Activity-dependent protein synthesis in neurons requires microglial-metabolic coupling

  • Cell Metab. 2026 Jun 4:S1550-4131(26)00191-9. doi: 10.1016/j.cmet.2026.05.006.
Drew Adler  1 ,  Alejandro Martín-Ávila  2 ,  Evan Cheng  3 ,  Mauricio M Oliveira  3 ,  Muxian Zhang  4 ,  Harrison T Evans  3 ,  Deliang Yuan  4 ,  Richard Sam  3 ,  Nicole D Zhang  3 ,  Maria Clara Selles  5 ,  Olivia Mosto  3 ,  Wendy J Liu  3 ,  Victor T Wu  3 ,  Amy X Guo  6 ,  Shane A Liddelow  7 ,  Robert C Froemke  8 ,  Moses V Chao  9 ,  Wen-Biao Gan  4 ,  Eric Klann  10
Affiliations
  • 1. Center for Neural Science, New York University, New York, NY 10003, USA; Department of Neuroscience, New York University Grossman School of Medicine, New York, NY 10016, USA; Institute for Translational Neuroscience, New York University Grossman School of Medicine, New York, NY 10016, USA.
  • 2. Center for Neural Science, New York University, New York, NY 10003, USA; Institute for Translational Neuroscience, New York University Grossman School of Medicine, New York, NY 10016, USA.
  • 3. Center for Neural Science, New York University, New York, NY 10003, USA.
  • 4. Institute of Neurological and Psychiatric Disorders, Shenzhen Bay Laboratory, Shenzhen, Guangdong, China.
  • 5. Department of Neuroscience, New York University Grossman School of Medicine, New York, NY 10016, USA; Institute for Translational Neuroscience, New York University Grossman School of Medicine, New York, NY 10016, USA.
  • 6. Institute for Translational Neuroscience, New York University Grossman School of Medicine, New York, NY 10016, USA.
  • 7. Department of Neuroscience, New York University Grossman School of Medicine, New York, NY 10016, USA; Department of Ophthalmology, New York University Grossman School of Medicine, New York, NY 10016, USA; Institute for Translational Neuroscience, New York University Grossman School of Medicine, New York, NY 10016, USA.
  • 8. Department of Neuroscience, New York University Grossman School of Medicine, New York, NY 10016, USA; Department of Otolaryngology, New York University Grossman School of Medicine, New York, NY 10016, USA; Institute for Translational Neuroscience, New York University Grossman School of Medicine, New York, NY 10016, USA.
  • 9. Department of Neuroscience, New York University Grossman School of Medicine, New York, NY 10016, USA; Department of Psychiatry, New York University Grossman School of Medicine, New York, NY 10015, USA; Institute for Translational Neuroscience, New York University Grossman School of Medicine, New York, NY 10016, USA.
  • 10. Center for Neural Science, New York University, New York, NY 10003, USA. Electronic address: [email protected].
PMID: 42242219 DOI: 10.1016/j.cmet.2026.05.006
Abstract

De novo protein synthesis is required for long-lasting synaptic plasticity and memory, but it comes with a great metabolic cost. In the mammalian brain, it remains unclear which cell types and biological mechanisms are critical for sensing and responding to increased metabolic demand. Here, we demonstrate that microglia, the resident macrophages of the brain, are required for metabolic coupling between endothelial cells, astrocytes, and neurons, which fuels protein synthesis in active neurons. Increasing metabolic demand via a motor task stimulates microglia to secrete the hypoxia-responsive protein CYR61, which increases glucose transporter expression in brain vasculature. Depleting microglia reduces training-induced metabolic fluxes and neuronal protein synthesis, which can be reproduced by blocking CYR61 signaling. Thus, we define a neuroimmune metabolic circuit that is required for on-demand protein synthesis in mouse motor cortex.

Keywords
astrocyte-neuron-lactate-shuttle; brain immunometabolism; brain metabolism; immunometabolism; mRNA translation; microglia; microglia-endothelial interaction; microglia-neuron interaction; microglial-metabolic coupling; neuroimmunology; protein synthesis.
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