The Addiction-Susceptibility TaqIA/Ankk1 Controls Reward and Metabolism Through D2 Receptor-Expressing Neurons

Enrica Montalban; Roman Walle; Julien Castel; Anthony Ansoult; Rim Hassouna; Ewout Foppen; Xi Fang; Zach Hutelin; Sophie Mickus; Emily Perszyk; Anna Petitbon; J. rémy Berthelet; Fernando Rodrigues-Lima; Alberto Cebrian-Serrano; Giuseppe Gangarossa; Claire Martin; Pierre Trifilieff; Clémentine Bosch-Bouju; Dana M. Small; Serge Luquet

doi:https://doi.org/10.1016/j.biopsych.2023.02.010

The Addiction-Susceptibility TaqIA/Ankk1 Controls Reward and Metabolism Through D2 Receptor-Expressing Neurons

Enrica Montalban, Roman Walle, Julien Castel, Anthony Ansoult, Rim Hassouna, Ewout Foppen, Xi Fang, Zach Hutelin, Sophie Mickus, Emily Perszyk, Anna Petitbon, J. rémy Berthelet, Fernando Rodrigues-Lima, Alberto Cebrian-Serrano, Giuseppe Gangarossa, Claire Martin, Pierre Trifilieff, Clémentine Bosch-Bouju, Dana M. Small, Serge Luquet

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

2 Citations (Scopus)

Abstract

Background: A large body of evidence highlights the importance of genetic variants in the development of psychiatric and metabolic conditions. Among these, the TaqIA polymorphism is one of the most commonly studied in psychiatry. TaqIA is located in the gene that codes for the ankyrin repeat and kinase domain containing 1 kinase (Ankk1) near the dopamine D2 receptor (D2R) gene. Homozygous expression of the A1 allele correlates with a 30% to 40% reduction of striatal D2R, a typical feature of addiction, overeating, and other psychiatric pathologies. The mechanisms by which the variant influences dopamine signaling and behavior are unknown. Methods: Here, we used transgenic and viral-mediated strategies to reveal the role of Ankk1 in the regulation of activity and functions of the striatum. Results: We found that Ankk1 is preferentially enriched in striatal D2R-expressing neurons and that Ankk1 loss of function in the dorsal and ventral striatum leads to alteration in learning, impulsivity, and flexibility resembling endophenotypes described in A1 carriers. We also observed an unsuspected role of Ankk1 in striatal D2R-expressing neurons of the ventral striatum in the regulation of energy homeostasis and documented differential nutrient partitioning in humans with or without the A1 allele. Conclusions: Overall, our data demonstrate that the Ankk1 gene is necessary for the integrity of striatal functions and reveal a new role for Ankk1 in the regulation of body metabolism.

Original language	English
Pages (from-to)	424-436
Number of pages	13
Journal	Biological Psychiatry
Volume	94
Issue number	5
Early online date	2023
DOIs	https://doi.org/10.1016/j.biopsych.2023.02.010
Publication status	Published - 1 Sept 2023

Keywords

DR receptor
Dopamine signaling
Eating disorders
Genetic polymorphism
Metabolism
Reward-associated behavior

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https://doi.org/10.1016/j.biopsych.2023.02.010

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Montalban, E., Walle, R., Castel, J., Ansoult, A., Hassouna, R., Foppen, E., Fang, X., Hutelin, Z., Mickus, S., Perszyk, E., Petitbon, A., Berthelet, J. R., Rodrigues-Lima, F., Cebrian-Serrano, A., Gangarossa, G., Martin, C., Trifilieff, P., Bosch-Bouju, C., Small, D. M., & Luquet, S. (2023). The Addiction-Susceptibility TaqIA/Ankk1 Controls Reward and Metabolism Through D2 Receptor-Expressing Neurons. Biological Psychiatry, 94(5), 424-436. https://doi.org/10.1016/j.biopsych.2023.02.010

