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CK1δ over-expressing mice display ADHD-like behaviors, frontostriatal neuronal abnormalities and altered expressions of ADHD-candidate genes

Molecular Psychiatry volume 25, pages 3322–3336 (2020)Cite this article

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Abstract

The cognitive mechanisms underlying attention-deficit hyperactivity disorder (ADHD), a highly heritable disorder with an array of candidate genes and unclear genetic architecture, remain poorly understood. We previously demonstrated that mice overexpressing CK1δ (CK1δ OE) in the forebrain show hyperactivity and ADHD-like pharmacological responses to d-amphetamine. Here, we demonstrate that CK1δ OE mice exhibit impaired visual attention and a lack of d-amphetamine-induced place preference, indicating a disruption of the dopamine-dependent reward pathway. We also demonstrate the presence of abnormalities in the frontostriatal circuitry, differences in synaptic ultra-structures by electron microscopy, as well as electrophysiological perturbations of both glutamatergic and GABAergic transmission, as observed by altered frequency and amplitude of mEPSCs and mIPSCs. Furthermore, gene expression profiling by next-generation sequencing alone, or in combination with bacTRAP technology to study specifically Drd1a versus Drd2 medium spiny neurons, revealed that developmental CK1δ OE alters transcriptional homeostasis in the striatum, including specific alterations in Drd1a versus Drd2 neurons. These results led us to perform a fine molecular characterization of targeted gene networks and pathway analysis. Importantly, a large fraction of 92 genes identified by GWAS studies as associated with ADHD in humans are significantly altered in our mouse model. The multiple abnormalities described here might be responsible for synaptic alterations and lead to complex behavioral abnormalities. Collectively, CK1δ OE mice share characteristics typically associated with ADHD and should represent a valuable model to investigate the disease in vivo.

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Acknowledgements

We would like to thank Drs. Jack Zhang and Wei Wang for their help analyzing deep sequencing data and 3CSRT data. We are grateful to Drs. Angus Nairn and Jean-Pierre Roussarie for helpful discussions. We thank Mallory Kerner, Julia Fram, and Randall Tassone for technical assistance. We would like to acknowledge the animal care and veterinary staff at RU for their excellent animal support, and especially Janelle Monnas, Craig Hunter, and Alejandra Gonzalez. This work was supported in part by National Institutes of Health Grants MH090963, DA010044, AG047781, by The Army Medical Research and Materiel Command (W81XWH-10-1-0691 to M.F.), and by the Black family foundation.

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  1. Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, 1230 York Avenue, New York, NY, 10065, USA

    Mingming Zhou, Jodi Gresack, Jia Cheng, Lars Brichta, Paul Greengard & Marc Flajolet

  2. Electron Microscopy Resource Center, The Rockefeller University, 1230 York Avenue, New York, NY, 10065, USA

    Kunihiro Uryu

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Correspondence to Marc Flajolet.

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Zhou, M., Gresack, J., Cheng, J. et al. CK1δ over-expressing mice display ADHD-like behaviors, frontostriatal neuronal abnormalities and altered expressions of ADHD-candidate genes. Mol Psychiatry 25, 3322–3336 (2020). https://doi.org/10.1038/s41380-018-0233-z

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