Abstract
Lactate plays an important role in brain energy metabolism. It contributes to normal brain development and to neuroprotection in diabetic hypoglycemia, but its role in neonatal hypoglycemia is unclear. Moreover, lactate can work as a signaling substance via the lactate receptor HCAR1 (Hydroxycarboxylic acid receptor 1). Recent studies indicate that HCAR1 is protective in mouse models of neonatal hypoxic ischemia and has a role in metabolic regulation in glial cells during hypoglycemia. Here we have studied potential impacts of HCAR1 on axonal and myelin development in the cerebral cortex and corpus callosum of young (p21) wild type (WT) mice and HCAR1 KO mice and in cortical organotypic brain slice cultures. The HCAR1 KO mice showed lower axonal area relative to WT in both cortex and corpus callosum. However, the myelin area was unaffected by HCAR1 KO. Using particle- and colocalization analysis we show that HCAR1 KO predominantly reduces axonal size in unmyelinated axons. Using an organotypic brain slice model of neonatal hypoglycemia, we find that lactate protects both axonal and myelin development in hypoglycemia, partially via HCAR1. Lastly, live imaging with a pH-sensitive dye on acute cortical brain slices indicates that cellular lactate uptake is influenced by HCAR1. In conclusion, our findings support a role of HCAR1 in axonal development and in lactate's protective effects in hypoglycemia.
Significance statement Lactate is a critical metabolite for brain energy metabolism, with established roles in neuroprotection and development. Our study provides new insights into the role of the lactate receptor HCAR1 in axonal and myelin development in the neonatal brain. We demonstrate that HCAR1 influences axonal size, particularly in unmyelinated axons, and mediates lactate’s protective effects during neonatal hypoglycemia. Using in vivo and ex vivo approaches, including organotypic brain slice cultures and live imaging, we show that HCAR1 influences cellular lactate uptake and protects axonal and myelin integrity under hypoglycemic conditions. These findings highlight the dual role of lactate as an energy substrate and signaling molecule via HCAR1, with implications for understanding brain development and resilience to metabolic stress.
Footnotes
Electron microscopy was carried out at the EM facility at the Institute of Oral Biology, UiO. Special thanks to Yiqing Cai at the Institute of Oral Biology for assistance with tissue processing and the preparation of ultrathin sections. Furthermore, we extend our gratitude to Krister Andersson for help with PCR (genotyping), Jon Storm-Mathisen for valuable scientific discussions and, Farrukh Abbas Chaudhry for the use of facilities and instruments at the Division of Anatomy, UiO. We also want to thank the group of Prof. Kåre-Olav Stensløkken for help with glucose measurements. Lastly, we thank Hilde Galtung at the institute of Oral Biology for lending out her cell lab for culturing organotypic brain slices.
Authors report no conflict of interest
This work was supported by the South-Eastern Norway Regional Health Authority (grants 2020042 and 2018050), the Norwegian Health Association (grant 4841) and the Medical research program at the University of Oslo.
This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