@article{7ccb27da1b9543718924ba06c778904c,

title = "The Addiction-Susceptibility TaqIA/Ankk1 Controls Reward and Metabolism Through D2 Receptor-Expressing Neurons",

abstract = "Background: A large body of evidence highlights the importance of genetic variants in the development of psychiatric and metabolic conditions. Among these, the TaqIA polymorphism is one of the most commonly studied in psychiatry. TaqIA is located in the gene that codes for the ankyrin repeat and kinase domain containing 1 kinase (Ankk1) near the dopamine D2 receptor (D2R) gene. Homozygous expression of the A1 allele correlates with a 30% to 40% reduction of striatal D2R, a typical feature of addiction, overeating, and other psychiatric pathologies. The mechanisms by which the variant influences dopamine signaling and behavior are unknown. Methods: Here, we used transgenic and viral-mediated strategies to reveal the role of Ankk1 in the regulation of activity and functions of the striatum. Results: We found that Ankk1 is preferentially enriched in striatal D2R-expressing neurons and that Ankk1 loss of function in the dorsal and ventral striatum leads to alteration in learning, impulsivity, and flexibility resembling endophenotypes described in A1 carriers. We also observed an unsuspected role of Ankk1 in striatal D2R-expressing neurons of the ventral striatum in the regulation of energy homeostasis and documented differential nutrient partitioning in humans with or without the A1 allele. Conclusions: Overall, our data demonstrate that the Ankk1 gene is necessary for the integrity of striatal functions and reveal a new role for Ankk1 in the regulation of body metabolism.",

keywords = "DR receptor, Dopamine signaling, Eating disorders, Genetic polymorphism, Metabolism, Reward-associated behavior",

author = "Enrica Montalban and Roman Walle and Julien Castel and Anthony Ansoult and Rim Hassouna and Ewout Foppen and Xi Fang and Zach Hutelin and Sophie Mickus and Emily Perszyk and Anna Petitbon and Berthelet, {J. r{\'e}my} and Fernando Rodrigues-Lima and Alberto Cebrian-Serrano and Giuseppe Gangarossa and Claire Martin and Pierre Trifilieff and Cl{\'e}mentine Bosch-Bouju and Small, {Dana M.} and Serge Luquet",

