Astrocytes Render Memory Flexible by Releasing D-Serine and Regulating NMDA Receptor Tone in the Hippocampus

Wuhyun Koh, Mijeong Park, Ye Eun Chun, Jaekwang Lee, Hyun Soo Shim, Mingu Gordon Park, Sunpil Kim, Moonsun Sa, Jinhyeong Joo, Hyunji Kang, Soo Jin Oh, Junsung Woo, Heejung Chun, Seung Eun Lee, Jinpyo Hong, Jiesi Feng, Yulong Li, Hoon Ryu, Jeiwon Cho, C. Justin Lee

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

Background: NMDA receptor (NMDAR) hypofunction has been implicated in several psychiatric disorders with impairment of cognitive flexibility. However, the molecular mechanism of how NMDAR hypofunction with decreased NMDAR tone causes the impairment of cognitive flexibility has been minimally understood. Furthermore, it has been unclear whether hippocampal astrocytes regulate NMDAR tone and cognitive flexibility. Methods: We employed cell type–specific genetic manipulations, ex vivo electrophysiological recordings, sniffer patch recordings, cutting-edge biosensor for norepinephrine, and behavioral assays to investigate whether astrocytes can regulate NMDAR tone by releasing D-serine and glutamate. Subsequently, we further investigated the role of NMDAR tone in heterosynaptic long-term depression, metaplasticity, and cognitive flexibility. Results: We found that hippocampal astrocytes regulate NMDAR tone via BEST1-mediated corelease of D-serine and glutamate. Best1 knockout mice exhibited reduced NMDAR tone and impairments of homosynaptic and α1 adrenergic receptor–dependent heterosynaptic long-term depression, which leads to defects in metaplasticity and cognitive flexibility. These impairments in Best1 knockout mice can be rescued by hippocampal astrocyte-specific BEST1 expression or enhanced NMDAR tone through D-serine supplement. D-serine injection in Best1 knockout mice during initial learning rescues subsequent reversal learning. Conclusions: These findings indicate that NMDAR tone during initial learning is important for subsequent learning, and hippocampal NMDAR tone regulated by astrocytic BEST1 is critical for heterosynaptic long-term depression, metaplasticity, and cognitive flexibility.

Original languageEnglish
Pages (from-to)740-752
Number of pages13
JournalBiological Psychiatry
Volume91
Issue number8
DOIs
Publication statusPublished - 2022 Apr 15

Bibliographical note

Funding Information:
This study was supported by the Creative Research Initiative Program funded by the National Research Foundation of Korea (Grant No. 2015R1A3A2066619 [to CJL]), Korea Institute of Science and Technology Institutional Program (Project No. 2E26860 [to CJL]), and Institute for Basic Science, Center for Cognition and Sociality (Grant No. IBSR001-D2 [to CJL]). WK, YEC, JL, MGP, HK, JW, and HC performed electrophysiological experiments. WK, MP, and HSS performed behavioral experiments. WK and SK performed slice imaging experiments. WK, MGP, MS, JJ, S-JO, SEL, JH, and JF performed molecular experiments. YL, HR, JC, and CJL gave technical support and conceptual advice. CJL supervised the project. WK and CJL wrote the manuscript. WK and CJL revised the manuscript. We thank Dr. Yuriy Pankratov for proofreading the manuscript. A previous version of this article was published as a preprint on bioRxiv: https://www.biorxiv.org/content/10.1101/2021.03.25.436945v1. The authors report no biomedical financial interests or potential conflicts of interest.

Funding Information:
This study was supported by the Creative Research Initiative Program funded by the National Research Foundation of Korea (Grant No. 2015R1A3A2066619 [to CJL]), Korea Institute of Science and Technology Institutional Program (Project No. 2E26860 [to CJL]), and Institute for Basic Science , Center for Cognition and Sociality (Grant No. IBSR001-D2 [to CJL]).

Publisher Copyright:
© 2021 Society of Biological Psychiatry

All Science Journal Classification (ASJC) codes

  • Biological Psychiatry

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