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Both Chronic Treatments by Epothilone D and Fluoxetine Increase the Short-Term Memory and Differentially Alter the Mood Status of STOP/MAP6 KO Mice

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Both Chronic Treatments by Epothilone D and Fluoxetine Increase the Short-Term Memory and Differentially Alter the Mood Status of STOP/MAP6 KO Mice Both chronic treatments by epothilone D and fluoxetine increase the short-term memory and differentially alter the mood status of STOP/MAP6 KO mice. Vincent Fournet, Gaetan de Lavilléon, Annie Schweitzer, Bruno Giros, Annie Andrieux, Marie-Pascale Martres To cite this version: Vincent Fournet, Gaetan de Lavilléon, Annie Schweitzer, Bruno Giros, Annie Andrieux, et al.. Both chronic treatments by epothilone D and fluoxetine increase the short-term memory and differentially alter the mood status of STOP/MAP6 KO mice.: epothilone and fluoxetine improve STOP KO memory. Journal of Neurochemistry, Wiley, 2012, 123 (6), pp.982-96. 10.1111/jnc.12027. inserm- 00838387 HAL Id: inserm-00838387 https://www.hal.inserm.fr/inserm-00838387 Submitted on 8 Oct 2013 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. Journal of Neurochemistry Both chronic treatments by epothilone D and fluoxetine increase the short-term memory and differentially alter the mood-status of STOP/MAP6 KO mice Journal:For Journal Peer of Neurochemistry Review Manuscript ID: JNC-E-2012-0772.R1 Manuscript Type: Original Article Date Submitted by the Author: n/a Complete List of Authors: Fournet, Vincent; INSERM UMRS 836, Grenoble Institut Neurosciences, CEA-iRTSV-GPC, Univesité Joseph Fourier, Physiopathologie du cytosquelette; INSERM UMRS 952, CNRS UMR 7224, Université Pierre et Marie Curie, Physiopathologie des maladies du système nerveux central de Lavilléon, Gaetan; INSERM UMRS 952, CNRS UMR 7224, Université Pierre et Marie Curie, Physiopathologie des maladies du système nerveux central Schweitzer, Annie; INSERM UMRS 836, Grenoble Institut Neurosciences, CEA-iRTSV-GPC, Univesité Joseph Fourier, Physiopathologie du cytosquelette Giros, Bruno; INSERM UMRS 952, CNRS UMR 7224, Université Pierre et Marie Curie, Physiopathologie des maladies du système nerveux central Andrieux, Annie; INSERM UMRS 836, Grenoble Institut Neurosciences, CEA-iRTSV-GPC, Univesité Joseph Fourier, Physiopathologie du cytosquelette MARTRES, Marie-Pascale; INSERM UMRS 952, CNRS UMR 7224, Université Pierre et Marie Curie, Physiopathologie des maladies du système nerveux central Area/Section: Molecular Basis of Disease antidepressant , microtubule-stabilizing compound, Keywords: serotonin/norepinephrine transporters, anxiety/depression , corticosterone, stress Page 1 of 50 Journal of Neurochemistry 1 Both chronic treatments by epothilone D and fluoxetine increase the short-term 2 memory and differentially alter the mood-status of STOP/MAP6 KO mice 3 4 5 6 7 8 9 Vincent Fournet, ‽,# Gaetan de Lavilléon, ‽ Annie Schweitzer, # Bruno Giros, ‽ Annie 10 11 Andrieux # and Marie-Pascale Martres ‽ 12 13 14 15 16 17 18 For Peer Review 19 ‽ 20 INSERM UMRS 952, CNRS UMR 7224, Université Pierre et Marie Curie, Paris, 21 France 22 23 #INSERM UMRS 836, Grenoble Institut Neurosciences, CEA-iRTSV-GPC, Université 24 25 Joseph Fourier, Grenoble, France 26 27 28 29 30 Address correspondence to Marie-Pascale Martres, INSERM UMRS 952, CNRS 31 32 UMR 7224, Université Pierre et Marie Curie, Physiopathologie des maladies du 33 système nerveux central, 9 Quai Saint Bernard, case courrier 37, 75252 Paris cedex 34 35 5, France. E-mail: [email protected] 36 37 38 39 40 Running title : epothilone and fluoxetine improve STOP KO memory 41 42 43 44 Abbreviations used: 45 46 5HT, serotonin; HPA, hypothalamic-pituitary-adrenal axis; KO, knockout; LTP, long term 47 potentiation; MAP, microtubule-associated-protein; NE, norepinephrine; NET, norepinephrine 48 49 transporter; PTP, post-tetanic potentiation; SERT, serotonin transporter; STOP, Stable 50 51 Tubule Only Polypeptide; WT, wild-type. 52 53 54 55 56 57 58 59 60 1 Journal of Neurochemistry Page 2 of 50 1 Abstract 2 3 4 Recent evidence underlines the crucial role of neuronal cytoskeleton in the pathophysiology 5 of psychiatric diseases. In this line, the deletion of STOP/MAP6 (Stable Tubule Only 6 7 Polypeptide), a microtubule-stabilizing protein, triggers various neurotransmission and 8 behavioral defects, suggesting that STOP knockout (KO) mice could be a relevant 9 10 experimental model for schizoaffective symptoms. To establish the predictive validity of such 11 a mouse line, in which the brain serotonergic tone is dramatically imbalanced, the effects of a 12 13 chronic fluoxetine treatment on the mood status of STOP KO mice were characterized. 