note = "Funding Information: This work was funded by la Fondation pour la Recherche M{\'e}dicale (FRM) Project (S.L Grant No. EQU202003010155), (S.L) Modern Diet and Physiology Research Center, the (S.L) Centre National de la Recherche Scientifique through the International Research Project BrainHealth, L'Agence Nationale de la Recherche (S.L Grant Nos. ANR-19-CE37-0020-02 and ANR-20-CE14-0020), The Universit{\'e} Paris Cit{\'e}, and l'Institut national de recherche pour l'agriculture, l'alimentation et l'environnement ( INRAE), Universit{\'e} de Bordeaux. The project has also been supported by the (S.L & P.T) F{\'e}d{\'e}ration pour la Recherche sur le Cerveau and the (E.M) Fondation des Treilles Fondation des Treilles cr{\'e}{\'e}e par Anne Gruner Schlumberger, a notamment pour vocation d{\textquoteright}ouvrir et de nourrir le dialogue entre les sciences et les arts afin de faire progresser la cr{\'e}ation et la recherche contemporaines. Elle accueille {\'e}galement des chercheurs et des {\'e}crivains dans le domaine des Treilles (Var) www.les-treilles.com . EM was supported by a postdoctoral fellowship from the FRM. Funding Information: This work was funded by la Fondation pour la Recherche M{\'e}dicale (FRM) Project (S.L Grant No. EQU202003010155), (S.L) Modern Diet and Physiology Research Center, the (S.L) Centre National de la Recherche Scientifique through the International Research Project BrainHealth, L'Agence Nationale de la Recherche (S.L Grant Nos. ANR-19-CE37-0020-02 and ANR-20-CE14-0020), The Universit{\'e} Paris Cit{\'e}, and l'Institut national de recherche pour l'agriculture, l'alimentation et l'environnement (INRAE), Universit{\'e} de Bordeaux. The project has also been supported by the (S.L & P.T) F{\'e}d{\'e}ration pour la Recherche sur le Cerveau and the (E.M) Fondation des Treilles Fondation des Treilles cr{\'e}{\'e}e par Anne Gruner Schlumberger, a notamment pour vocation d'ouvrir et de nourrir le dialogue entre les sciences et les arts afin de faire progresser la cr{\'e}ation et la recherche contemporaines. Elle accueille {\'e}galement des chercheurs et des {\'e}crivains dans le domaine des Treilles (Var) www.les-treilles.com. EM was supported by a postdoctoral fellowship from the FRM. We thank Dr. Thomas S. Hnasko and Professor Ralph DiLeone for valuable inputs on the study. We thank Olja Kacanski for administrative support, Isabelle Le Parco, Aur{\'e}lie Djemat, Daniel Quintas, Magguy Boa, Ludovic Maingault, and Ang{\'e}lique Dauvin for animals{\textquoteright} care and Florianne Michel for genotyping. We acknowledge the Functional and Physiological Exploration platform of the Universit{\'e} Paris Cit{\'e}, CNRS, Unit{\'e} de Biologie Fonctionnelle et Adaptative, F-75013 Paris, France, the viral production facility of the UMR INSERM 1089 and the animal core facility Buffon of the Universit{\'e} Paris Cit{\'e}/Institut Jacques Monod. We also thank the animal facility of the Institut de Biologie Paris-Seine (IBPS) of Sorbonne Universit{\'e}, Paris. EM conceived the project, designed and performed most of the experiments, analyzed and interpreted the data, and wrote the manuscript. RW performed the electrophysiology experiments. JC performed the nucleus accumbens surgeries, EF performed the dorsal striatum surgeries, and AA, RH, AP, and JB performed experiments. JB and AC-S edited the manuscript. XF, ZH, SM, and EP performed the human experiments. GG and FRL discussed the data and provided input to experiments and manuscript; CM supervised experiments; PT supervised the electrophysiology experiments and provided input and improvements to behavioral experiments and manuscript; CB-B supervised and performed the electrophysiology experiments; and DMS participated in the initial conception of the project, conceived and supervised the clinical study, and provided input and corrections on the manuscript. SL conceived and supervised the overall project, analyzed and interpreted the data, secured funding, and provided input and corrections to the manuscript with the help of co-authors. A previous version of this article was published as a preprint on bioRxiv: https://www.biorxiv.org/content/10.1101/2022.08.12.503577v1. The authors report no biomedical financial interests or potential conflicts of interest. Publisher Copyright: {\textcopyright} 2023 Society of Biological Psychiatry",

year = "2023",

month = sep,

day = "1",

doi = "https://doi.org/10.1016/j.biopsych.2023.02.010",

language = "English",

volume = "94",

pages = "424--436",

journal = "Biological Psychiatry",

issn = "0006-3223",

publisher = "Elsevier USA",

number = "5",

}

Montalban, E, Walle, R, Castel, J, Ansoult, A, Hassouna, R, Foppen, E, Fang, X, Hutelin, Z, Mickus, S, Perszyk, E, Petitbon, A, Berthelet, JR, Rodrigues-Lima, F, Cebrian-Serrano, A, Gangarossa, G, Martin, C, Trifilieff, P, Bosch-Bouju, C, Small, DM & Luquet, S 2023, 'The Addiction-Susceptibility TaqIA/Ankk1 Controls Reward and Metabolism Through D2 Receptor-Expressing Neurons', Biological Psychiatry, vol. 94, no. 5, pp. 424-436. https://doi.org/10.1016/j.biopsych.2023.02.010

TY - JOUR

T1 - The Addiction-Susceptibility TaqIA/Ankk1 Controls Reward and Metabolism Through D2 Receptor-Expressing Neurons

AU - Montalban, Enrica

AU - Walle, Roman

AU - Castel, Julien

AU - Ansoult, Anthony

AU - Hassouna, Rim

AU - Foppen, Ewout

AU - Fang, Xi

AU - Hutelin, Zach

AU - Mickus, Sophie

AU - Perszyk, Emily

AU - Petitbon, Anna

AU - Berthelet, J. rémy

AU - Rodrigues-Lima, Fernando

AU - Cebrian-Serrano, Alberto

AU - Gangarossa, Giuseppe

AU - Martin, Claire

AU - Trifilieff, Pierre

AU - Bosch-Bouju, Clémentine

AU - Small, Dana M.

