Astrocytes Render Memory Flexible by Releasing D-Serine and Regulating NMDA Receptor Tone in the Hippocampus
Astrocytes Render Memory Flexible by Releasing D-Serine and Regulating NMDA Receptor Tone in the Hippocampus
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DOI：
10.1016/j.biopsych.2021.10.012
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发表时间：
2022-03-21
影响因子：
10.6
通讯作者：
Lee, C. Justin
中科院分区：
文献类型：
--
作者：
Koh, Wuhyun;Park, Mijeong;Lee, C. Justin
背景：N-甲基-D-天冬氨酸受体(NMDAR)功能低下与几种伴有认知灵活性损害的精神障碍有关。然而，NMDAR功能低下和NMDAR音调降低导致认知灵活性受损的分子机制还知之甚少。此外，目前还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：我们采用特定细胞类型的遗传操作、体外电生理记录、嗅探贴片记录、先进的去甲肾上腺素生物传感器和行为测试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张力。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同释放来调节NMDAR张力。Bestl基因敲除小鼠表现出NMDAR音调降低以及同型和ci受体依赖的异型突触长期抑郁的损害，这导致了变塑性和认知灵活性的缺陷。Bestl基因敲除小鼠的这些损伤可以通过海马区星形胶质细胞特异性BEST1的表达或通过补充D-丝氨酸增强NMDAR张力来挽救。在Bestl基因敲除小鼠的初始学习期间注射D-丝氨酸可以挽救随后的反向学习。结论：这些发现表明，初始学习期间的NMDAR音调对随后的学习非常重要，而由星形细胞BEST1调节的海马NMDAR音调对于异突触的长期抑郁、变态和认知灵活性至关重要。
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.