The autism- and schizophrenia-associated protein CYFIP1 regulates bilateral brain connectivity and behaviour

Nuria Domínguez-Iturza; Adrian C. Lo; Disha Shah; Marcelo Armendáriz; Anna Vannelli; Valentina Mercaldo; Massimo Trusel; Ka Wan Li; Denise Gastaldo; Ana Rita Santos; Zsuzsanna Callaerts-Vegh; Rudi D'Hooge; Manuel Mameli; Annemie Van der Linden; August B. Smit; Tilmann Achsel; Claudia Bagni

doi:10.1038/s41467-019-11203-y

The autism- and schizophrenia-associated protein CYFIP1 regulates bilateral brain connectivity and behaviour

Nuria Domínguez-Iturza, Adrian C. Lo, Disha Shah, Marcelo Armendáriz, Anna Vannelli, Valentina Mercaldo, Massimo Trusel, Ka Wan Li, Denise Gastaldo, Ana Rita Santos, Zsuzsanna Callaerts-Vegh, Rudi D'Hooge, Manuel Mameli, Annemie Van der Linden, August B. Smit, Tilmann Achsel, Claudia Bagni

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

Copy-number variants of the CYFIP1 gene in humans have been linked to autism spectrum disorders (ASD) and schizophrenia (SCZ), two neuropsychiatric disorders characterized by defects in brain connectivity. Here, we show that CYFIP1 plays an important role in brain functional connectivity and callosal functions. We find that Cyfip1-heterozygous mice have reduced functional connectivity and defects in white matter architecture, similar to phenotypes found in patients with ASD, SCZ and other neuropsychiatric disorders. Cyfip1-deficient mice also present decreased myelination in the callosal axons, altered presynaptic function, and impaired bilateral connectivity. Finally, Cyfip1 deficiency leads to abnormalities in motor coordination, sensorimotor gating and sensory perception, which are also known neuropsychiatric disorder-related symptoms. These results show that Cyfip1 haploinsufficiency compromises brain connectivity and function, which might explain its genetic association to neuropsychiatric disorders.

Original language	English
Article number	3454
Pages (from-to)	1-13
Number of pages	13
Journal	Nature Communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-11203-y
Publication status	Published - 1 Aug 2019

Funding

We thank Joanna Viguie, Karin Jonckers and Jonathan Royaert for valuable technical assistance and Annick Crevoisier and Eef Lemmens for excellent administrative support. We are grateful to Annette Gärtner, Eleonora Rosina, Laura D’Andrea, Esperanza Fer-nández, Vittoria Mariano, and all the members of the Bagni laboratory for helping during the development of this project with scientific discussions. We would like to thank Graham Knott and Gadea Mata for their assistance in imaging and image processing of EM and immunohistochemistry data, Wim Vanduffel (KU Leuven) for supporting Marcelo Armendáriz and Egbert Welker for scientific discussions. We are grateful to Muna Hilal for helping in setting up the MEA system and to Leonardo Restivo (NEU-ROBAU) for advice on behavioural assays. We also would like to thank Romano Regazzi, Beat M. Riederer and Matthijs Verhage for providing us antibodies during the course of the study. This work was supported by KU Leuven funds (OTF), FWO G088415N, SNSF NCCR Synapsy 51NF40-158776, SNSF 310030-182651, Novartis Foundation for Medical-Biological Research and Canton Etat de Vaud. N.D.I. was recipient of an FWO aspirant fellowship. D.S. is recipient of an FWO (12R1119N) and IWT (13160) fellowships.

Funders	Funder number
Novartis Foundation for Medical-Biological Research and Canton Etat de Vaud
Fonds Wetenschappelijk Onderzoek	51NF40-158776, G088415N, SNSF 310030-182651
KU Leuven

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Domínguez-Iturza, N., Lo, A. C., Shah, D., Armendáriz, M., Vannelli, A., Mercaldo, V., Trusel, M., Li, K. W., Gastaldo, D., Santos, A. R., Callaerts-Vegh, Z., D'Hooge, R., Mameli, M., Van der Linden, A., Smit, A. B., Achsel, T., & Bagni, C. (2019). The autism- and schizophrenia-associated protein CYFIP1 regulates bilateral brain connectivity and behaviour. Nature Communications, 10(1), 1-13. Article 3454. https://doi.org/10.1038/s41467-019-11203-y

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abstract = "Copy-number variants of the CYFIP1 gene in humans have been linked to autism spectrum disorders (ASD) and schizophrenia (SCZ), two neuropsychiatric disorders characterized by defects in brain connectivity. Here, we show that CYFIP1 plays an important role in brain functional connectivity and callosal functions. We find that Cyfip1-heterozygous mice have reduced functional connectivity and defects in white matter architecture, similar to phenotypes found in patients with ASD, SCZ and other neuropsychiatric disorders. Cyfip1-deficient mice also present decreased myelination in the callosal axons, altered presynaptic function, and impaired bilateral connectivity. Finally, Cyfip1 deficiency leads to abnormalities in motor coordination, sensorimotor gating and sensory perception, which are also known neuropsychiatric disorder-related symptoms. These results show that Cyfip1 haploinsufficiency compromises brain connectivity and function, which might explain its genetic association to neuropsychiatric disorders.",

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Domínguez-Iturza, N, Lo, AC, Shah, D, Armendáriz, M, Vannelli, A, Mercaldo, V, Trusel, M, Li, KW, Gastaldo, D, Santos, AR, Callaerts-Vegh, Z, D'Hooge, R, Mameli, M, Van der Linden, A, Smit, AB, Achsel, T & Bagni, C 2019, 'The autism- and schizophrenia-associated protein CYFIP1 regulates bilateral brain connectivity and behaviour', Nature Communications, vol. 10, no. 1, 3454, pp. 1-13. https://doi.org/10.1038/s41467-019-11203-y

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AU - Domínguez-Iturza, Nuria

AU - Lo, Adrian C.

AU - Shah, Disha

AU - Armendáriz, Marcelo

AU - Vannelli, Anna

AU - Mercaldo, Valentina

AU - Trusel, Massimo

AU - Li, Ka Wan

AU - Gastaldo, Denise

AU - Santos, Ana Rita

AU - Callaerts-Vegh, Zsuzsanna

AU - D'Hooge, Rudi

AU - Mameli, Manuel

AU - Van der Linden, Annemie

AU - Smit, August B.

AU - Achsel, Tilmann

AU - Bagni, Claudia

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N2 - Copy-number variants of the CYFIP1 gene in humans have been linked to autism spectrum disorders (ASD) and schizophrenia (SCZ), two neuropsychiatric disorders characterized by defects in brain connectivity. Here, we show that CYFIP1 plays an important role in brain functional connectivity and callosal functions. We find that Cyfip1-heterozygous mice have reduced functional connectivity and defects in white matter architecture, similar to phenotypes found in patients with ASD, SCZ and other neuropsychiatric disorders. Cyfip1-deficient mice also present decreased myelination in the callosal axons, altered presynaptic function, and impaired bilateral connectivity. Finally, Cyfip1 deficiency leads to abnormalities in motor coordination, sensorimotor gating and sensory perception, which are also known neuropsychiatric disorder-related symptoms. These results show that Cyfip1 haploinsufficiency compromises brain connectivity and function, which might explain its genetic association to neuropsychiatric disorders.

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The autism- and schizophrenia-associated protein CYFIP1 regulates bilateral brain connectivity and behaviour

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