AU - Luquet, Serge

N1 - Funding Information: This work was funded by la Fondation pour la Recherche Médicale (FRM) Project (S.L Grant No. EQU202003010155), (S.L) Modern Diet and Physiology Research Center, the (S.L) Centre National de la Recherche Scientifique through the International Research Project BrainHealth, L'Agence Nationale de la Recherche (S.L Grant Nos. ANR-19-CE37-0020-02 and ANR-20-CE14-0020), The Université Paris Cité, and l'Institut national de recherche pour l'agriculture, l'alimentation et l'environnement ( INRAE), Université de Bordeaux. The project has also been supported by the (S.L & P.T) Fédération pour la Recherche sur le Cerveau and the (E.M) Fondation des Treilles Fondation des Treilles créée par Anne Gruner Schlumberger, a notamment pour vocation d’ouvrir et de nourrir le dialogue entre les sciences et les arts afin de faire progresser la création et la recherche contemporaines. Elle accueille également des chercheurs et des écrivains dans le domaine des Treilles (Var) www.les-treilles.com . EM was supported by a postdoctoral fellowship from the FRM. Funding Information: This work was funded by la Fondation pour la Recherche Médicale (FRM) Project (S.L Grant No. EQU202003010155), (S.L) Modern Diet and Physiology Research Center, the (S.L) Centre National de la Recherche Scientifique through the International Research Project BrainHealth, L'Agence Nationale de la Recherche (S.L Grant Nos. ANR-19-CE37-0020-02 and ANR-20-CE14-0020), The Université Paris Cité, and l'Institut national de recherche pour l'agriculture, l'alimentation et l'environnement (INRAE), Université de Bordeaux. The project has also been supported by the (S.L & P.T) Fédération pour la Recherche sur le Cerveau and the (E.M) Fondation des Treilles Fondation des Treilles créée par Anne Gruner Schlumberger, a notamment pour vocation d'ouvrir et de nourrir le dialogue entre les sciences et les arts afin de faire progresser la création et la recherche contemporaines. Elle accueille également des chercheurs et des écrivains dans le domaine des Treilles (Var) www.les-treilles.com. EM was supported by a postdoctoral fellowship from the FRM. We thank Dr. Thomas S. Hnasko and Professor Ralph DiLeone for valuable inputs on the study. We thank Olja Kacanski for administrative support, Isabelle Le Parco, Aurélie Djemat, Daniel Quintas, Magguy Boa, Ludovic Maingault, and Angélique Dauvin for animals’ care and Florianne Michel for genotyping. We acknowledge the Functional and Physiological Exploration platform of the Université Paris Cité, CNRS, Unité de Biologie Fonctionnelle et Adaptative, F-75013 Paris, France, the viral production facility of the UMR INSERM 1089 and the animal core facility Buffon of the Université Paris Cité/Institut Jacques Monod. We also thank the animal facility of the Institut de Biologie Paris-Seine (IBPS) of Sorbonne Université, Paris. EM conceived the project, designed and performed most of the experiments, analyzed and interpreted the data, and wrote the manuscript. RW performed the electrophysiology experiments. JC performed the nucleus accumbens surgeries, EF performed the dorsal striatum surgeries, and AA, RH, AP, and JB performed experiments. JB and AC-S edited the manuscript. XF, ZH, SM, and EP performed the human experiments. GG and FRL discussed the data and provided input to experiments and manuscript; CM supervised experiments; PT supervised the electrophysiology experiments and provided input and improvements to behavioral experiments and manuscript; CB-B supervised and performed the electrophysiology experiments; and DMS participated in the initial conception of the project, conceived and supervised the clinical study, and provided input and corrections on the manuscript. SL conceived and supervised the overall project, analyzed and interpreted the data, secured funding, and provided input and corrections to the manuscript with the help of co-authors. A previous version of this article was published as a preprint on bioRxiv: https://www.biorxiv.org/content/10.1101/2022.08.12.503577v1. The authors report no biomedical financial interests or potential conflicts of interest. Publisher Copyright: © 2023 Society of Biological Psychiatry

