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.
Biol Psychiatry. 2022 Apr 15;91(8):740-752. doi: 10.1016/j.biopsych.2021.10.012. Epub 2021 Oct 20.
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.
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.
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 α 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.
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.
N-甲基-D-天冬氨酸受体（NMDAR）功能低下与多种精神疾病有关，这些疾病会损害认知灵活性。然而，对于 NMDAR 功能低下导致认知灵活性受损的分子机制，我们知之甚少。此外，海马星形胶质细胞是否调节 NMDAR 活性和认知灵活性也不清楚。
我们采用了细胞类型特异性遗传操作、离体电生理记录、嗅探贴片记录、去甲肾上腺素的尖端生物传感器以及行为学测试，以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 活性。随后，我们进一步研究了 NMDAR 活性在异突触长时程抑制、易化和认知灵活性中的作用。
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 活性。Best1 敲除小鼠表现出 NMDAR 活性降低以及同突触和α肾上腺素受体依赖性异突触长时程抑制受损，导致易化和认知灵活性缺陷。通过海马星形胶质细胞特异性 BEST1 表达或通过 D-丝氨酸补充增强 NMDAR 活性，可以挽救 Best1 敲除小鼠中的这些缺陷。在初始学习期间向 Best1 敲除小鼠注射 D-丝氨酸可以挽救随后的反转学习。
这些发现表明，初始学习期间的 NMDAR 活性对于后续学习很重要，而星形胶质细胞 BEST1 调节的海马 NMDAR 活性对于异突触长时程抑制、易化和认知灵活性至关重要。
