Gray and white matter astrocytes differ in basal metabolism but respond similarly to neuronal activity

Abstract

Astrocytes are a heterogeneous population of glial cells in the brain, which adapt their properties to the requirements of the local environment. Two major groups of astrocytes are protoplasmic astrocytes residing in gray matter as well as fibrous astrocytes of white matter. Here, we compared the energy metabolism of astrocytes in the cortex and corpus callosum as representative gray matter and white matter regions, in acute brain slices taking advantage of genetically encoded fluorescent nanosensors for the NADH/NAD + redox ratio and for ATP.Astrocytes of the corpus callosum presented a more reduced basal NADH/NAD + redox ratio, and a lower cytosolic concentration of ATP compared to cortical astrocytes. In cortical astrocytes, the neurotransmitter glutamate and increased extracellular concentrations of K + , typical correlates of neuronal activity, induced a more reduced NADH/NAD + redox ratio. While application of glutamate decreased [ATP], K + as well as the combination of glutamate and K + resulted in an increase of ATP levels. Strikingly, a very similar regulation of metabolism by K + and glutamate was observed in astrocytes in the corpus callosum. Finally, strong intrinsic neuronal activity provoked by application of bicuculline and withdrawal of Mg 2+ caused a shift of the NADH/NAD + redox ratio to a more reduced state as well as a slight reduction of [ATP] in gray and white matter astrocytes. In summary, the metabolism of astrocytes in cortex and corpus callosum shows distinct basal properties, but qualitatively similar responses to neuronal activity, probably reflecting the different environment and requirements of these brain regions.

Activation of TRPV4 channels promotes the loss of cellular ATP in organotypic slices of the mouse neocortex exposed to chemical ischemia

“…Notably, the majority of astrocytes experienced a brief initial increase in their ATeam ratio, a phenomenon never observed in neurons. An initial rise in the ATP concentration of astrocytes, but not neurons, was also observed in earlier studies upon increasing extracellular K + concentrations or upon synaptic stimulation (Baeza-Lehnert et al, 2019;Gerkau et al, 2019;Kohler et al, 2023;Lerchundi et al, 2019). The same was true when neuronal bursting activity was induced, upon which astrocytes (but not neurons) showed an initial rise in ATP levels before their ATP slowly declined (Gerkau et al, 2019;Lerchundi et al, 2020;Toloe et al, 2014).…”

Altered astrocytic and microglial homeostasis characterizes a decreased proinflammatory state in bipolar disorder

“…Given the morphological and functional differences of astrocytes between WM and GM 81 and the fact that astrocyte alterations in BD have been reported to differ between the WM and the GM 82 , we next tested if the BD-associated molecular alterations in astrocytes were dependent on their localization 83,84 . We thus employed spatial transcriptomics and the Digital Spatial Profiling (DSP) to perform a gene expression analysis in GFAP-“enriched” regions of interest (ROI) in WM and GM (Figure 6A).…”

FXTAS Neuropathology Includes Widespread Reactive Astrogliosis and White Matter Specific Astrocyte Degeneration

“…However, WM astrocytes do have metabolic differences, including reduced basal glycogen and ATP content and a more reduced NADH/NAD+ redox ratio than GM astrocytes. 39 It is possible that these differences render WM astrocytes less able to cope metabolically with FMR1 toxicity. In addition to astrocytes, WM is composed predominantly of oligodendrocytes and myelinated axons, as well as vasculature and microglia.…”

“…There are no known differences in FMR1 expression or toxicity in WM relative to GM astrocytes. However, WM astrocytes do have metabolic differences, including reduced basal glycogen and ATP content and a more reduced NADH/NAD+ redox ratio than GM astrocytes 39 . It is possible that these differences render WM astrocytes less able to cope metabolically with FMR1 toxicity.…”