PY - 2023/9/1

Y1 - 2023/9/1

N2 - Background: A large body of evidence highlights the importance of genetic variants in the development of psychiatric and metabolic conditions. Among these, the TaqIA polymorphism is one of the most commonly studied in psychiatry. TaqIA is located in the gene that codes for the ankyrin repeat and kinase domain containing 1 kinase (Ankk1) near the dopamine D2 receptor (D2R) gene. Homozygous expression of the A1 allele correlates with a 30% to 40% reduction of striatal D2R, a typical feature of addiction, overeating, and other psychiatric pathologies. The mechanisms by which the variant influences dopamine signaling and behavior are unknown. Methods: Here, we used transgenic and viral-mediated strategies to reveal the role of Ankk1 in the regulation of activity and functions of the striatum. Results: We found that Ankk1 is preferentially enriched in striatal D2R-expressing neurons and that Ankk1 loss of function in the dorsal and ventral striatum leads to alteration in learning, impulsivity, and flexibility resembling endophenotypes described in A1 carriers. We also observed an unsuspected role of Ankk1 in striatal D2R-expressing neurons of the ventral striatum in the regulation of energy homeostasis and documented differential nutrient partitioning in humans with or without the A1 allele. Conclusions: Overall, our data demonstrate that the Ankk1 gene is necessary for the integrity of striatal functions and reveal a new role for Ankk1 in the regulation of body metabolism.

AB - Background: A large body of evidence highlights the importance of genetic variants in the development of psychiatric and metabolic conditions. Among these, the TaqIA polymorphism is one of the most commonly studied in psychiatry. TaqIA is located in the gene that codes for the ankyrin repeat and kinase domain containing 1 kinase (Ankk1) near the dopamine D2 receptor (D2R) gene. Homozygous expression of the A1 allele correlates with a 30% to 40% reduction of striatal D2R, a typical feature of addiction, overeating, and other psychiatric pathologies. The mechanisms by which the variant influences dopamine signaling and behavior are unknown. Methods: Here, we used transgenic and viral-mediated strategies to reveal the role of Ankk1 in the regulation of activity and functions of the striatum. Results: We found that Ankk1 is preferentially enriched in striatal D2R-expressing neurons and that Ankk1 loss of function in the dorsal and ventral striatum leads to alteration in learning, impulsivity, and flexibility resembling endophenotypes described in A1 carriers. We also observed an unsuspected role of Ankk1 in striatal D2R-expressing neurons of the ventral striatum in the regulation of energy homeostasis and documented differential nutrient partitioning in humans with or without the A1 allele. Conclusions: Overall, our data demonstrate that the Ankk1 gene is necessary for the integrity of striatal functions and reveal a new role for Ankk1 in the regulation of body metabolism.

KW - DR receptor

KW - Dopamine signaling

KW - Eating disorders

KW - Genetic polymorphism

KW - Metabolism

KW - Reward-associated behavior

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U2 - https://doi.org/10.1016/j.biopsych.2023.02.010

DO - https://doi.org/10.1016/j.biopsych.2023.02.010

M3 - Article

C2 - 36805080

SN - 0006-3223

VL - 94

SP - 424

EP - 436

JO - Biological Psychiatry

JF - Biological Psychiatry

IS - 5

ER -

The Addiction-Susceptibility TaqIA/Ankk1 Controls Reward and Metabolism Through D2 Receptor-Expressing Neurons

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Keywords

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