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CADPS functional mutations in patients with bipolar disorder increase the sensitivity to stress

Molecular Psychiatry volume 27, pages 1145–1157 (2022)Cite this article

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Abstract

Bipolar disorder is a severe and chronic psychiatric disease resulting from a combination of genetic and environmental risk factors. Here, we identified a significant higher mutation rate in a gene encoding the calcium-dependent activator protein for secretion (CADPS) in 132 individuals with bipolar disorder, when compared to 184 unaffected controls or to 21,070 non-psychiatric and non-Finnish European subjects from the Exome Aggregation Consortium. We found that most of these variants resulted either in a lower abundance or a partial impairment in one of the basic functions of CADPS in regulating neuronal exocytosis, synaptic plasticity and vesicular transporter-dependent uptake of catecholamines. Heterozygous mutant mice for Cadps+/− revealed that a decreased level of CADPS leads to manic-like behaviours, changes in BDNF level and a hypersensitivity to stress. This was consistent with more childhood trauma reported in families with mutation in CADPS, and more specifically in mutated individuals. Furthermore, hyperactivity observed in mutant animals was rescued by the mood-stabilizing drug lithium. Overall, our results suggest that dysfunction in calcium-dependent vesicular exocytosis may increase the sensitivity to environmental stressors enhancing the risk of developing bipolar disorder.

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Fig. 1: Genetic exploration of CADPS in patients with BD.
Fig. 2: Characterization of missense variants identified in CADPS.
Fig. 3: Mutations in CADPS decreased the FFN511 release and monoamine uptake.
Fig. 4: Cultured neurons expressing CADPSp.I148_E185del or CADPSp.S399L exhibit altered short-term plasticity characteristics.
Fig. 5: Heterozygous mutant mice for CADPS display manic-like behaviours and a higher sensitivity to stress.
Fig. 6: Assessment of childhood trauma in families with mutations in CADPS, 355 independent patients with BD and 86 unaffected controls.

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Acknowledgements

This work was supported by the Investissements d’Avenir program managed by the Agence Nationale pour la Recherche (ANR) under reference ANR-11-IDEX-0004-02 (Labex BioPsy). This work also received financial support from the Institut National pour la Santé et la Recherche Médicale (Inserm), the Réseau Thématique de Recherche et de Soins en Santé Mentale (Fondation FondaMental®, Prix Marcel Dassault to SJ), the Domaine d’Intérêt Majeur (DIM) Cerveau et Pensée (to JS) and the National Institute of General Medical Sciences of the National Institutes of Health under award number R01GM119158 (to TFJM). The Jamain team is affiliated with the Paris School of Neuroscience (ENP) and the Bio-Psy Laboratory of Excellence. D.N. was supported by a Boehringer Ingelheim Fonds PhD fellowship. We are very grateful to patients with bipolar disorder, their family and control subjects for their participation. We acknowledge Prof. Gudrun Ahnert-Hilger for CHOVMAT1 cells and Dr. R. Toro for the SniPeep software. We thank E. Abadie, the Cochin Hospital cell library (Prof. J. Chelly), the Clinical Investigation Centre and the Biological Resources Platform of Mondor Hospital for technical assistance. We also thank Anja Günther for excellent technical assistance.

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Author notes

  1. These authors contributed equally: Jérémy Sitbon, Dennis Nestvogel, Caroline Kappeler, Aude Nicolas

Authors and Affiliations

  1. Univ Paris Est Créteil, INSERM, IMRB, Translational Neuropsychiatry, Créteil, France

    Jérémy Sitbon, Caroline Kappeler, Aude Nicolas, Annabelle Henrion, Réjane Troudet, Elisa Courtois, Violaine Latapie, Chantal Henry, Marion Leboyer & Stéphane Jamain

  2. Fondation FondaMental, Créteil, France

    Jérémy Sitbon, Caroline Kappeler, Aude Nicolas, Annabelle Henrion, Réjane Troudet, Elisa Courtois, Violaine Latapie, Chantal Henry, Marion Leboyer, Bruno Etain & Stéphane Jamain

  3. Department of Molecular Neurobiology, Max Planck Institute of Experimental Medicine, Göttingen, Germany

    Dennis Nestvogel & JeongSeop Rhee

  4. Department of Biochemistry, University of Wisconsin, Madison, WI, USA

    Stephanie Maciuba & Thomas F. J. Martin

  5. INSERM U1270, Sorbonne Université, Institut du Fer à Moulin, Paris, France

    Gaël Grannec & Marika Nosten-Bertrand

  6. AP-HP, Hôpital H. Mondor – A. Chenevier, Plateforme de Ressources Biologiques, Créteil, France

    Caroline Barau

  7. Inserm, Centre d’Investigation Clinique 1430 and APHP, Créteil, France

    Philippe Le Corvoisier

  8. Sorbonne University, École Normale Supérieure, PSL University, CNRS, Laboratoire des biomolécules (LBM), Paris, France

    Nicolas Pietrancosta

  9. Neuroscience Paris Seine - Institut de Biologie Paris Seine (NPS - IBPS) INSERM, CNRS, Sorbonne Université, Paris, France

    Nicolas Pietrancosta

  10. AP-HP, Hôpitaux Universitaires H. Mondor, DMU IMPACT, Créteil, France

    Chantal Henry & Marion Leboyer

  11. Département de Psychiatrie et de Médecine Addictologique, AP-HP, GH Saint-Louis - Lariboisière - F. Widal, Paris, France

    Bruno Etain

  12. Université de Paris, Sorbonne Paris Cité, Paris, France

    Bruno Etain

  13. Inserm, UMR-S1144, Paris, France

    Bruno Etain

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Contributions

SJ designed the study, with the help of JR and DN for electrophysiological experiments, CK and MNB for mouse behavioural analyses and TFJM for CADPS in vitro analysis; SJ, JS, CK, AN, AH and EC generated genetic data and conducted genetic analyses; JS, NP, AH, VL, RT, SM and TFJM performed biochemical experiments; CK, GG and MNB conducted behavioural analyses in mice; DN and JR performed electrophysiological experiments on hippocampal mouse neurons; CH, BE and ML designed, collected and analysed clinical data, with the help of CB and PLC who collected biological samples in patients and controls; SJ, JS, DN, CK, BE, MNB and TFJM wrote the article.

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Correspondence to Stéphane Jamain.

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Sitbon, J., Nestvogel, D., Kappeler, C. et al. CADPS functional mutations in patients with bipolar disorder increase the sensitivity to stress. Mol Psychiatry 27, 1145–1157 (2022). https://doi.org/10.1038/s41380-021-01151-9

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