Long-lasting correction of in vivo LTP and cognitive deficits of mice modelling Down syndrome with an α5-selective GABAA inverse agonist Arnaud Duchon, Agnès Gruart, Christelle Albac, Benoît Delatour, Javier Zorrilla de San Martin, José María Delgado-garcía, Yann Hérault, Marie-claude Potier To cite this version: Arnaud Duchon, Agnès Gruart, Christelle Albac, Benoît Delatour, Javier Zorrilla de San Martin, et al.. Long-lasting correction of in vivo LTP and cognitive deficits of mice modelling Down syn- drome with an α5-selective GABAA inverse agonist. British Journal of Pharmacology, Wiley, 2019, 10.1111/bph.14903. hal-02388584 HAL Id: hal-02388584 https://hal.archives-ouvertes.fr/hal-02388584 Submitted on 25 May 2021 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Received: 9 May 2019 Revised: 12 September 2019 Accepted: 15 September 2019 DOI: 10.1111/bph.14903 RESEARCH PAPER Long-lasting correction of in vivo LTP and cognitive deficits of mice modelling Down syndrome with an α5-selective GABAA inverse agonist Arnaud Duchon1,2,3,4 | Agnès Gruart5 | Christelle Albac6,7,8,9 | Benoît Delatour6,7,8,9 | Javier Zorrilla de San Martin6,7,8,9 | José María Delgado-García5 | Yann Hérault1,2,3,4 | Marie-Claude Potier6,7,8,9 1Translational Medicine and Neurogenetics, Institut de Génétique et de Biologie Background and Purpose: Excessive GABAergic inhibition contributes to cognitive Moléculaire et Cellulaire, Illkirch, France dysfunctions in Down syndrome (DS). Selective negative allosteric modulators 2Centre National de la Recherche Scientifique, α α α UMR7104, Illkirch, France (NAMs) of 5-containing GABAA receptors such as the 5 inverse agonist ( 5IA) 3Institut National de la Santé et de la restore learning and memory deficits in Ts65Dn mice, a model of DS. In this study we Recherche Médicale, U1258, Illkirch, France have assessed the long-lasting effects of α5IA on in vivo LTP and behaviour in 4Neuropôle, Université de Strasbourg, Illkirch, Ts65Dn mice. France 5División de Neurociencias, Universidad Pablo Experimental Approach: We made in vivo LTP recordings for six consecutive days in de Olavide, Seville, Spain freely moving Ts65Dn mice and their wild-type littermates, treated with vehicle or 6 Institut du Cerveau et de la Moelle épinière, α5IA. In parallel, Ts65Dn mice were assessed by various learning and memory tests Hôpital de la Pitié-Salpêtrière, Paris, France 7Institut National de la Santé et de la (Y maze, Morris water maze, or the novel object recognition) for up to 7 days, Recherche Médicale, U1127, Hôpital de la following one single injection of α5IA or vehicle. Pitié-Salpêtrière, Paris, France Key Results: LTP was not evoked in vivo in Ts65Dn mice at hippocampal 8Centre National de la Recherche Scientifique, UMR7225, Hôpital de la Pitié-Salpêtrière, CA3-CA1 synapses. However, this deficit was sustainably reversed for at least six Paris, France consecutive days following a single injection of α5IA. This long-lasting effect of 9Sorbonne Université, Hôpital de la Pitié- α5IA was also observed when assessing working and long-term memory deficits in Salpêtrière, Paris, France Ts65Dn mice. Correspondence Conclusion and Implications: We show for the first time in vivo LTP deficits in Marie-Claude Potier, ICM Institut du Cerveau et de la Moelle épinière, CNRS UMR7225, Ts65Dn mice. These deficits were restored for at least 6 days following acute INSERM U1127, Sorbonne Université, Hôpital treatment with α5IA and might be the substrate for the long-lasting pharmacological de la Pitié-Salpêtrière, Paris, France. Email: [email protected] effects of α5IA on spatial working and long-term recognition and spatial memory tasks. Our results demonstrate the relevance of negative allosteric modulators of Funding information Fondation Jérôme Lejeune; Investissements α5-containing GABAA receptors to the treatment of cognitive deficits associated d'avenir, Grant/Award Numbers: ANR- with DS. 10-INBS-07 PHENOMIN, ANR-10-LABX- 0030-INRT, ANR-10-IDEX-0002-02, ANR- Abbreviations: α5IA, 1-methyl-4-({[3-(5-methyl-1,2-oxazol-3-yl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]oxy}methyl)-1H-1,2,3-triazole (α5 inverse agonist); DS, Down syndrome; fEPSP, field EPSP; HFS, high frequency stimulation; IEG, immediate early gene; MWM, Morris water maze; NAM, negative allosteric modulator; NOR, novel object recognition. Yann Hérault and Marie-Claude Potier have equal contribution. