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

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Astrocytes Render Memory Flexible by Releasing D-Serine and Regulating NMDA Receptor Tone in the Hippocampus
Biological Psychiatry ( IF 9.6 ) Pub Date : 2021-10-20 , DOI: 10.1016/j.biopsych.2021.10.012
Wuhyun Koh ₁ , Mijeong Park ₂ , Ye Eun Chun ₃ , Jaekwang Lee ₄ , Hyun Soo Shim ₅ , Mingu Gordon Park ₆ , Sunpil Kim ₇ , Moonsun Sa ₆ , Jinhyeong Joo ₈ , Hyunji Kang ₈ , Soo-Jin Oh ₉ , Junsung Woo ₃ , Heejung Chun ₁₀ , Seung Eun Lee ₁₁ , Jinpyo Hong ₄ , Jiesi Feng ₁₂ , Yulong Li ₁₂ , Hoon Ryu ₅ , Jeiwon Cho ₁₃ , C Justin Lee ₁₄

Affiliation

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.
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.
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.
Center for Functional Connectomics, Brain Science Institute, Korea Institute of Science and Technology, Seoul, South Korea.
Center for Neuroscience, Brain Science Institute, Korea Institute of Science and Technology, Seoul, South Korea.
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 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.
Center for Cognition and Sociality, Institute for Basic Science, Daejeon, South Korea; IBS School, Korea University of Science and Technology, Daejeon, South Korea.
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.
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.
Virus Facility, Research Animal Resource Center, Korea Institute of Science and Technology, Seoul, South Korea.
State Key Laboratory of Membrane Biology, Peking University School of Life Sciences, Beijing, China.
Brain and Cognitive Science, Scranton College, Ewha Womans University, Seoul, 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; 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.

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.

中文翻译：

星形胶质细胞通过释放 D-丝氨酸和调节海马中的 NMDA 受体音调使记忆变得灵活

背景

NMDA 受体 (NMDAR) 功能减退与认知灵活性受损的几种精神疾病有关。然而，关于 NMDAR 功能减退和 NMDAR 音调降低如何导致认知灵活性受损的分子机制知之甚少。此外，尚不清楚海马星形胶质细胞是否调节 NMDAR 张力和认知灵活性。

方法

我们采用细胞类型特异性基因操作、离体电生理记录、嗅探器贴片记录、用于去甲肾上腺素的尖端生物传感器和行为分析来研究星形胶质细胞是否可以通过释放 D-丝氨酸和谷氨酸来调节 NMDAR 音调。随后，我们进一步研究了 NMDAR 音调在异突触长期抑郁、元可塑性和认知灵活性中的作用。

结果

我们发现海马星形胶质细胞通过 BEST1 介导的 D-丝氨酸和谷氨酸的共释放来调节 NMDAR 音调。Best1基因敲除小鼠表现出 NMDAR 音调降低以及同突触和 α ₁肾上腺素能受体依赖性异突触长期抑制的损伤，这导致化生性和认知灵活性缺陷。Best1敲除小鼠的这些损伤可以通过海马星形胶质细胞特异性 BEST1 表达或通过 D-丝氨酸补充剂增强 NMDAR 音调来挽救。在初始学习期间向Best1敲除小鼠中注射 D-丝氨酸可挽救随后的逆转学习。