PDF《in restoration》

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 , SO O ¨ gren2 and P Svenningsson1

1 Center of Molecular Medicine, Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden;

2 Department of Neuroscience, Karolinska Institute, Stockholm, Sweden;

3 Inst De Recherches Servier, Experimental Sciences, Suresnes, France;

4 Center of Neuropharmacology, Department of Pharmacological Sciences, Center of Excellence on Neurodegenerative Diseases, University of Milan, Milan, Italy and

5 Department 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, 173C184;

doi:10.1038/mp.2010.131;

published online

18 January

2011 Keywords: antidepressant;

BDNF;

MAPK;

passive avoidance;

signal transduction;

TrkB Introduction The clinical impact of emotional dysfunction on cognitive capacity is recognized but difficult to treat.1C3 Besides depressed mood, the DSM-IV criteria of major depressive disorder (MDD) involve cognitive aspects, that is, diminished ability to think and concentrate, or indecisiveness, with devastating effects on executive functions, short- and long-term learning and memory.2,3 These cognitive impairments appear to involve altera- tions in the neuronal processing of emotional stimuli, that is, negative attentional bias including feelings of worthlessness or excessive guilt and recurrent thoughts of suicide.4 Multiple brain areas, involved in emotion- ality and cognition, that is, prefrontal cortex (PFC), hippocampus (HPC), parahippocampal region (PHR), amygdala and striatum, show altered functions in MDD.1,2,5 In particular, volume reduction and impaired functionality of hippocampus have been repeatedly reported in MDD.2,6,7 Studies in depressed patients have linked dysfunc- tion of the central serotonergic system with abnormal cognitive processing of emotional stimuli, and indi- cated that an important component in antidepressant therapy is support of cognitive functions, which can be separated from elevation of mood.8 The clinical efficacy of selective serotonin reuptake inhibitors (SSRIs) in MDD is exerted by several of the

14 cloned 5-HT receptors, with 5-HT1AR being the most studied.9 Several studies have described alteration of 5-HT1AR in postmortem samples from patients with MDD.10C15 Interestingly, 5-HT1AR antagonists facilitate learning and counteract memory impairments.9 In addition, 5- HT4R agonists may have antidepressant16 and procog- nitive effects in learning and memory tasks.17 The delayed onset of SSRIs and most other anti- depressants implicate that therapeutic effects are mediated beyond elevations of monoamines, such as changes of receptor coupling to intracellular signaling cascades and cross talk with non-monoaminergic mechanisms. Several lines of evidence indicate that brain-derived neurotrophic factor (BDNF)-induced activation of TrkB mediate actions of antidepres- sants.18C21 TrkB receptors, in turn, stimulate several intracellular cascades including the mitogen-activated protein kinase (MAPK), AKT and phospholipase C Received