ The study from Lauritzen and colleagues is important because it suggests that age-related changes in astrocytic function may contribute to the vulnerability of the aged brain to injury, and in particular, hypoxic injury.