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Emotional Memory Impairments in a Genetic Rat Model of Depression

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Emotional Memory Impairments in a Genetic Rat Model of Depression View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by AIR Universita degli studi di Milano Molecular Psychiatry (2012) 17, 173–184 & 2012 Macmillan Publishers Limited All rights reserved 1359-4184/12 www.nature.com/mp ORIGINAL ARTICLE Emotional memory impairments in a genetic rat model of depression: involvement of 5-HT/MEK/Arc signaling in restoration TM Eriksson1,2, P Delagrange3, M Spedding3, M Popoli4, AA Mathe´ 5,SOO¨ gren2 and P Svenningsson1 1Center of Molecular Medicine, Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden; 2Department of Neuroscience, Karolinska Institute, Stockholm, Sweden; 3Inst De Recherches Servier, Experimental Sciences, Suresnes, France; 4Center of Neuropharmacology, Department of Pharmacological Sciences, Center of Excellence on Neurodegenerative Diseases, University of Milan, Milan, Italy and 5Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden Cognitive dysfunctions are common in major depressive disorder, but have been difficult to recapitulate in animal models. This study shows that Flinders sensitive line (FSL) rats, a genetic rat model of depression, display a pronounced impairment of emotional memory function in the passive avoidance (PA) task, accompanied by reduced transcription of Arc in prefrontal cortex and hippocampus. At the cellular level, FSL rats have selective reductions in levels of NMDA receptor subunits, serotonin 5-HT1A receptors and MEK activity. Treatment with chronic escitalopram, but not with an antidepressant regimen of nortriptyline, restored memory performance and increased Arc transcription in FSL rats. Multiple pharmacological manipulations demonstrated that procognitive effects could also be achieved by either disinhibition of 5-HT1AR/MEK/Arc or stimulation of 5-HT4R/MEK/Arc signaling cascades. Taken together, studies of FSL rats in the PA task revealed reversible deficits in emotional memory processing, providing a potential model with predictive and construct validity for assessments of procognitive actions of antidepressant drug therapies. Molecular Psychiatry (2012) 17, 173–184; doi:10.1038/mp.2010.131; published online 18 January 2011 Keywords: antidepressant; BDNF; MAPK; passive avoidance; signal transduction; TrkB Introduction Studies in depressed patients have linked dysfunc- tion of the central serotonergic system with abnormal The clinical impact of emotional dysfunction on cognitive processing of emotional stimuli, and indi- cognitive capacity is recognized but difficult to treat.1–3 cated that an important component in antidepressant Besides depressed mood, the DSM-IV criteria of major therapy is support of cognitive functions, which can be depressive disorder (MDD) involve cognitive aspects, separated from elevation of mood.8 The clinical that is, diminished ability to think and concentrate, or efficacy of selective serotonin reuptake inhibitors indecisiveness, with devastating effects on executive (SSRIs) in MDD is exerted by several of the 14 cloned 2,3 9 functions, short- and long-term learning and memory. 5-HT receptors, with 5-HT1AR being the most studied. These cognitive impairments appear to involve altera- Several studies have described alteration of 5-HT1ARin tions in the neuronal processing of emotional stimuli, postmortem samples from patients with MDD.10–15 that is, negative attentional bias including feelings of Interestingly, 5-HT1AR antagonists facilitate learning worthlessness or excessive guilt and recurrent thoughts and counteract memory impairments.9 In addition, 5- 4 16 of suicide. Multiple brain areas, involved in emotion- HT4R agonists may have antidepressant and procog- ality and cognition, that is, prefrontal cortex (PFC), nitive effects in learning and memory tasks.17 hippocampus (HPC), parahippocampal region (PHR), The delayed onset of SSRIs and most other anti- amygdala and striatum, show altered functions in depressants implicate that therapeutic effects are MDD.1,2,5 In particular, volume reduction and impaired mediated beyond elevations of monoamines, such as functionality of hippocampus have been repeatedly changes of receptor coupling to intracellular signaling reported in MDD.2,6,7 cascades and cross talk with non-monoaminergic mechanisms. Several lines of evidence indicate that Correspondence: Dr P Svenningsson, Center of Molecular Med- brain-derived neurotrophic factor (BDNF)-induced icine, Department of Physiology and Pharmacology, Nanna Svartz activation of TrkB mediate actions of antidepres- va¨g 2, Karolinska Institute, Stockholm SE-171 77, Sweden. sants.18–21 TrkB receptors, in turn, stimulate several E-mail: [email protected] Received 26 April 