Use of GABA Alpha5-Selective Inverse Agonists Carmen Martinez-Cué, B
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Treating enhanced GABAergic inhibition in Down syndrome: use of GABA alpha5-selective inverse agonists Carmen Martinez-Cué, B. Delatour, M. C. Potier To cite this version: Carmen Martinez-Cué, B. Delatour, M. C. Potier. Treating enhanced GABAergic inhibition in Down syndrome: use of GABA alpha5-selective inverse agonists. Neurosci Biobehav Rev, 2014, 46 Pt 2, pp.218-27. 10.1016/j.neubiorev.2013.12.008. hal-03236876 HAL Id: hal-03236876 https://hal-cnrs.archives-ouvertes.fr/hal-03236876 Submitted on 26 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. *Manuscript Click here to view linked References Title: Treating enhanced GABAergic inhibition in Down syndrome: use of GABA α5-selective 1 2 inverse agonists. 3 4 5 6 7 1 2 2* 8 Authors: Carmen Martínez-Cué , Benoît Delatour , and Marie-Claude Potier 9 10 11 12 13 14 15 1 16 Affiliations: Department of Physiology and Pharmacology, Faculty of Medicine, University of 17 2 18 Cantabria, Santander, Spain; Centre de Recherche de l'Institut du Cerveau et de Moelle 19 20 Epinière, CNRS UMR7225, INSERM UMRS 975, UPMC, ICM, Hôpital Pitié-Salpêtrière, 21 22 Paris, France. 23 24 *Corresponding author: 25 26 27 Dr. Marie-Claude POTIER 28 29 ICM 30 31 Hôpital Pitié-Salpêtrière 32 33 CNRS UMR7225, INSERM UMRS975, UPMC 34 35 36 47, Bd de l’Hôpital 37 38 75013 PARIS, FRANCE 39 40 +33157274519 41 42 [email protected] 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 1 65 ABSTRACT 1 2 3 Excess inhibition in the brain of individuals carrying an extra copy of chromosome 21 could be 4 5 responsible for cognitive deficits observed throughout their lives. A change in the 6 7 excitatory/inhibitory balance in adulthood would alter synaptic plasticity, potentially triggering 8 9 10 learning and memory deficits. -aminobutyric acid (GABA) is the major inhibitory 11 12 neurotransmitter in the mature central nervous system and binds to GABAA receptors, opens a 13 14 chloride channel, and reduces neuronal excitability. In this review we discuss methods to 15 16 17 alleviate neuronal inhibition in a mouse model of Down syndrome, the Ts65Dn mouse, using 18 19 either an antagonist (pentylenetetrazol) or two different inverse agonists selective for the - 20 21 subunit containing receptor. Both inverse agonists, which reduce inhibitory GABAergic 22 23 transmission, could rescue learning and memory deficits in Ts65Dn mice. We also discuss 24 25 26 safety issues since modulation of the excitatory-inhibitory balance to improve cognition without 27 28 inducing seizures remains particularly difficult when using GABA antagonists. 29 30 31 32 Key words: Down syndrome, -aminobutyric acid, inverse agonist, -subunit containing 33 34 35 GABAA receptor, convulsion, behavior. 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 2 65 1. INTRODUCTION 1 2 Down syndrome (DS), resulting from trisomy of chromosome 21, is the most common genetic 3 4 cause of intellectual disability (Lejeune et al., 1959; Bittles et al., 2007; Sherman et al., 2007). 5 6 This disorder is associated with neurological complications including cognitive deficits that lead 7 8 9 to mild to profound impairment in intellectual functioning (Lott & Dierssen, 2010). 10 11 Some cognitive deficits have been alleviated by advances in teaching methods and educational 12 13 mainstreaming, but these approaches are not sufficient to counteract all cognitive deficits 14 15 (Wishart, 2007). Treatments aimed at enhancing cognitive skills to provide higher autonomy 16 17 18 remain necessary. However, pharmacological treatments were dismissed as unlikely to improve 19 20 cognition in DS because many neurotransmitter systems and brain circuits are affected from 21 22 early developmental stages in this disorder. 23 24 25 26 Several murine models of DS have been developed in recent years. Studies of these models 27 28 29 have provided significant insight on the neurobiological mechanisms underlying cognitive 30 31 deficits in DS. In addition, they have proven to be useful in testing new pharmacological 32 33 approaches to reduce DS-related cognitive impairments (Bartesaghi et al., 2011; Rueda et al., 34 35 2012). Indeed, recent studies in mouse models have suggested that affected brain circuits could 36 37 38 be potential targets of pharmacotherapies to enhance cognitive deficits in the DS population 39 40 (Fernandez et al., 2007; Costa et al., 2008; Rueda et al., 2008; Salehi et al., 2009; Faizi et al., 41 42 2011). In this way, mouse models can provide the pre-clinical basis for new treatments to 43 44 emerge. 