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. 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.
Keywords
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Article Info
Publication History
Published online: October 20, 2021
Accepted:
October 8,
2021
Received in revised form:
October 7,
2021
Received:
May 20,
2021
Publication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2021 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
