Increased Signaling via Adenosine A1 Receptors, Sleep Deprivation, Imipramine, and Ketamine Inhibit Depressive-like Behavior via Induction of Homer1a
Tsvetan Serchov, H. Clement, M. Schwarz, Felice Iasevoli, D. Tosh, M. Idzko, K. Jacobson, Andrea De Bartolomeis, Claus Normann, K. Biber, D. van Calker
Neuron August 5, 2015 DOI: 10.1016/j.neuron.2015.07.010 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Animal study Peer reviewed |
|---|---|
| Population | Transgenic and knockout mice |
| Interventions | A1R upregulation sleep deprivation imipramine ketamine |
| Topics | Esketamine Ketamine |
| Key points | The authors report that upregulating adenosine A1 receptors in forebrain neurons produced resilience to depressive-like behavior in mice, while A1R knockout mice showed increased depressive-like behavior and resistance to sleep deprivation's antidepressant effects. They argue that increased homer1a expression in the medial prefrontal cortex is a final common pathway mediating antidepressant effects, since homer1a knockdown blocked and homer1a overexpression mimicked antidepressant effects. |
Abstract
SUMMARY Major depressive disorder is among the most commonly diagnosed disabling mental diseases. Several non-pharmacological treatments of depression upregulate adenosine concentration and/or adenosine A1 receptors (A1R) in the brain. To test whether enhanced A1R signaling mediates antidepressant effects, we generated a transgenic mouse with enhanced doxycycline-regulated A1R expression, specifically in forebrain neurons. Upregulating A1R led to pronounced acute and chronic resilience toward depressive-like behavior in various tests. Conversely, A1R knockout mice displayed an increased depressive-like behavior and were resistant to the antidepressant effects of sleep deprivation (SD). Various antidepressant treatments increase homer1a expression in medial prefrontal cortex (mPFC). Specific siRNA knockdown of homer1a in mPFC enhanced depressive-like behavior and prevented the antidepressant effects of A1R upregulation, SD, imipramine, and ketamine treatment. In contrast, viral overexpression of homer1a in the mPFC had antidepressant effects. Thus, increased expression of homer1a is a final common pathway mediating the antidepressant effects of different antidepressant treatments.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |
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- Prefrontal cortex molecular clock modulates development of depression-like phenotype and rapid antidepressant response in mice. Nature Communications August 23, 2024
- Adenosine signalling drives antidepressant actions of ketamine and ECT Nature November 5, 2025
- Ketamine treatment effects on DNA methylation and Epigenetic Biomarkers of aging medRxiv Preprint Server September 10, 2024
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