Time-dependent modulation of glutamate synapses onto 5-HT neurons by antidepressant treatment.
Antidepressants, including the selective serotonin reuptake inhibitors (SSRIs), are thought to exert their clinical effects by enhancing serotonin (5-HT) transmission. However, animal studies show that the full magnitude of this enhancement is reached only following prolonged treatments with SSRIs, consistent with the well-described therapeutic delay of this class of medications. Thus, the clinical efficacy of SSRIs most likely does not emerge from their acute pharmacological actions, but rather indirectly from cellular alterations that develop over the course of a sustained treatment. Here, we show that sustained administration of the SSRI citalopram leads to a homeostatic-like increase in the strength of excitatory glutamate synapses onto 5-HT neurons of the dorsal raphe nucleus that was apparent following one week of treatment. A shorter treatment with citalopram rather induced a paradoxical decrease in the strength of these synapses, which manifested itself by both pre- and postsynaptic mechanisms. As such, these results show that an SSRI treatment induced a concerted and time-dependent modulation of the synaptic drive of 5-HT neurons, which are known to be critically involved in mood regulation. This regulation, and its time course, provide a mechanistic framework that may be relevant not only for explaining the therapeutic delay of antidepressants, but also for the perplexing increases in suicide risks reportedly occurring early in the course of antidepressant treatments.
Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, K1H 8M5, Canada; Neuroscience Graduate Program, Faculty of Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada; Canadian Partnership for Stroke Recovery, Faculty of Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada.
Sean D
SD
Geddes
Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, K1H 8M5, Canada; Neuroscience Graduate Program, Faculty of Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada; Canadian Partnership for Stroke Recovery, Faculty of Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada.
Saleha
S
Assadzada
Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, K1H 8M5, Canada; Ottawa Hospital Research Institute, Ottawa, Ontario, K1Y 4E9, Canada.
Alexandra
A
Sokolovski
Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, K1H 8M5, Canada; Ottawa Hospital Research Institute, Ottawa, Ontario, K1Y 4E9, Canada.
Richard
R
Bergeron
Research Institute on Addictions, University at Buffalo, State University of New York, Buffalo, NY 14203, USA.
Samir
S
Haj-Dahmane
Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, K1H 8M5, Canada; Neuroscience Graduate Program, Faculty of Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada; Canadian Partnership for Stroke Recovery, Faculty of Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada; Centre for Neural Dynamics, Faculty of Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada. Electronic address: jbeique@uottawa.ca.
Jean-Claude
JC
Béïque
D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000494:pharmacology*; D002352:Carrier Proteins / Q000494:pharmacology*; D065847:Dorsal Raphe Nucleus / Q000187:drug effects / Q000502:physiology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D007150:Immunohistochemistry; D018408:Patch-Clamp Techniques; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D059326:Serotonergic Neurons / Q000187:drug effects* / Q000502:physiology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D027981:Symporters; D013569:Synapses / Q000187:drug effects* / Q000502:physiology; D013997:Time Factors; D046509:Tissue Culture Techniques
D018687:Antidepressive Agents, Second-Generation; D001426:Bacterial Proteins; D002352:Carrier Proteins; D018698:Glutamic Acid; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D017367:Selective Serotonin Reuptake Inhibitors; D027981:Symporters; C102671:CitM protein, Bacillus subtilis
AMPAR; Antidepressants; Dorsal raphe nucleus (DRN); Glutamate; Major depression; NMDAR; Serotonin (5-HT); Synapse