Elsevier

Neuropharmacology

Volume 162, 1 January 2020, 107834
Neuropharmacology

Enhanced adenosine A1 receptor and Homer1a expression in hippocampus modulates the resilience to stress-induced depression-like behavior

https://doi.org/10.1016/j.neuropharm.2019.107834Get rights and content

Highlights

  • Enhanced adenosine A1 receptor (A1R) expression in cortex has antidepressant effect.

  • Hippocampal overexpression of A1R decreases resilience to depression-like behavior.

  • Upregulated A1R expression in hippocampus increases Homer1a level and impairs LTP.

  • Viral overexpression of Homer1a in hippocampus decreases stress resilience.

Abstract

Resilience to stress is critical for the development of depression. Enhanced adenosine A1 receptor (A1R) signaling mediates the antidepressant effects of acute sleep deprivation (SD). However, chronic SD causes long-lasting upregulation of brain A1R and increases the risk of depression. To investigate the effects of A1R on mood, we utilized two transgenic mouse lines with inducible A1R overexpression in forebrain neurons. These two lines have identical levels of A1R increase in the cortex, but differ in the transgenic A1R expression in the hippocampus. Switching on the transgene promotes robust antidepressant and anxiolytic effects in both lines. The mice of the line without transgenic A1R overexpression in the hippocampus (A1Hipp-) show very strong resistance towards development of stress-induced chronic depression-like behavior. In contrast, the mice of the line in which A1R upregulation extends to the hippocampus (A1Hipp+), exhibit decreased resilience to depression as compared to A1Hipp-. Similarly, automatic analysis of reward behavior of the two lines reveals that depression resistant A1Hipp-transgenic mice exhibit high sucrose preference, while mice of the vulnerable A1Hipp + line developed stress-induced anhedonic phenotype. The A1Hipp + mice have increased Homer1a expression in hippocampus, correlating with impaired long-term potentiation in the CA1 region, mimicking the stressed mice. Furthermore, virus-mediated overexpression of Homer1a in the hippocampus decreases stress resilience. Taken together our data indicate for first time that increased expression of A1R and Homer1a in the hippocampus modulates the resilience to stress-induced depression and thus might potentially mediate the detrimental effects of chronic sleep restriction on mood.

Introduction

Major depression (MD) affects more than 300 million people worldwide and is associated with high individual suffering, increased risk of suicide and an enormous economic burden for the society (Eaton et al., 2008; Mrazek et al., 2014). Understanding the neurobiology of depression remains one of the foremost challenges in modern psychiatry. Stress resilience plays a critical role in regulating the development of depression and the identification of the neurobiological substrates underlying the resilience to stress is essential to the development of strategies for the prevention of stress-mediated depression.

While research on alterations in monoamines has dominated the field for years, recent studies have implicated the glutamatergic and adenosinergic systems in the neurobiology and treatment of depression (Sadek et al., 2011; Sanacora et al., 2012; van Calker and Biber, 2005; van Calker et al., 2018, 2019). Non-pharmacological treatments of depression, like sleep deprivation (SD) and electroconvulsive therapy are associated with an increased stimulation of adenosine A1 receptor (A1R) (Elmenhorst et al., 2007, 2009; Sadek et al., 2011; van Calker and Biber, 2005). Accordingly, it has been shown that enhanced A1R signaling via inducible upregulation of A1R expression in forebrain neurons of transgenic mice or specific A1R agonist administration inhibits depressive-like behavior and that A1R is necessary for the antidepressant effects of SD (Hines et al., 2013; Serchov et al., 2015). Moreover, we have demonstrated that the antidepressant effects of SD are mediated by A1R-induced induction of the synaptic protein Homer1a specifically in the medial prefrontal cortex (mPFC) (Serchov et al., 2015).

