Garcia-Segura, M. E. | Search bioRxiv

bioRxiv2024

Dark Microglia Are Abundant in Normal Postnatal Development, where they Remodel Synapses via Phagocytosis and Trogocytosis, and Are Dependent on TREM2

This study examined dark microglia--a state linked to central nervous system pathology and neurodegeneration--during postnatal development in the mouse ventral hippocampus, finding that dark microglia interact with blood vessels and synapses and perform trogocytosis of pre-synaptic axon terminals. Furthermore, we found that dark microglia in development notably expressed C-type lectin domain family 7 member A (CLEC7a), lipoprotein lipase (LPL) and triggering receptor expressed on myeloid cells 2 (TREM2) and required TREM2, differently from other microglia, suggesting a link between their role in remodeling during development and central nervous system pathology. Together, these results point towards a previously under-appreciated role for dark microglia in synaptic pruning and plasticity during normal postnatal development.

neuroscience↗

bioRxiv2023

Integrative transcriptomic and metabolic analyses of the mammalian hibernating brain identifies a key role for succinate dehydrogenase in ischemic tolerance

Ischemic stroke results in a loss of tissue homeostasis and integrity, the underlying pathobiology of which stems primarily from the depletion of cellular energy stores and perturbation of available metabolites1. Hibernation in thirteen-lined ground squirrels (TLGS), Ictidomys tridecemlineatus, provides a natural model of ischemic tolerance as these mammals undergo prolonged periods of critically low cerebral blood flow without evidence of central nervous system (CNS) damage2. Studying the complex interplay of genes and metabolites that unfolds during hibernation may provide novel insights into key regulators of cellular homeostasis during brain ischemia. Herein, we interrogated the molecular profiles of TLGS brains at different time points within the hibernation cycle via RNA sequencing coupled with untargeted metabolomics. We demonstrate that hibernation in TLGS leads to major changes in the expression of genes involved in oxidative phosphorylation and this is correlated with an accumulation of the tricarboxylic acid (TCA) cycle intermediates citrate, cis-aconitate, and -ketoglutarate-KG. Integration of the gene expression and metabolomics datasets led to the identification of succinate dehydrogenase (SDH) as the critical enzyme during hibernation, uncovering a break in the TCA cycle at that level. Accordingly, the SDH inhibitor dimethyl malonate (DMM) was able to rescue the effects of hypoxia on human neuronal cells in vitro and in mice subjected to permanent ischemic stroke in vivo. Our findings indicate that studying the regulation of the controlled metabolic depression that occurs in hibernating mammals may lead to novel therapeutic approaches capable of increasing ischemic tolerance in the CNS.

neuroscience↗