Metabolic dynamics in astrocytes and microglia during post-natal development and their implications for autism spectrum disorders

Abstract

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition characterized by elusive underlying mechanisms. Recent attention has focused on the involvement of astrocytes and microglia in ASD pathology. These glial cells play pivotal roles in maintaining neuronal homeostasis, including the regulation of metabolism. Emerging evidence suggests a potential association between ASD and inborn errors of metabolism. Therefore, gaining a comprehensive understanding of the functions of microglia and astrocytes in ASD is crucial for the development of effective therapeutic interventions. This review aims to provide a summary of the metabolism of astrocytes and microglia during post-natal development and the evidence of disrupted metabolic pathways in ASD, with particular emphasis on those potentially important for the regulation of neuronal post-natal maturation by astrocytes and microglia.

Keywords: astrocyte; autism spectrum disorders; brain metabolism; fatty acid oxidation; lactate; lipids; microglia; mitochondria.

FIGURE 1

Alterations in arterial concentrations, cerebral enzyme activities, and cerebral transporters for (A) glucose and (B) ketone metabolism throughout postnatal development are depicted in the graphs. The shaded area in each graph corresponds to the suckling period. Changes in arterial concentrations (solid lines) are represented by the mmol/L values on the y-axis (right). Enzymatic activities (broken lines) and changes in transporter density (bars) are presented as a percentage of the adult levels. Figure modified from Vannucci et al., 1994 and Vannucci and Simpson, 2003.

FIGURE 2

(A) The heatmap shows the gene expression levels of glycolytic enzymes in astrocytes, neurons, microglia, endothelial cells, and oligodendrocytes. Data obtained from published data by Zhang et al. (2014, ; Bennett et al. (2016); Clarke et al. (2018); Düking et al. (2022); (B) The graph shows normalized enrichment score of the “metabolic pathways” gene sets by gene set enrichment analysis, comparing z-scores of astrocyte and microglia proteomes from P42 vs. P14. The figure is a modified version of Figure 1D in Düking et al. (2022).

FIGURE 3

The mitochondria play a key role in both ketogenesis and ketolysis pathways. Ketogenesis primarily takes place in hepatic mitochondria, utilizing acetyl-CoA generated through the β-oxidation of fatty acyl-CoA. Subsequently, extrahepatic tissues absorb these ketone bodies, such as β-hydroxybutyrate (BHB) and acetoacetate (AcAc), via the monocarboxylic acid transporter (MCT). BHB can fuel the brain as alternative energy substrates under non-physiological conditions such as starvation, insulin-resistance and during post-natal development. In the mitochondria of the brain cells, ketolysis occurs, converting BHB and AcAc back into Acetyl-CoA. This process generates ATP through the tricarboxylic acid (TCA) cycle and the electron transport chain (ETC). Figure modified from Hwang et al. (2022).

FIGURE 4

The alteration in metabolism of astrocytes and microglia observed during the perinatal critical period aligns with the onset of dendritogenesis, synaptogenesis and pruning in mice. Figure modified from Oury and Pierani (2023).