45 46 47 48 49 The best-characterized and most widely used model of DS is the Ts65Dn mouse. Ts65Dn has 50 51 segmental trisomy of murine chromosome 16, containing 92 human orthologs between Mrp139 52 53 and Znf295 (Sturgeon & Gardiner, 2011). This murine model recapitulates several fundamental 54 55 56 features of DS including cognitive deficits and alterations in brain morphology and function 57 58 (Bartesaghi et al., 2011; Haydar & Reeves, 2012; Rueda et al., 2012). At the behavioral level 59 60 Ts65Dn mice are hyperactive (Escorihuela et al., 1995; Reeves et al., 1995; Holtzman et al., 61 62 63 64 3 65 1996), have developmental delay (Holtzman et al., 1996), and exhibit alterations in processes 1 2 involved in learning and memory, such as spatial reference and working memory, as well as 3 4 reduced attention (Escorihuela et al., 1998; Driscoll et al., 2004; Martinez-Cue et al., 2006; 5 6 Rueda et al., 2012; Martinez-Cue et al., 2013). These cognitive deficits likely result, in part, 7 8 9 from various neuromorphological alterations including changes in 1) the size, morphology, and 10 11 cellular density of different brain areas; 2) pre- and post-natal neurogenesis; 3) dendritic 12 13 structure; and 4) the morphology of synapses and spines (Bartesaghi et al., 2011; Rueda et al., 14 15 2012). Finally, abnormal synaptic plasticity, as shown by the reduction in long-term potentiation 16 17 18 (LTP) in the hippocampal CA1 and dentate gyrus (DG) areas, also compromises the cognition 19 20 of Ts65Dn mice (Siarey et al., 1999; Kleschevnikov et al., 2004). 21 22 23 24 2. EXCESSIVE INHIBITION: A MAJOR FEATURE OF DS 25 26 2.1. Over-inhibition in DS 27 28 29 One major functional defect observed in the brains of both individuals with DS and the Ts65Dn 30 31 mouse model appears to be an imbalance between excitatory and inhibitory neurotransmission. 32 33 In particular, excessive inhibition has been proposed as one of the underlying causes of the 34 35 cognitive deficits in DS. Overinhibition can result from increased -aminobutyric acid (GABA) 36 37 38 concentration at the synapse. Interestingly, however, several studies have shown either a 39 40 decrease or no change in GABA concentration in individuals with DS compared with euploid 41 42 individuals. Specifically, 60% less GABA was detected in the frontal cortex of fetuses with DS 43 44 45 (Whittle et al., 2007). Similarly, decreased GABA was observed in temporal lobes, but not 46 47 frontal lobes, of children with DS between 3 and 17 years old using in vivo magnetic resonance 48 49 spectroscopy (MRS) (Smigielska-Kuzia & Sobaniec, 2007; Smigielska-Kuzia et al., 2010). 50 51 Further, the only MRS study of Ts65Dn mouse brain published to date could not identify the 52 53 resonance peak corresponding to GABA (Huang et al., 2000). 54 55 56 57 58 Post-mortem studies of adults with DS and Alzheimer’s disease (AD) neuropathology using 59 60 radioassay chromatography showed that levels of GABA were globally unchanged in 61 62 63 64 4 65 individuals with DS and AD (Seidl et al., 2001). However, a significant deficit of GABA was 1 2 detected in the hippocampus and the temporal cortex of individuals with DS and neocortical 3 4 neurofibrillary tangles. These results are consistent with losses of cortical neurons containing 5 6 these neurotransmitters (Reynolds & Warner, 1988). Together, these studies showing either a 7 8 9 decrease or no change in GABA levels in fetuses, children, and adults with DS make it unlikely 10 11 that over-inhibition in the brain of individuals with DS results from increased GABA 12 13 concentrations. 14 15 16 17 18 Another potential explanation for altered inhibition in individuals with DS has been postulated. 19 20 Brains of individuals with DS have fewer small, granular, (presumably) GABAergic neurons in 21 22 layers II and IV of the cortex (Ross et al., 1984). In addition, microarray studies of human 23 24 neural progenitor cells (hNPCs) in DS revealed gene expression changes indicative of defects in 25 26 interneuron progenitor development that may lead to decreased GABAergic interneuron 27 28 29 neurogenesis (Bhattacharyya et al., 2009). 30 31 32 33 Further information may be gained from ongoing studies aiming at quantifying the expression 34 35 of GABA receptors. Positron Emission Tomography (PET) studies using either [11C]Ro15 4513 36 37 11 38 or [ C]flumazenil help measure in vivo GABAA receptor subtype occupancy, particularly for 39 40 those containing the 5 subtype (Lingford-Hughes et al., 2002; Eng et al., 2010).