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

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 bipol...

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Published inMolecular 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
LanguageEnglish
Published London Nature Publishing Group UK 01.02.2022
Nature Publishing Group
Subjects
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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
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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.
AbstractList 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.
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.
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.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.
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.
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.
Author Kappeler, Caroline
Henry, Chantal
Sitbon, Jérémy
Jamain, Stéphane
Nicolas, Aude
Grannec, Gaël
Troudet, Réjane
Pietrancosta, Nicolas
Nestvogel, Dennis
Latapie, Violaine
Nosten-Bertrand, Marika
Martin, Thomas F. J.
Barau, Caroline
Leboyer, Marion
Etain, Bruno
Henrion, Annabelle
Rhee, JeongSeop
Le Corvoisier, Philippe
Maciuba, Stephanie
Courtois, Elisa
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2022. The Author(s), under exclusive licence to Springer Nature Limited.
The Author(s), under exclusive licence to Springer Nature Limited 2022.
Distributed under a Creative Commons Attribution 4.0 International License
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PublicationTitle Molecular psychiatry
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Publisher Nature Publishing Group UK
Nature Publishing Group
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Snippet Bipolar disorder is a severe and chronic psychiatric disease resulting from a combination of genetic and environmental risk factors. Here, we identified a...
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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
Title CADPS functional mutations in patients with bipolar disorder increase the sensitivity to stress
URI https://link.springer.com/article/10.1038/s41380-021-01151-9
https://www.ncbi.nlm.nih.gov/pubmed/35169262
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Volume 27
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