title: Pushing the threshold: How NMDAR antagonists induce homeostasis through protein synthesis to remedy depression.
abstract: Healthy neurons have an optimal operating range, coded globally by the frequency of action potentials or locally by calcium. The maintenance of this range is governed by homeostatic plasticity. Here, we discuss how new approaches to treat depression alter synaptic activity. These approaches induce the neuron to recruit homeostatic mechanisms to relieve depression. Homeostasis generally implies that the direction of activity necessary to restore the neuron's critical operating range is opposite in direction to its current activity pattern. Unconventional antidepressant therapies-deep brain stimulation and NMDAR antagonists-alter the neuron's "depressed" state by pushing the neuron's current activity in the same direction but to the extreme edge. These therapies rally the intrinsic drive of neurons in the opposite direction, thereby allowing the cell to return to baseline activity, form new synapses, and restore proper communication. In this review, we discuss seminal studies on protein synthesis dependent homeostatic plasticity and their contribution to our understanding of molecular mechanisms underlying the effectiveness of NMDAR antagonists as rapid antidepressants. Rapid antidepressant efficacy is likely to require a cascade of mRNA translational regulation. Emerging evidence suggests that changes in synaptic strength or intrinsic excitability converge on the same protein synthesis pathways, relieving depressive symptoms. Thus, we address the question: Are there multiple homeostatic mechanisms that induce the neuron and neuronal circuits to self-correct to regulate mood in vivo? Targeting alternative ways to induce homeostatic protein synthesis may provide, faster, safer, and longer lasting antidepressants. This article is part of a Special Issue entitled SI:RNA Metabolism in Disease.
authors.affiliation: Center for Learning and Memory, Department of Neuroscience, Institute of Neuroscience, University of Texas at Austin, Austin, TX 78712, United States; Waggoner Center for Alcohol and Addiction Research, University of Texas at Austin, Austin, TX 78712, United States; Institute for Cell and Molecular Biology, University of Texas at Austin, Austin, TX 78712, United States. Electronic address: Kimberly@mail.clm.utexas.edu.
authors.forename: Kimberly F
authors.initials: KF
authors.lastname: Raab-Graham
authors.affiliation: Center for Learning and Memory, Department of Neuroscience, Institute of Neuroscience, University of Texas at Austin, Austin, TX 78712, United States; Waggoner Center for Alcohol and Addiction Research, University of Texas at Austin, Austin, TX 78712, United States.
authors.forename: Emily R
authors.initials: ER
authors.lastname: Workman
authors.affiliation: Center for Learning and Memory, Department of Neuroscience, Institute of Neuroscience, University of Texas at Austin, Austin, TX 78712, United States; Institute for Cell and Molecular Biology, University of Texas at Austin, Austin, TX 78712, United States.
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Namjoshi
authors.affiliation: Center for Learning and Memory, Department of Neuroscience, Institute of Neuroscience, University of Texas at Austin, Austin, TX 78712, United States; Waggoner Center for Alcohol and Addiction Research, University of Texas at Austin, Austin, TX 78712, United States.
authors.forename: Farr
authors.initials: F
authors.lastname: Niere
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001343:Autophagy / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000502:physiology; D003866:Depressive Disorder / Q000188:drug therapy* / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects*; D006801:Humans; D009473:Neuronal Plasticity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D014176:Protein Biosynthesis / Q000187:drug effects*; D018080:Receptors, GABA-B / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D000928:Antidepressive Agents; D018080:Receptors, GABA-B; D016194:Receptors, N-Methyl-D-Aspartate; D058570:TOR Serine-Threonine Kinases
keywords: Homeostasis; MRNA translation; Major Depressive Disorder; Mammalian target of rapamycin complex; NMDA receptors; RNA binding protein