D-serine reconstitutes synaptic and intrinsic inhibitory control of pyramidal neurons in a neurodevelopmental mouse model for schizophrenia

Xiao-Qin Zhang, Le Xu, Xin-Yi Zhu, Zi-Hang Tang, Yi-Bei Dong, Zhi-Peng Yu, Qing Shang, Zheng-Chun Wang and Hao-Wei Shen ()
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Xiao-Qin Zhang: Ningbo University
Le Xu: Ningbo University
Xin-Yi Zhu: Ningbo University
Zi-Hang Tang: Ningbo University
Yi-Bei Dong: Ningbo University
Zhi-Peng Yu: Ningbo University
Qing Shang: The First Affiliated Hospital of Ningbo University
Zheng-Chun Wang: Ningbo University
Hao-Wei Shen: Ningbo University

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract The hypothesis of N-methyl-D-aspartate receptor (NMDAR) dysfunction for cognitive impairment in schizophrenia constitutes the theoretical basis for the translational application of NMDAR co-agonist D-serine or its analogs. However, the cellular mechanism underlying the therapeutic effect of D-serine remains unclear. In this study, we utilize a mouse neurodevelopmental model for schizophrenia that mimics prenatal pathogenesis and exhibits hypoexcitability of parvalbumin-positive (PV) neurons, as well as PV-preferential NMDAR dysfunction. We find that D-serine restores excitation/inhibition balance by reconstituting both synaptic and intrinsic inhibitory control of cingulate pyramidal neurons through facilitating PV excitability and activating small-conductance Ca2+-activated K+ (SK) channels in pyramidal neurons, respectively. Either amplifying inhibitory drive via directly strengthening PV neuron activity or inhibiting pyramidal excitability via activating SK channels is sufficient to improve cognitive function in this model. These findings unveil a dual mechanism for how D-serine improves cognitive function in this model.

Date: 2023
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DOI: 10.1038/s41467-023-43930-8

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