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Elevated expression of complement C4 in the mouse prefrontal cortex causes schizophrenia-associated phenotypes

Abstract

Accumulating evidence supports immune involvement in the pathogenesis of schizophrenia, a severe psychiatric disorder. In particular, high expression variants of C4, a gene of the innate immune complement system, were shown to confer susceptibility to schizophrenia. However, how elevated C4 expression may impact brain circuits remains largely unknown. We used in utero electroporation to overexpress C4 in the mouse prefrontal cortex. We found reduced glutamatergic input to pyramidal cells of juvenile and adult, but not of newborn C4-overexpressing (C4-OE) mice, together with decreased spine density, which mirrors spine loss observed in the schizophrenic cortex. Using time-lapse two-photon imaging in vivo, we observed that these deficits were associated with decreased dendritic spine gain and elimination in juvenile C4-OE mice, which may reflect poor formation and/or stabilization of immature spines. In juvenile and adult C4-OE mice, we found evidence for NMDA receptor hypofunction, another schizophrenia-associated phenotype, and synaptic accumulation of calcium-permeable AMPA receptors. Alterations in cortical GABAergic networks have been repeatedly associated with schizophrenia. We found that functional GABAergic transmission was reduced in C4-OE mice, in line with diminished GABA release probability from parvalbumin interneurons, lower GAD67 expression, and decreased intrinsic excitability in parvalbumin interneurons. These cellular abnormalities were associated with working memory impairment. Our results substantiate the causal relationship between an immunogenetic risk factor and several distinct cortical endophenotypes of schizophrenia and shed light on the underlying cellular mechanisms.

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Fig. 1: Reduced excitatory input onto C4-OE pyramidal cells.
Fig. 2: Decreased spine turnover in young (P15–P18) C4-OE mice.
Fig. 3: Altered AMPA/NMDA ratio and AMPAR rectification index in C4-OE mice.
Fig. 4: Alterations of GABAergic networks in C4-OE mice.
Fig. 5: Impaired working memory in C4-OE mice.

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Acknowledgements

MD was the recipient of fellowships from Sorbonne University and from FRM/Venite Cantemus (FDT20190400802). The project was supported by funds from the Investissements d’Avenir program under reference ANR-11-IDEX-0004-02 to CLM and RT, the Emergence program of Sorbonne University to CLM, and from an ERANET Neuron Grant to RT (ANR-18-0008-01), MF (BMBF 01EW1905), and CLM (ANR-18-0008-02). The authors thank Dr. L. Maroteaux, Dr. P. Gaspar, and Dr. J.-C. Poncer for critically reading the manuscript.

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Druart, M., Nosten-Bertrand, M., Poll, S. et al. Elevated expression of complement C4 in the mouse prefrontal cortex causes schizophrenia-associated phenotypes. Mol Psychiatry (2021). https://doi.org/10.1038/s41380-021-01081-6

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