1. Antidepressants Rescue Stress-Induced Disruption of Synaptic Plasticity via Serotonin Transporter–Independent Inhibition of L-Type Calcium Channels
- Author
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Alexandra Dorner, Max Horn, Kristin Clark, Sibylle Frase, Norbert Klugbauer, Tanja Vo Van, Claus Normann, Josef Bischofberger, Knut Biber, Jonas Scholliers, Patrick Münzer, Christoph Nissen, Verena Haug, Gabriel Seifert, Tsvetan Serchov, and Gregor von Wolff
- Subjects
Male ,0301 basic medicine ,Patch-Clamp Techniques ,Pyridines ,Nonsynaptic plasticity ,Hippocampus ,Synaptic Transmission ,Piperazines ,Membrane Potentials ,0302 clinical medicine ,Cadmium Chloride ,Homeostatic plasticity ,Serotonin transporter ,Synaptic scaling ,biology ,Age Factors ,RNA-Binding Proteins ,Calcium Channel Blockers ,Antidepressive Agents ,Paroxetine ,Hindlimb Suspension ,Female ,Serotonin Antagonists ,Rats, Transgenic ,Psychology ,Selective Serotonin Reuptake Inhibitors ,Serotonin ,Calcium Channels, L-Type ,Nifedipine ,CHO Cells ,In Vitro Techniques ,Transfection ,03 medical and health sciences ,Cricetulus ,Animal models of depression ,Metaplasticity ,Animals ,Humans ,Rats, Wistar ,Swimming ,Biological Psychiatry ,Electric Stimulation ,Rats ,Disease Models, Animal ,HEK293 Cells ,030104 developmental biology ,Synaptic fatigue ,Fluvoxamine ,Synaptic plasticity ,biology.protein ,Neuroscience ,Stress, Psychological ,030217 neurology & neurosurgery - Abstract
Background Long-term synaptic plasticity is a basic ability of the brain to dynamically adapt to external stimuli and regulate synaptic strength and ultimately network function. It is dysregulated by behavioral stress in animal models of depression and in humans with major depressive disorder. Antidepressants have been shown to restore disrupted synaptic plasticity in both animal models and humans; however, the underlying mechanism is unclear. Methods We examined modulation of synaptic plasticity by selective serotonin reuptake inhibitors (SSRIs) in hippocampal brain slices from wild-type rats and serotonin transporter (SERT) knockout mice. Recombinant voltage-gated calcium (Ca2+) channels in heterologous expression systems were used to determine the modulation of Ca2+ channels by SSRIs. We tested the behavioral effects of SSRIs in the chronic behavioral despair model of depression both in the presence and in the absence of SERT. Results SSRIs selectively inhibited hippocampal long-term depression. The inhibition of long-term depression by SSRIs was mediated by a direct block of voltage-activated L-type Ca2+ channels and was independent of SERT. Furthermore, SSRIs protected both wild-type and SERT knockout mice from behavioral despair induced by chronic stress. Finally, long-term depression was facilitated in animals subjected to the behavioral despair model, which was prevented by SSRI treatment. Conclusions These results showed that antidepressants protected synaptic plasticity and neuronal circuitry from the effects of stress via a modulation of Ca2+ channels and synaptic plasticity independent of SERT. Thus, L-type Ca2+ channels might constitute an important signaling hub for stress response and for pathophysiology and treatment of depression.
- Published
- 2018