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

Wuhyun Koh¹, Mijeong Park², Ye Eun Chun³, Jaekwang Lee⁴, Hyun Soo Shim⁵, Mingu Gordon Park⁶, Sunpil Kim⁷, Moonsun Sa⁶, Jinhyeong Joo⁸, Hyunji Kang⁸, Soo-Jin Oh⁹, Junsung Woo³, Heejung Chun¹⁰, Seung Eun Lee¹¹, Jinpyo Hong⁴, Jiesi Feng¹², Yulong Li¹², Hoon Ryu⁵, Jeiwon Cho¹³, C Justin Lee¹⁴

Affiliations

¹ Center for Cognition and Sociality, Institute for Basic Science, Daejeon, South Korea; Department of Neuroscience, Division of BioMedical Science & Technology, Korea Institute of Science and Technology School, Korea University of Science and Technology, Seoul, South Korea; Center for Functional Connectomics, Brain Science Institute, Korea Institute of Science and Technology, Seoul, South Korea.
² Department of Neuroscience, Division of BioMedical Science & Technology, Korea Institute of Science and Technology School, Korea University of Science and Technology, Seoul, South Korea; Center for Neuroscience, Brain Science Institute, Korea Institute of Science and Technology, Seoul, South Korea.
³ Department of Neuroscience, Division of BioMedical Science & Technology, Korea Institute of Science and Technology School, Korea University of Science and Technology, Seoul, South Korea; Center for Functional Connectomics, Brain Science Institute, Korea Institute of Science and Technology, Seoul, South Korea.
⁴ Center for Functional Connectomics, Brain Science Institute, Korea Institute of Science and Technology, Seoul, South Korea.
⁵ Center for Neuroscience, Brain Science Institute, Korea Institute of Science and Technology, Seoul, South Korea.
⁶ Center for Cognition and Sociality, Institute for Basic Science, Daejeon, South Korea; KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, South Korea.
⁷ Center for Cognition and Sociality, Institute for Basic Science, Daejeon, South Korea; KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, South Korea; Center for Functional Connectomics, Brain Science Institute, Korea Institute of Science and Technology, Seoul, South Korea.
⁸ Center for Cognition and Sociality, Institute for Basic Science, Daejeon, South Korea; IBS School, Korea University of Science and Technology, Daejeon, South Korea.
⁹ Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology, Seoul, South Korea; Center for Neuroscience, Brain Science Institute, Korea Institute of Science and Technology, Seoul, South Korea.
¹⁰ Center for Cognition and Sociality, Institute for Basic Science, Daejeon, South Korea; Center for Functional Connectomics, Brain Science Institute, Korea Institute of Science and Technology, Seoul, South Korea.
¹¹ Virus Facility, Research Animal Resource Center, Korea Institute of Science and Technology, Seoul, South Korea.
¹² State Key Laboratory of Membrane Biology, Peking University School of Life Sciences, Beijing, China.
¹³ Brain and Cognitive Science, Scranton College, Ewha Womans University, Seoul, South Korea.
¹⁴ Department of Neuroscience, Division of BioMedical Science & Technology, Korea Institute of Science and Technology School, Korea University of Science and Technology, Seoul, South Korea; KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, South Korea; KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, South Korea; IBS School, Korea University of Science and Technology, Daejeon, South Korea. Electronic address: cjl@ibs.re.kr.

PMID: 34952697
DOI: 10.1016/j.biopsych.2021.10.012

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

Wuhyun Koh et al. Biol Psychiatry. 2022.

. 2022 Apr 15;91(8):740-752.

doi: 10.1016/j.biopsych.2021.10.012. Epub 2021 Oct 20.

Authors

Affiliations

¹ Center for Cognition and Sociality, Institute for Basic Science, Daejeon, South Korea; Department of Neuroscience, Division of BioMedical Science & Technology, Korea Institute of Science and Technology School, Korea University of Science and Technology, Seoul, South Korea; Center for Functional Connectomics, Brain Science Institute, Korea Institute of Science and Technology, Seoul, South Korea.
² Department of Neuroscience, Division of BioMedical Science & Technology, Korea Institute of Science and Technology School, Korea University of Science and Technology, Seoul, South Korea; Center for Neuroscience, Brain Science Institute, Korea Institute of Science and Technology, Seoul, South Korea.
³ Department of Neuroscience, Division of BioMedical Science & Technology, Korea Institute of Science and Technology School, Korea University of Science and Technology, Seoul, South Korea; Center for Functional Connectomics, Brain Science Institute, Korea Institute of Science and Technology, Seoul, South Korea.
⁴ Center for Functional Connectomics, Brain Science Institute, Korea Institute of Science and Technology, Seoul, South Korea.
⁵ Center for Neuroscience, Brain Science Institute, Korea Institute of Science and Technology, Seoul, South Korea.
⁶ Center for Cognition and Sociality, Institute for Basic Science, Daejeon, South Korea; KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, South Korea.
⁷ Center for Cognition and Sociality, Institute for Basic Science, Daejeon, South Korea; KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, South Korea; Center for Functional Connectomics, Brain Science Institute, Korea Institute of Science and Technology, Seoul, South Korea.
⁸ Center for Cognition and Sociality, Institute for Basic Science, Daejeon, South Korea; IBS School, Korea University of Science and Technology, Daejeon, South Korea.
⁹ Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology, Seoul, South Korea; Center for Neuroscience, Brain Science Institute, Korea Institute of Science and Technology, Seoul, South Korea.
¹⁰ Center for Cognition and Sociality, Institute for Basic Science, Daejeon, South Korea; Center for Functional Connectomics, Brain Science Institute, Korea Institute of Science and Technology, Seoul, South Korea.
¹¹ Virus Facility, Research Animal Resource Center, Korea Institute of Science and Technology, Seoul, South Korea.
¹² State Key Laboratory of Membrane Biology, Peking University School of Life Sciences, Beijing, China.
¹³ Brain and Cognitive Science, Scranton College, Ewha Womans University, Seoul, South Korea.
¹⁴ Department of Neuroscience, Division of BioMedical Science & Technology, Korea Institute of Science and Technology School, Korea University of Science and Technology, Seoul, South Korea; KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, South Korea; KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, South Korea; IBS School, Korea University of Science and Technology, Daejeon, South Korea. Electronic address: cjl@ibs.re.kr.

PMID: 34952697
DOI: 10.1016/j.biopsych.2021.10.012

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.

Keywords: Astrocyte; Best1; Cognitive flexibility; Metaplasticity; NMDAR tone; Norepinephrine.

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Astrocytes Get the BEST1 Out of NMDA Receptors.
Berlin S. Berlin S. Biol Psychiatry. 2022 Apr 15;91(8):e29-e30. doi: 10.1016/j.biopsych.2022.01.014. Biol Psychiatry. 2022. PMID: 35331393 No abstract available.

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

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

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