The Transcriptome and Metabolic Gene Signature of Protoplasmic Astrocytes in the Adult Murine Cortex

Abstract

Protoplasmic astrocytes are critically important to energy metabolism in the CNS. Our current understanding of the metabolic interactions between neurons and glia is based on studies using cultured cells, from which mainly inferential conclusions have been drawn as to the relative roles of neurons and glia in brain metabolism. In this study, we used functional genomics to establish the relative compartmentalization of neuronal and astrocytic metabolic pathways in the adult brain. To this end, fluorescence-activated cell sorting was used to directly isolate neurons and protoplasmic astrocytes from the cortex of adult mice. Microarray analysis showed that astrocytes and neurons each express transcripts predicting individual self-sufficiency in both glycolysis and oxidative metabolism. Surprisingly, most enzymes in the tricarboxylic acid (TCA) cycle were expressed at higher relative levels in astrocytes than in neurons. Mass spectrometric analysis of the TCA cycle intermediates confirmed that freshly isolated adult astrocytes maintained an active TCA cycle, whereas immuno-electron microscopy revealed that fine astrocytic processes encompassing synapses contained a higher density of mitochondria than surrounding cells. These observations indicate that astrocytes exhibit robust oxidative metabolism in the intact adult brain and suggest a prominent contribution of astrocytic metabolism to functional brain imaging, including BOLD (blood-oxygen level-dependent) functional magnetic resonance imaging signals.

Brain Lactate Metabolism: The Discoveries and the Controversies

“…The astrocytic filopodial processes that surround and interact with synaptic structures contain mitochondria (Lovatt et al, 2007;Pardo et al, 2011;Lavialle et al, 2011) and have the potential to oxidize glucose, glycogen, and glutamate during activation. If brain activation stimulated only glycolysis in astrocytes, it would be reasonable to assign the ATP derived from this pathway toward the energetics of glutamate uptake.…”

Astroglia as a cellular target for neuroprotection and treatment of neuro‐psychiatric disorders

“…In contrast to the mixed distribution of GPR37, GPR37L1 is highly expressed in astrocytes, with in situ hybridization revealing greatest density of GPR37L1 within the Bergmann glia of the cerebellum (Valdenaire et al, 1998). Microarray studies reported more than 100 times higher expression of GPR37L1 in rat and mice astrocytes compared with neurons (Cahoy et al, 2008; Lovatt et al, 2007; Zhang et al, 2014). GPR37L1 is also expressed in oligodendrocytes (Zhang et al, 2014).…”

Supportive or information-processing functions of the mature protoplasmic astrocyte in the mammalian CNS? A critical appraisal

“…Primary cultures of astrocytes, which provide a seductive experimental simplicity, are not reliable indicators of the properties of astrocytes and how they behave in situ (Kimelberg, 1995;Kimelberg et al, 1997;Kimelberg, 2001;Lovatt et al, 2007;Cahoy et al, 2008). These alternative paths are (1) release by reversal of excitatory amino acid (EAA) transporters, which is only likely to occur under pathological conditions, (2) swelling activated anion channels and also hemi-channels, and (3) P2X receptors for ATP.…”

“…Otherwise the energy requirements at the process ends would have to be met by glycolysis, which is much less efficient. However, a recent paper in which GFAP promoter-driven GFP was used to identify small astrocyte perisynaptic end-feet found that the number of mitochondria in the end-feet was either as great or greater than other profiles in the surrounding neuropil (Lovatt et al, 2007). However, Chao et al (2002) using electron microscopy and S100-immunoreactivity to identify the processes have noted previously that the fine lamellae and filipodia are devoid of organelles, unlike the astrocytic cell body and processes.…”