14 Moreover, we determined the impact on mood of a chronic treatment by epothilone D, a 15 16 taxol-like microtubule-stabilizing compound that has previously been shown to improve the 17 synaptic plasticity deficits of STOP KO mice. We demonstrated that chronic fluoxetine was 18 For Peer Review 19 either anti-depressive and anxiolytic, or pro-depressive and anxiogenic, depending on the 20 paradigm used to test treated-mutant mice. Furthermore, control-treated STOP KO mice 21 22 exhibited paradoxical behaviors, compared to their clear-cut basal mood-status. Paradoxical 23 fluoxetine effects and control-treated STOP KO behaviors could be due to their hyper- 24 25 reactivity to acute and chronic stress. Interestingly, both epothilone D and fluoxetine chronic 26 27 treatments improved the short-term memory of STOP KO mice. Such treatments did not 28 affect the serotonin and norepinephrine transporter densities in cerebral areas of mice. 29 30 Altogether, these data demonstrated that STOP KO mice could represent a useful model to 31 study the relationship between cytoskeleton, mood and stress. and to test innovative mood 32 33 treatments, as microtubule-stabilizing compounds. 34 35 36 37 38 39 Keywords: antidepressant, anxiety/depression, corticosterone, microtubule-stabilizing 40 compound, serotonin/norepinephrine transporters, stress. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 2 Page 3 of 50 Journal of Neurochemistry 1 Introduction 2 3 4 Schizophrenia and mood disorders are common, chronic and debilitating psychiatric 5 illnesses, which have a high prevalence, regardless of countries and cultures, and have a 6 7 considerable socio-economic cost (Eaton et al. 2008). For example, unipolar major 8 depression, bipolar disorder and schizophrenia are ranked 1st, 6th and 9th, respectively, in 9 10 the World Health Organization estimates for disease-related lifetime disabilities and 2% of 11 humans are affected by schizophrenia or bipolar disorder (Lopez et al. 2006, Mathers & 12 13 Loncar 2006). Although, the aetiology of schizophrenia and mood disorders is yet poorly 14 understood, converging evidences support the view that they can arise from a deficit in 15 16 cerebral connectivity, synaptic plasticity and/or neuronal architecture (Mirnics et al. 2001, 17 Frankle et al. 2003, Owen et al. 2005, Schloesser et al. 2008). 18 For Peer Review 19 Microtubules and microtubule effectors are of fundamental importance to neuronal 20 differentiation and functions. Dysfunctions of the microtubule network have been shown to 21 22 lead to neurodegenerative diseases and to psychiatric disorders (Gardiner et al. 2011). 23 Recently, it was found that microtubule deregulation and alterations were related to 24 25 modifications of integrated brain functions both in animal models and in psychiatric diseases. 26 27 The first evidence for such a role of cytoskeleton disorganization in psychiatric-like 28 characteristics arises from the deletion in mice of the microtubule-stabilizing protein STOP 29 30 (Stable Tubule Only Polypeptide, Andrieux et al. 2002). Indeed, STOP knockout (KO) mice 31 exhibit abnormalities of glutamatergic, dopaminergic, acetylcholinergic/nicotinic, serotonergic 32 33 and noradrenergic neurotransmissions, deficits of neuronal and synaptic plasticity, 34 sensorimotor gating impairment, associated with profound and widespread behavioral 35 36 defects (Andrieux et al. 2002, Brun et al. 2005, Fradley et al. 2005, Bouvrais-Veret et al. 37 2007 and 2008, Powell et al. 2007, Delotterie et al. 2010, Kajitani et al. 2010, Fournet et al. 38 39 2010, 2012). The overall phenotype of STOP KO mice suggests that they represent a 40 relevant experimental model for schizoaffective-like characteristics. Other studies, based on 41 42 human genetics, also indicate relationship between microtubule regulatory proteins and 43 mental functions. For example, dysbindin-1 gene mutations have been reported in both 44 45 schizophrenic (Straub et al. 2002, Benson et al. 2004, Norton et al. 2006) and bipolar 46 patients (Maier 2008, Domschke et al. 2011) and this protein interacts with and regulates 47 48 microtubules (Talbot et al. 2006). Similarly, mutations in DISC1 (Disrupted-In-Schizophrenia 49 1) gene are associated with several psychiatric diseases (schizophrenia, bipolar disorders, 50 51 depression and autism (Millar et al. 2000, Ishizuka et al. 2006, Blackwood et al. 2007, Chubb 52 53 et al. 2008, Kilpinen et al. 2008) and its product is a multifunctional protein acting on 54 microtubules and on microtubule-regulatory proteins (Morris et al. 2003, Kamiya et al. 2006, 55 56 Taya et al. 2007). 57 58 59 60 3 Journal of Neurochemistry Page 4 of 50 1 A large portion of psychiatric patients are refractory to therapeutic drugs and, during 2 drug treatments, some symptoms are moderately improved or resistant to the current 3 4 therapy. For example, antipsychotics do not improve negative symptoms and cognitive 5 deficits (Keefe et al. 2007), in spite of a therapeutic benefit for positive schizophrenia 6 7 symptoms (Seeman et al. 2006). In addition, some drugs need a delay for their therapeutic 8 action, as in the case of antidepressants that necessitate 3-6 weeks to be active (Blier & de 9 10 Montigny 1994). Finally, most of psychiatric drugs elicit a broad range of undesirable side 11 effects, which often lead patients to cease their treatment.
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