While the antidepressant effect of acute SD is very fast and robust, it is only transient (Benedetti and Colombo, 2011) (Elmenhorst et al., 2017; Hines et al., 2013; Serchov et al., 2015). SD or agonist activation of A1R lose their therapeutic effects on depression-like behavior when prolonged (Hines et al., 2013). Chronic exposure to SD is even associated with an increased risk of depression (Baum et al., 2014; Conklin et al., 2018). Chronic sleep restriction induces long-lasting increase in A1R expression in several brain regions, including cortex and hippocampus (Kim et al., 2015), suggesting that this may underlay the negative effects on mood regulation (Novati et al., 2008). Moreover, chronic SD appears to be particularly detrimental to functions of the hippocampus and negatively affects molecular signaling important for synaptic plasticity (Areal et al., 2017; Clasadonte et al., 2014; Havekes and Abel, 2017; Kreutzmann et al., 2015; Novati et al., 2008). Thus, the long-lasting increase of A1R expression induced by chronic sleep restriction might decrease resilience to depression-like behavior via affecting synaptic plasticity in the hippocampus.

In order to model the effects of SD on A1R levels and their role in stress response and resilience to depression, we utilized two transgenic mouse lines with identical levels of A1R increase in the cortex, but distinct transgenic A1R expression in the hippocampus. We show that the mice without transgenic A1R overexpression in the hippocampus (A1Hipp-) have strong resistance towards development of repeated swim stress-induced chronic depression-like behavior, thus providing evidence that enhanced A1R expression in the cortex promotes stress resilience. However, mice of the strain in which A1R is upregulated also in the hippocampus (A1Hipp+), exhibit vulnerability to develop repeated swim stress-induced chronic depression-like behavior in various tests as compared to A1Hipp-line. Moreover, the decreased resilience to stress in these mice is associated with impaired synaptic plasticity and is mediated by upregulated expression of Homer1a in the hippocampus. Thus, increased expression of A1R and Homer1a in the hippocampus modulates stress-induced depression-like behavior and might be potential mechanism mediating the detrimental effects of chronic sleep restriction on mood.

Section snippets

Animals

All procedures were performed in accordance with the German animal protection law (TierSchG), FELASA (www.felasa.eu/guidelines.php), the national animal welfare body GV-SOLAS (www.gv-solas.de/index.html) guide for the care and use of laboratory animals, National Institute of Health Guide for Care and Use of Laboratory Animals, the EU Directive 2010/63/EU for animal experiments and were approved by the animal welfare committee of the University of Freiburg and University of Bonn, as well as

Inducible enhanced A1R expression in different brain areas of two transgenic mouse strains

In order to mimic the effects of SD on the A1R levels, we generated transgenic mouse models with enhanced neuronal A1R expression regulated by a tetracycline inducible bidirectional promoter allowing the simultaneous expression of mouse A1R and mCherry reporter gene (Serchov et al., 2012, 2015) (Fig. 1A). Due to the random integration of the transgene cassette in the founder mouse genome, we found that the generated founder lines differed in levels and patterns of transgenic expression. For

Discussion

In order to investigate the role of A1R in the brain and mimic the effects of SD on mouse behavior, we have generated multiple transgenic mouse lines with conditional up-regulation of A1R selectively in forebrain neurons via CaMKII promoter and Tet-OFF system, to avoid possible artifacts of the transgene throughout development. Each line had a unique expression pattern, due to the random integration site of the transgene into the founder mouse genome. In this study, we have selected two founder

Author contributions

Conceptualization, T.S., C.N., K.B., D.v.C.; Methodology, T.S., M.K.S, C.N.; Investigation, T.S., A.T., I.S., L.S. A.H.; Writing-Original draft, T.S., C.N., D.v.C.; Writing-Review and Editing, T.S., C.N., A.H., M.D.D., K.B., D.v.C.; Funding Acquisition, T.S., K.B., D.v.C.; Supervision, C.N., K.B., D.v.C.

Declaration of competing interest

The authors declare no competing financial interests.

Acknowledgments

The study was funded by grants from the German Research Council (CA 115/5-4) to D.v.C and K.B., (SE 2666/2-1) to T.S., the European Union FP7 program ‘‘MoodInflame’’ to D.v.C. and the German Ministry for Research and Education (BMBF) grant e:bio – Modul I –ReelinSys (Project B: 0316174A) to K.B.

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    The two senior authors have contributed equally to this research.

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