Atypical astrocytes in the aging cortex

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SUMMARY. During normal aging, astrocytes change their transcriptional and functional properties. Astrocyte play a central role in shaping neuronal function through their expression of excitatory amino acid transporters (EAATs: GLT-1 and GLAST), which mediate glutamate uptake, and the inwardly rectifying K+ channel, Kir4.1, which buffers extracellular K+. While we know that EAAT and Kir4.1 expression are developmentally regulated, we know little about their role in normal aging. This proposal is built on our novel finding that progressively more astrocytes lose EAAT and Kir4.1 expression during aging. Surprisingly, this loss is not a gradual, global change but occurs on a cell-by-cell basis with individual astrocytes expressing minimal EAAT and Kir4.1, while neighboring astrocytes remain normal. These “atypical astrocytes” are found predominantly in the retrosplenial and prefrontal cortices (RSC and PFC), but not in the hippocampus or somatosensory cortex. Atypical astrocytes are more abundant in males, and grow in number as animals age. By  1 year of age, up to 15% of astrocytes are atypical in these regions. Interestingly, atypical astrocytes are not reactive, as they lack elevated GFAP immunoreactivity. Importantly, atypical astrocytes are Sox9 positive, showing that they are in fact astrocytes. They also do not label for NG2 (OPC marker), MBP (oligodendrocyte marker), or NeuN (neuronal marker). Atypical astrocytes are often associated with blood vessels, but whether vascular changes contribute to their emergence is unknown. Based on preliminary data, we hypothesize that atypical astrocytes accumulate in the RSC and PFC during normal aging and cause domains of impaired glutamate and K+ uptake. This is significant because these areas play a prominent role in spatial memory and executive function. If our hypothesis is correct, the loss of glutamate and K+ uptake could contribute to age-related losses in cognitive functions associated with these regions. In addition, the combined loss of EAATs and Kir4.1 during aging may be especially detrimental. We recently published that bursts of neuronal activity > 30 Hz drives synapse-specific inhibition of glutamate uptake. We suspect this is due to focal K+-mediated depolarization of astrocyte distal processes driving voltage-dependent inhibition of EAAT function. Using genetically encoded voltage indicators (GEVIs), our preliminary data shows that astrocyte distal processes undergo significant activity-induced depolarization, in line with voltage-dependent EAAT inhibition. Because Kir4.1 is critical to buffering extracellular K+, its loss in aging likely exacerbates activity-induced astrocyte depolarization and increases voltage-dependent suppression of glutamate uptake. Here, we will use electrophysiology, glutamate and GEVI imaging, and anatomical approaches to determine whether RSC and PFC astrocytes lose expression of EAATs and Kir4.1 during aging and whether this leads to disrupted glutamate uptake and K+ buffering. When completed, we will be poised to establish the mechanisms that induce atypical astrocytes and determine whether atypical astrocytes contribute to age-related synaptic and cognitive dysfunction.