Increased Signaling via Adenosine A1 Receptors, Sleep Deprivation, Imipramine, and Ketamine Inhibit Depressive-like Behavior via Induction of Homer1a

🥇 Top 1% JournalAug 7, 2015Neuron

Increased Adenosine A1 Receptor Activity, Sleep Loss, Imipramine, and Ketamine Reduce Depression-like Behavior by Triggering Homer1a

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Abstract

Enhanced expression of adenosine A1 receptors (A1R) in transgenic mice resulted in pronounced resilience to depressive-like behavior.

Upregulating A1R in forebrain neurons led to both acute and chronic resistance to depression in various behavioral tests.
A1R knockout mice exhibited increased depressive-like behavior and did not respond to the antidepressant effects of sleep deprivation.
Different antidepressant treatments were found to increase homer1a expression in the medial prefrontal cortex (mPFC).
Knocking down homer1a in the mPFC resulted in greater depressive-like behavior and blocked the antidepressant effects of A1R upregulation and other treatments.
Viral overexpression of homer1a in the mPFC produced antidepressant effects, suggesting its role in mediating the effects of various antidepressants.

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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.

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