Aging-related cellular and molecular changes reveal a role for Bglap3+ neurons in MEC spatial cognition

Aging-related cognitive decline, including impairments in spatial orientation and memory, has been linked to dysfunction within the hippocampus and medial entorhinal cortex (MEC). However, the cellular and molecular alterations underlying MEC aging remain poorly understood. Here, we show that old mice exhibit a reduced proportion of grid cells and decreased spatial stability.

Transcriptomic profiling of the MEC using 10x Genomics Visium technology reveals 1664 differentially expressed genes between young and old mice. Among these, Bglap3 is identified as a marker gene for a subpopulation of layer III neurons that showed an age-associated reduction in cell number. Chemogenetic silencing of Bglap3+ neurons in young mice impairs spatial tuning of MEC neurons.

Together, these findings elucidate cellular and molecular mechanisms contributing to age-related MEC dysfunction and suggest that the loss of Bglap3+ neurons may underlie spatial coding deficits in aging. We thank Jialing Zhao and Julien Rousseau for proofreading the manuscript. We thank the Core Facilities of the School of Life Sciences, the State Key Laboratory of Membrane Biology at Peking University for assistance with confocal microscopy and Miniaturized Two-Photon Microscope.

This work was funded by the Science Fund for Distinguished Young Scholars of Beijing (JQ23023; C.M.), Qidong-SLS Innovation Fund (2023002029 and 2020001540; C.M.), Lingang Laboratory (Grant No. LG-TKN-202204-01), Open Project for Chenglin Miao, State Key Laboratory of Membrane Biology. These authors contributed equally: Qichen Cao, Guge Suri, Sihui Cheng, Yuanjing Liu.

State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University, Beijing, China Qichen Cao, Guge Suri, Sihui Cheng, Yuanjing Liu, Jiangyuan Liu, Shidan Wen, Meng Zhong, Jun Hao, Shuyang Yao, Yikai Yang, Shuai Xu, Hong Jin, Xinyu Yan & Chenglin Miao PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing, China Peking University–Tsinghua University–National Institute of Biological Sciences Joint Graduate Program, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China Peking–Tsinghua Center for Life Sciences, Beijing, China Sihui Cheng, Yuanjing Liu, Jiangyuan Liu, Shuai Xu & Chenglin Miao State Key Laboratory for Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China Peking University Chengdu Academy for Advanced Interdisciplinary Biotechnologies, Chengdu, China Correspondence to Guge Suri or Chenglin Miao. The authors declare no competing interests. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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