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Astrocytes Render Memory Flexible by Releasing D-Serine and Regulating NMDA Receptor Tone in the Hippocampus
- Title
- Astrocytes Render Memory Flexible by Releasing D-Serine and Regulating NMDA Receptor Tone in the Hippocampus
- Authors
- Koh, Wuhyun; Park, Mijeong; Chun, Ye Eun; Lee, Jaekwang; Shim, Hyun Soo; Park, Mingu Gordon; Kim, Sunpil; Sa, Moonsun; Joo, Jinhyeong; Kang, Hyunji; Oh, Soo-Jin; Woo, Junsung; Chun, Heejung; Lee, Seung Eun; Hong, Jinpyo; Feng, Jiesi; Li, Yulong; Ryu, Hoon; Cho, Jeiwon; Lee, C. Justin
- Ewha Authors
- 조제원
- SCOPUS Author ID
- 조제원
- Issue Date
- 2022
- Journal Title
- BIOLOGICAL PSYCHIATRY
- ISSN
- 0006-3223
1873-2402
- Citation
- BIOLOGICAL PSYCHIATRY vol. 91, no. 8, pp. 740 - 752
- Publisher
- ELSEVIER SCIENCE INC
- Indexed
- SCIE; SCOPUS
- Document Type
- Article
- 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. Bestl knockout mice exhibited reduced NMDAR tone and impairments of homosynaptic and cc i adrenergic receptor-dependent heterosynaptic long-term depression, which leads to defects in metaplasticity and cognitive flexibility. These impairments in Bestl knockout mice can be rescued by hippocampal astrocyte-specific BEST1 expression or enhanced NMDAR tone through D-serine supplement. D-serine injection in Bestl 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.
- DOI
- 10.1016/j.biopsych.2021.10.012
- Appears in Collections:
- 일반대학원 > 뇌·인지과학과 > Journal papers
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