The Addiction-Susceptibility TaqIA/Ankk1 Controls Reward and Metabolism Through D2 Receptor-Expressing Neurons
Biological Psychiatry. 2023-02-01; :
DOI: 10.1016/j.biopsych.2023.02.010
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Montalban E(1), Walle R(2), Castel J(3), Ansoult A(3), Hassouna R(3), Foppen E(3), Fang X(4), Hutelin Z(4), Mickus S(4), Perszyk E(4), Petitbon A(2), Berthelet J(5), Rodrigues-Lima F(3), Cebrian-Serrano A(6), Gangarossa G(3), Martin C(3), Trifilieff P(2), Bosch-Bouju C(2), Small DM(4), Luquet S(7).
Author information:
(1)Université Paris Cité, CNRS, Unité de Biologie Fonctionnelle et Adaptative, F-75013 Paris, France. Electronic address: .
(2)Université Bordeaux, INRAE, Bordeaux INP, NutriNeuro, UMR 1286, F-33000, Bordeaux, France.
(3)Université Paris Cité, CNRS, Unité de Biologie Fonctionnelle et Adaptative, F-75013 Paris, France.
(4)The Modern Diet and Physiology Research Center, New Haven CT, USA; Department of Psychiatry, Yale University School of Medicine, New Haven CT, USA.
(5)Université Paris Cité, CNRS, Unité Epigenetique et Destin Cellulaire, F-75013 Paris, France.
(6)Institute for Diabetes and Obesity, Helmholtz Diabetes Center (HDC), Helmholtz Zentrum Munchen, 85764 Neuherberg, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany.
(7)Université Paris Cité, CNRS, Unité de Biologie Fonctionnelle et Adaptative, F-75013 Paris, France; The Modern Diet and Physiology Research Center, New Haven CT, USA. Electronic address: .
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 dopamine receptor (D2R) gene. Homozygous expression of the A1 allele correlates with a 30 to 40% reduction of striatal D2R, a typical feature of addiction, over-eating 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 dorsal and ventral striatum leads to alteration in learning, impulsivity and flexibibility 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.
Copyright © 2023. Published by Elsevier Inc.