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Biol. Psychiatry, Available online 20 October 2021 | https://doi.org/10.1016/j.biopsych.2021.10.012 Astrocytes render memory flexible by releasing D-serine and regulating NMDAR tone in the hippocampus

Wuhyun Koh^a,b,f, Mijeong Park^b,g, Ye Eun Chun^b,f, Jaekwang Lee^f, Hyun Soo Shim^g, Mingu Gordon Park^a,c, Sunpil Kim^a,c,f, Moonsun Sa^a,c, Jinhyeong Joo^a,i, Hyunji Kang^a,i, Soo-Jin Oh^d,g, Junsung Woo^b,f, Heejung Chun^a,f, Seung Eun Lee^e, Jinpyo Hong^f, Jiesi Feng^j, Yulong Li^j, Hoon Ryu^g, Jeiwon Cho^h, C. Justin Lee^a,b,c,i,*

^aCenter for Cognition and Sociality, Institute for Basic Science, Daejeon, South Korea
^bDepartment of Neuroscience, Division of BioMedical Science & Technology, Korea Institute of Science and Technology School, Korea University of Science and Technology, Seoul, South Korea
^cKU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, South Korea
^dConvergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology, Seoul, South Korea
^eVirus Facility, Research Animal Resource Center, Korea Institute of Science and Technology, Seoul, South Korea
^fCenter for Functional Connectomics, Brain Science Institute, Korea Institute of Science and Technology, Seoul, South Korea
^gCenter for Neuroscience, Brain Science Institute, Korea Institute of Science and Technology, Seoul, South Korea
^hBrain and Cognitive Science, Scranton College, Ewha Womans University, Seoul, South Korea
ⁱIBS School, Korea University of Science and Technology, Daejeon, South Korea
^jState Key Laboratory of Membrane Biology, Peking University School of Life Sciences, Beijing, China

^*Corresponding author.

Abstract

Background
NMDAR hypofunction has been implicated in several psychiatric disorders with an 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 the heterosynaptic long-term depression, metaplasticity and cognitive flexibility.

Results
We found that hippocampal astrocytes regulate NMDAR tone via Best1-mediated co-release of D-serine and glutamate. Best1 knockout mice (Best1 KO) exhibited reduced NMDAR tone and impairments of homosynaptic and α1-adrenergic receptor-dependent heterosynaptic long-term depression, which leads to the defects in metaplasticity and cognitive flexibility. These impairments in Best1 KO can be rescued by hippocampal astrocyte-specific Best1 expression or enhanced NMDAR tone through D-serine supplement. Importantly, D-serine injection in Best1 KO 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.

논문정보

형식Research article
게재일2021년 10월 (BRIC 등록일 2021-12-22)
연구진국내(교신)+국외 연구진
분야 생명과학 > 신경생물학
피인용횟수60회 이상 인용된 논문 (상위피인용논문 등록일 2025-03-28)

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