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

• Published in: Molecular psychiatry Vol. 27; no. 2; pp. 1145 - 1157
• Main Authors: Sitbon, Jérémy, Nestvogel, Dennis, Kappeler, Caroline, Nicolas, Aude, Maciuba, Stephanie, Henrion, Annabelle, Troudet, Réjane, Courtois, Elisa, Grannec, Gaël, Latapie, Violaine, Barau, Caroline, Le Corvoisier, Philippe, Pietrancosta, Nicolas, Henry, Chantal, Leboyer, Marion, Etain, Bruno, Nosten-Bertrand, Marika, Martin, Thomas F. J., Rhee, JeongSeop, Jamain, Stéphane
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.02.2022; Nature Publishing Group
• Subjects: 38/70; 45/23; 631/208; 631/45; 64/110; 64/60; 692/699/476/1333; 82/80; 96/109; 96/34; 96/44; Animals; Behavioral Sciences; Biological Psychology; Bipolar disorder; Bipolar Disorder - genetics; Brain-derived neurotrophic factor; Calcium; Calcium - metabolism; Calcium-Binding Proteins; Catecholamines; Children; Exocytosis; Genetics; Human genetics; Human health and pathology; Humans; Hyperactivity; Life Sciences; Lithium; Medicine; Medicine & Public Health; Mental disorders; Mice; Mutants; Mutation; Mutation - genetics; Mutation rates; Nerve Tissue Proteins; Neurobiology; Neuronal Plasticity; Neurons and Cognition; Neurosciences; Pharmacotherapy; Psychiatrics and mental health; Psychiatry; Risk factors; Synaptic plasticity; Trauma; Vesicular Transport Proteins
• ISSN: 1359-4184; 1476-5578; 1476-5578
• DOI: 10.1038/s41380-021-01151-9

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.