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2019 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society 1106 wileyonlinelibrary.com/journal/bph Br J Pharmacol. 2020;177:1106–1118. DUCHON ET AL. 1107 10-IAIHU-06; Agence Nationale de la Recherche; Junta de Andalucía, Grant/Award Numbers: BIO122, CVI 2487, P07-CVI-02686; MINECO, Grant/Award Numbers: BFU2011-29089, BFU2011-29286 1 | INTRODUCTION What is already known Down syndrome (DS) is the consequence of a third complete or partial • The α5 inverse agonist (α5IA) reverses cognitive deficits copy of human chromosome 21 (Antonarakis, 2017; Antonarakis, Lyle, in Ts65Dn mice modelling Down syndrome. Dermitzakis, Reymond, & Deutsch, 2004; Lejeune, Gautier, & Turpin, 1959). It is associated with physical abnormalities including character- What does this study add istic facial features and cognitive deficits producing variable impair- • α5IA produces long-lasting pharmacological effects by ments in intellectual functioning. In recent years, beside cognitive sustainably restoring in vivo LTP in Ts65Dn mice. therapies that have proven to be useful for improving deficits in DS, active research has identified possible pharmacological treatments in What is the clinical significance mouse models (Martinez-Cue, Delatour, & Potier, 2014; Ruparelia, • These results highlight the interest of α5IA for treating Pearn, & Mobley, 2012; Stagni, Giacomini, Guidi, Ciani, & Bartesaghi, cognitive deficits in Down syndrome. 2015). Several mouse models have been extremely useful for deci- phering the mechanisms involved in cognitive defects in DS and for the design of preclinical studies (Herault et al., 2017; Sheppard, Wise- man, Ruparelia, Tybulewicz, & Fisher, 2012). The most widely used mouse model is the Ts(1716)65Dn, Ts65Dn mouse (Reeves et al., 1995). These mice, carrying a partial Mmu16 trisomy for 122 genes, α5IA could produce in parallel a long-lasting effect on cognition and reproduce DS memory defects and show deficits in LTP on hippocam- found that indeed a single dose of α5IA was able to reverse learning pal slices, that are reversed by non-selective antagonists of GABAA and memory deficits up to 7 days after injection. We propose that a receptors (Kleschevnikov et al., 2004). In addition, GABAA antagonists single dose of α5IA is sufficient to induce a profound and long-lasting restore cognitive impairments in Ts65Dn mice (Colas et al., 2013; remodelling of neuronal circuits involved in the cognitive functions Colas, Chuluun, Garner, & Heller, 2017; Fernandez et al., 2007; Rueda, that are affected in DS. Florez, & Cue, 2008). Previously, we demonstrated that a single dose of the α5 inverse agonist (α5IA), a selective negative allosteric modulator 2 | METHODS (NAM) of GABAA receptors containing the α5 subunit (Dawson et al., 2006), was able to rescue learning and memory deficits and 2.1 | Mouse lines to promote immediate early gene (IEG) synthesis in the hippocam- pus of Ts65Dn mice (Braudeau et al., 2011; Braudeau et al., 2011). All animal care and experimental procedures complied with European Subsequently, another inverse agonist of α5-containing GABAA Union Council (2010/63/EU), the French Ministry of Agriculture (87 receptors, RO4938581, was shown to correct cognitive deficits of 848), and Spanish (BOE 252/34367-91, 2005) guidelines for the use Ts65Dn mice and to restore LTP in hippocampal slices after of laboratory animals in chronic electrophysiological and behavioural long-term treatment (Martinez-Cue et al., 2013). The same study studies. In addition, French National Ethics Committees approved all showed that RO4938581 improved density of GABAergic synaptic experimental protocols under the accreditation numbers APAFIS3152 markers in the molecular layer of the hippocampus of Ts65Dn mice. and 4670. Marie-Claude Potier and Yann Hérault received official The GABAA receptors containing the α5 subunit are involved in cog- authorization from the French Ministry of Agriculture to carry out nitive processes of learning and memory and are preferentially research and experiments on animals (authorization numbers 75-2138 expressed in the hippocampus (Prut et al., 2010; Wisden, Laurie, and 67-369, respectively). Consistent with these guidelines, statistical Monyer, & Seeburg, 1992). analyses were used to minimize the number of animals used, within Although NAMs of α5-containing GABAA receptors reversed LTP the constraints of necessary