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Reversal of synaptic and behavioral deficits in a 16p11.2 duplication mouse model via restoration of the GABA synapse regulator Npas4

Molecular Psychiatry volume 26, pages 1967–1979 (2021)Cite this article

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Abstract

The human 16p11.2 gene locus is a hot spot for copy number variations, which predispose carriers to a range of neuropsychiatric phenotypes. Microduplications of 16p11.2 are associated with autism spectrum disorder (ASD), intellectual disability (ID), and schizophrenia (SZ). Despite the debilitating nature of 16p11.2 duplications, the underlying molecular mechanisms remain poorly understood. Here we performed a comprehensive behavioral characterization of 16p11.2 duplication mice (16p11.2dp/+) and identified social and cognitive deficits reminiscent of ASD and ID phenotypes. 16p11.2dp/+ mice did not exhibit the SZ-related sensorimotor gating deficits, psychostimulant-induced hypersensitivity, or motor impairment. Electrophysiological recordings of 16p11.2dp/+ mice found deficient GABAergic synaptic transmission and elevated neuronal excitability in the prefrontal cortex (PFC), a brain region critical for social and cognitive functions. RNA-sequencing identified genome-wide transcriptional aberrance in the PFC of 16p11.2dp/+ mice, including downregulation of the GABA synapse regulator Npas4. Restoring Npas4 expression in PFC of 16p11.2dp/+ mice ameliorated the social and cognitive deficits and reversed GABAergic synaptic impairment and neuronal hyperexcitability. These findings suggest that prefrontal cortical GABAergic synaptic circuitry and Npas4 are strongly implicated in 16p11.2 duplication pathology, and may represent potential targets for therapeutic intervention in ASD.

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Fig. 1: 16p11.2dp/+ mice exhibit social deficits, repetitive behaviors, and cognitive impairment reminiscent of ASD and ID symptoms.
Fig. 2: 16p11.2dp/+ mPFC pyramidal neurons exhibit GABAergic synaptic deficits and elevated excitability.
Fig. 3: RNA-sequencing identifies numerous upregulated genes in PFC of 16p11.2dp/+ mice.
Fig. 4: RNA-sequencing identifies downregulated genes from diverse classes in 16p11.2dp/+ PFC, including the GABA synapse regulator Npas4.
Fig. 5: Restoring Npas4 expression in PFC ameliorates the social and cognitive deficits and restores GABAergic synaptic transmission in 16p11.2dp/+ mice.

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Acknowledgements

We thank Xiaoqing Chen, Dr Zi-Jun Wang, and Dr Luye Qin for excellent technical support. We acknowledge the support of University at Buffalo’s Genomics and Bioinformatics Core and the New York State Center of Excellence in Bioinformatics and Life Sciences. We are grateful for Dr Michael Greenberg at Harvard University for providing Npas4 antibody. This work was supported by Nancy Lurie Marks Family Foundation and National Institutes of Health (MH112237; MH108842) to ZY.

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  1. Department of Physiology and Biophysics, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY, 14214, USA

    Benjamin Rein, Tao Tan, Fengwei Yang, Wei Wang, Jamal Williams, Freddy Zhang & Zhen Yan

  2. Cold Spring Harbor Laboratory, One Bungtown Road, Cold Spring Harbor, NY, 11724, USA

    Alea Mills

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Contributions

BR performed behavioral and biochemical experiments, designed experiments, analyzed data, and wrote the paper; TT performed electrophysiological experiments and analyzed data; FY performed bioinformatic analysis; WW performed electrophysiological experiments and analyzed data; JW performed parts of biochemical experiments; FZ performed parts of biochemical experiments; AM generated transgenic 16p11.2dp/+ mice; ZY designed experiments, supervised the project and wrote the paper.

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Correspondence to Zhen Yan.

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Rein, B., Tan, T., Yang, F. et al. Reversal of synaptic and behavioral deficits in a 16p11.2 duplication mouse model via restoration of the GABA synapse regulator Npas4. Mol Psychiatry 26, 1967–1979 (2021). https://doi.org/10.1038/s41380-020-0693-9

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