2. Academic Validation
  3. D-serine reconstitutes synaptic and intrinsic inhibitory control of pyramidal neurons in a neurodevelopmental mouse model for schizophrenia

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

  • Nat Commun. 2023 Dec 12;14(1):8255. doi: 10.1038/s41467-023-43930-8.
Xiao-Qin Zhang 1,  Le Xu 1,  Xin-Yi Zhu 1,  Zi-Hang Tang 1,  Yi-Bei Dong 1,  Zhi-Peng Yu 1,  Qing Shang 2,  Zheng-Chun Wang 1,  Hao-Wei Shen 3
Affiliations

Affiliations

  • 1 Department of Pharmacology, School of Medicine, Ningbo University, 818 Fenghua Rd, Ningbo, Zhejiang, 315211, China.
  • 2 Department of Neurology, The First Affiliated Hospital of Ningbo University, 59 Liuting Street, Haishu District, Ningbo, Zhejiang, 315211, China.
  • 3 Department of Pharmacology, School of Medicine, Ningbo University, 818 Fenghua Rd, Ningbo, Zhejiang, 315211, China. shenhaowei@nbu.edu.cn.
PMID: 38086803 DOI: 10.1038/s41467-023-43930-8
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.

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