2010; revised 27 November 2010; accepted 6 intracellular cascades including the mitogen-activated December 2010; published online 18 January 2011 protein kinase (MAPK), AKT and phospholipase C Memory impairments in a rat model of depression TM Eriksson et al 174 pathways.21,22 In particular, the MAPK pathway is age. Rats were kept in standard cages (TypeIV Macrolon, involved in behavioral effects of antidepressants and Bayer Material Science, Leverkusen, Germany, 26 Â an important modulator of ionotropic receptor signal- 42 Â 15 cm) with sawdust, at room temperature and ing, structural remodeling and consolidation of fear relative humidity (45–55%) under a constant light/dark memories.23–25 Synaptic activation of MAPK induces, cycle (lights on at 0700 hours). Water and food pellets via CREB and Elk-1, expression of activity-related (LactaminR36, Stockholm, Sweden) were available ad cytoskeletal-associated protein (Arc/Arg 3.1).23,26–28 libitum. Experimental procedures were approved by the Arc expression is induced by long-term potentiation- local Animal Ethics Committee (Stockholms Norra inducing stimuli, requiring NMDAR,27,29 involved in Djurfo¨rso¨ksetiska Na¨mnd). synaptic memory consolidation and enriched in FRL and FSL rats were randomly assigned to groups hippocampal dendritic spines where its activation is given either escitalopram, nortriptyline or vehicle required for acquisition of contextual and spatial administered to standard rat pellets38,39 (Supplemen- learning.26,30,31 Arc expression is also activated by tary Figure S4) (Lactamin AB). Escitalopram was several other mechanism(s), including BDNF,28 protein given at 340 mg kgÀ1 pellets for 3 weeks, followed by kinase A,30 and pertussis-induced inhibition of 410 mg kgÀ1 pellets. Nortriptyline was administered at 32 À1 Gi-mediated signaling. Accordingly, blockade of 5- 330 mg kg pellet. HT1AR augments the effect of an acute dose of NAD-299 ((R)-3-N,N-dicyclobutylamino-8-fluoro- paroxetine on increasing transcription of Arc mRNA.33 3,4-dihydro-2H-1-benzopyran-5-carboxamide hydro- Thus, Arc transcription may be a key nodal point in gen (2R,3R)tartrate monohydrate; 1 mg kgÀ1 subcuta- integration of monoaminergic antidepressant effects neous (s.c.); AstraZeneca R&D, So¨derta¨lje, Sweden) with glutamate-driven activity-dependent neuronal and RS67333 (1 mg kgÀ1 intraperitoneal (i.p.); Tocris, adaptations regulating gene transcription associated Bristol, UK) were administered 30 min before test- with information processing and associative learning. ing.40,41 The (±)-8-OH-DPAT (8-hydroxy-2-(di-n-pro- The Flinders sensitive line (FSL) is a rat strain pylamino)tetralin; 0.3 mg kgÀ1 s.c.; Sigma, St Louis, associated with distinct behavioral and neurochem- MO, USA) and MK-801 (( þ )-10,11-dihydro-5-methyl- ical features of major depression, including face 5H-dibenzo[a,d]-cyclohepten-5,10-imine hydrogen validity, that is, psychomotor retardation and maleate; 0.05 mg kgÀ1 s.c.; Sigma) were both adminis- increased rapid eye movement sleep. FSL rats display tered 15 min before training.41 GR125487 (5-fluoro-2- a genetic vulnerability to environmental stressors methoxy-[1-[2-[(methylsulfonyl)amino]ethyl]-4-piperi and have been successfully used for validation of dinyl]-1H-indole-3-methylcarboxylate sulfamate; antidepressant effects.34 Interestingly, promotion of 10 mg kgÀ1 i.p.; Tocris) was given 60 min before hippocampal neuroplasticity, by means of intra- training.17 Drugs were dissolved in 2 ml kgÀ1 of 0.9% cerebroventricular injections of bone marrow me- NaCl. PD184161(Servier, Suresnes, France) was senchymal stem cells, reverses the depressive-like administered 60 min before testing at a dose of phenotype of FSL rats.35 Long-term potentiation is 30 mg kgÀ1 i.p. and dissolved in 1% Tween80 in also reduced in the cornu ammonis 1 (CA1) area of 6mlkgÀ1 of 0.9% NaCl. hippocampus, shown during in vivo recordings in anesthetized FSL rats36 paralleled by reduced NR1 Passive avoidance, forced-swim test, open field and subunits of the NMDAR in hippocampal synapto- elevated plus-maze somes.36 FSL rats also have reduced hippocampal The step-through passive avoidance (PA) was per- volume and dendritic spines, which is reversed by formed as described earlier41 (see Supplementary antidepressants.37 These alterations may affect emo- Figure S1). During PA training, rats were placed in tional memory processes that, indeed, are believed to the bright compartment and allowed to explore for depend on enduring remodeling of neuronal mor- 120 s. Thereafter, the sliding door was opened and phology and activity-dependent structural plasticity, once the rat had entered the dark compartment, the particularly of glutamatergic dendritic spines, indi- sliding door was automatically closed and a weak cating possible cognitive impairments in FSL rats.
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