Astrocytes render memory flexible by releasing D-serine and regulating NMDAR tone in the hippocampus

Abstract Background NMDAR hypofunction has been implicated in several psychiatric disorders with an 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 the heterosynaptic long-term depression, metaplasticity and cognitive flexibility. Results We found that hippocampal astrocytes regulate NMDAR tone via Best1-mediated co-release of D-serine and glutamate. Best1 knockout mice (Best1 KO) exhibited reduced NMDAR tone and impairments of homosynaptic and α1-adrenergic receptor-dependent heterosynaptic long-term depression, which leads to the defects in metaplasticity and cognitive flexibility. These impairments in Best1 KO can be rescued by hippocampal astrocyte-specific Best1 expression or enhanced NMDAR tone through D-serine supplement. Importantly, D-serine injection in Best1 KO 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.