고우현 PARK, MI JEONG Chun, Ye eun Lee, Jae kwang 심현수 Mingu Gordon Park kim, sun pil Moonsun Sa Jinhyeong Joo Hyunji Kang 오수진 Woo, Jun Sung Heejung Chun 이승은 Hong, Jin pyo Jiesi Feng Yulong Li 류훈 Jeiwon Cho C. Justin Lee 2024-01-19T12:30:59Z 2024-01-19T12:30:59Z 2022-01-10 2022-04 0006-3223 https://pubs.kist.re.kr/handle/201004/115500 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. ？ 2021 Society of Biological Psychiatry English Elsevier BV Astrocytes render memory flexible by releasing D-serine and regulating NMDAR tone in the hippocampus Article 10.1016/j.biopsych.2021.10.012 1 Biological Psychiatry, v.91, no.8, pp.740 - 752 Biological Psychiatry 91 8 740 752 N scie scopus 000820422800012 2-s2.0-85122981640 Neurosciences Psychiatry Neurosciences & Neurology Psychiatry Article LONG-TERM DEPRESSION NEURONAL D-SERINE SPATIAL MEMORY COGNITIVE FLEXIBILITY SYNAPTIC DEPRESSION GLUTAMATE RELEASE RAT ACTIVATION IMPAIRMENT PLASTICITY Astrocyte Best1 Cognitive flexibility Metaplasticity NMDAR tone Norepinephrine