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Chronic mild stress-induced alterations of local protein synthesis: a role for cognitive impairment Francesca Calabrese, Paola Brivio, Piotr Gruca, Magdalena Lason-Tyburkiewicz, Mariusz Papp, and Marco A. Riva ACS Chem. Neurosci., Just Accepted Manuscript • DOI: 10.1021/acschemneuro.6b00392 • Publication Date (Web): 17 Jan 2017 Downloaded from http://pubs.acs.org on January 21, 2017
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ACS Chemical Neuroscience
Chronic mild stress-induced alterations of local protein synthesis: a role for cognitive impairment.
Francesca Calabrese1, Paola Brivio1, Piotr Gruca2, Magdalena Lason-Tyburkiewicz2, Mariusz Papp2 and Marco A. Riva1* 1Department 2Institute
of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy
of Pharmacology, Polish Academy of Sciences, Krakow, Poland
*Corresponding author: Prof. Marco A. Riva Department of Pharmacological and Biomolecular Sciences Università di Milano, Via Balzaretti 9, 20133 Milan, Italy Phone: +39-02 50318334; Fax: +39-02 50318278 E-mail:
[email protected] Running title: Altered local protein synthesis induces cognitive deficits
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Abstract Depression, a major cause of disability worldwide, is characterized by a complex and heterogeneous symptomatology. With this respect, cognitive deterioration represents a major problem that has a strong impact on patient’s function. Thus, within the context of a depressive phenotype, it is important to characterize the mechanisms that sustain cognitive dysfunctions and may represent an important target for pharmacological intervention. Here, using the chronic mild stress (CMS) paradigm of depression, we found that, independently from the anhedonic phenotype, CMS rats showed a deficit in the novel object recognition (NOR) test, which is associated with an inability to phosphorylate GluN2B subunit on Ser1303 and to activate the mTOR pathway. In agreement with the role of these systems in the control of local protein synthesis, we observed an increase phosphorylated of the eukaryotic Elongation Factor 2 (eEF2) in the crude synaptosomal fraction after the NOR test specifically in control animals. Since it has been demonstrated that peEF2 leads to the translation of specific mRNAs, we investigated if the gene-specific translational control depends on the presence of uORFs. Interestingly, we found a significant increase of oligophrenin-1 (2 uORFs) and of Bmal1 (7 uORFs) protein levels specifically in the control animals exposed to the NOR test. Our results demonstrated that the cognitive decline associated with stress exposure might be due to alterations in local protein translation of specific mRNAs, suggesting that a pharmacological intervention able to correct these defects might be useful in the improvement of deteriorated functions in patients with major depression and stress-related disorders.
Keywords: depression, cognition, elongation, stress, glutamate, cognition, rats.
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ACS Chemical Neuroscience
Introduction Major depression disorder (MDD) is a severe disease affecting more than 10% of the general population and it is estimated to become the second leading cause of disability by 2020 1. MDD is characterized by a plethora of behavioral, emotional and cognitive symptoms. The type and the severity of the symptoms vary among individuals and over time. Cognitive dysfunctions have long been recognized as an intrinsic characteristic of major depressive disorder and are among the most persistent symptoms both during a current major depressive episode (MDE) and in remission
2, 3.
Indeed, even when depressive disorders are successfully treated residual symptoms, especially cognitive impairments 4, 5
or social dysfunctions, can weaken the general performance and cause considerable distress. Moreover, incomplete
remission is problematic because residual depressive symptomatology constitutes a serious risk for relapse
6-8.
For
example, residual subsyndromal depression has been associated with an odds ratio of 3.5 for patients with subsequent relapse compared with those who experienced full recovery 9. Interestingly, cognitive dysfunction is present during the first episodes of depression, in recurrent depression, as well as in late-life depression
10-12.
There is also evidence
suggesting that cognition in patients with recurrent depression further deteriorates with each MDE. Furthermore, some patients show evidence of dysfunction even after remission has been achieved 10. Given this critical shortcoming, it is imperative to understand the nature and the molecular mechanisms underlying the link between difficulties or impairments in cognition and deregulation of emotions (a core feature of depressive disorders). Thus, we used the chronic mild stress (CMS) paradigm, a well-established animal model of depression, which has been extensively characterized at behavioral and molecular levels 13. Indeed, in the last years, we have demonstrated that CMS exposure is associated with alterations of the inflammatory system 14, deficits of neuroplastic mechanisms
15, 16,
dysregulation of clock genes 17, abnormalities of the HPA axis
18
as well as of the glutamatergic
system 19. Interestingly, most of these effects are associated with the development of anhedonia and normalized by pharmacological treatment 14, 15, 17. On this ground, we decided to investigate if the exposure to CMS for 7 weeks led to a cognitive impairments measured in the novel object recognition test 20, while, at the molecular levels, we focused on the de-novo protein synthesis at synaptic levels, considered important for memory and synaptic plasticity consolidation
21.
All the analyses were
conducted in the dorsal hippocampus, seen the involvement of this brain region in memory and learning processes 22. Moreover, we focused on the synaptic compartment since several evidence
23
reported that several dysfunctions
associated with MDD are specifically related to the synapse, suggesting that this pathology may be considered a
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synaptopathy.
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Results and DIscussion Behavioral characterization of animals exposed to CMS According to our previous studies 15, 17, 7 weeks of stress exposure exerted a significant effect on sucrose consumption (F2,40=22.40, p
