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Major depressive disorder (MDD) remains a huge personal and societal encumbrance. Particularly burdensome is a virulent subtype of MDD, treatment resistant major depression (TMRD), which afflicts 15-30% of MDD patients. There has been recent interest in N-methyl-D-aspartate (receptors (NMDARs) as targets for treatment of MDD and perhaps TMRD. To date, most pre-clinical and clinical studies have focused on ketamine, although psychotomimetic and other side effects may limit ketamine’s utility. These considerations prompted a recent promising pilot clinical trial of nitrous oxide, an NMDAR antagonist that acts through a mechanism distinct from that of ketamine, in patients with severe TRMD. In this paper, we review the clinical picture of TRMD as a subtype of MDD, the evolution of ketamine as a fast-acting antidepressant, and clinical and basic science studies supporting the possible use of nitrous oxide as a rapid antidepressant.

Neuromuscular fatigue contributes to decrements in quality of life in Multiple Sclerosis (MS), yet available treatments demonstrate limited efficacy. Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique which presents promise in managing fatigue, possibly related to its capacity to modulate corticospinal excitability. There is evidence for capitalising on metaplasticity using tDCS for improving outcomes. However, this remains to be explored with fatigue in people with MS (pwMS). We investigated cathodal tDCS (ctDCS) priming on anodal tDCS (atDCS)-induced corticospinal excitability and fatigue modulation in pwMS. 15 pwMS and 15 healthy controls completed fatiguing exercise whilst receiving either ctDCS or sham (stDCS) primed atDCS to the motor cortex. We assessed change in contraction force and motor evoked potential (MEP) amplitude across time to represent changes in fatigue and corticospinal excitability. ctDCS primed atDCS induced MEP elevation in healthy participants but not in pwMS, possibly indicating impaired metaplasticity in pwMS. No tDCS-mediated change in the magnitude of fatigue was observed, implying that development of fatigue may not rely on changes in corticospinal excitability. These findings expand understanding of tDCS effects in pwMS, highlighting differences that may be relevant in the disease pathophysiology. • There is evidence for metaplasticity improving functional outcomes, but this remains unexplored during neuromuscular fatigue in people with MS • Corticospinal excitability during fatigue is unchanged with priming Transcranial Direct Current Stimulation in people with Multiple Sclerosis • Metaplasticity is possibly impaired in people with Multiple Sclerosis [ABSTRACT FROM AUTHOR]

AIM: Metaplasticity refers to the modulation of synaptic activity based on previous activity. It has been reported that experimental hypothyroidism induced in adulthood causes impaired hippocampal metaplasticity in rats. In this study, it was investigated which thyroid hormone derivative (T3 or T4) is responsible for these electrophysiological changes observed in hypothyroidism. METHODS: Two-month-old Wistar albino male rats were used in the study; control group (KG; n=18) and hypothyroid group (HG; n=18). After stimulation of perforant pathway-dentate gyrus synapses with low frequency stimulation (LFS) consisting of 5Hz and 900 pulses, long-term potentiation (UDG) was induced by highfrequency stimulation (HFS: 4 X 100Hz) in control and hypothyroid rats which are induced by 6-n-propyl-2-thiouracil (0.05% PTU in drinking water for 21 days). Starting from the induction of metaplasticity, SF or T3 and T4 were infused intrahippocampally for 1 hour (Subgroups: CG-SF, CG-T3, CG-T4; HG-SF, HG-T3, HG-T4). Metaplasticity were evaluated as field excitatory postsynaptic potential (fEPSP) slope and population spike (PS) amplitude. RESULTS: It was found that both EPSP slope and PS amplitude of hypothyroid and hypothyroid+T4 infusion group rats were significantly reduced compared to control and control+T4 infusion group rats (p's<0.05). It was also found that both EPSP slope and PS amplitude of hypothyroid group rats were significantly decreased compared to control, control+T3 and hypothyroid+T3 infusion group rats (p's<0.05). These findings show that hypothyroidism reduces hippocampal metaplasticity responses in young-adult rats, and T3 hormone infusion prevents this decrease, whereas T4 hormone has no effect. RESULTS: It was found that both EPSP slope and PS amplitude of hypothyroid and hypothyroid+T4 infusion group rats were significantly reduced compared to control and control+T4 infusion group rats (p's<0.05). It was also found that both EPSP slope and PS amplitude of hypothyroid group rats were significantly decreased compared to control, control+T3 and hypothyroid+T3 infusion group rats (p's<0.05). These findings show that hypothyroidism reduces hippocampal metaplasticity responses in young-adult rats, and T3 hormone infusion prevents this decrease, whereas T4 hormone has no effect. CONCLUSION: This study revealed that hypothyroidism impairs metaplasticity in hippocampal perforant pathway-dentate gyrus synapses, and T3 hormone, but not T4 hormone, is responsible for this disruption. [ABSTRACT FROM AUTHOR]

Part of hippocampal or cortical plasticity is characterized by synaptic modifications as a function of the joint activity of the pre- and postsynaptic neurons. Whether those changes strongly depends on the exact timing, or more on the average firing rates, is still a matter of debate and may vary from areas to areas. However, it has been robustly observed both in vitro and in vivo, that plasticity itself slowly adapts as a function of the dynamic context, and this phenomena is commonly referred to as metaplasticity. An alternative concept considers the regulation of groups of synapses directly to approach a given average firing rate. Then, the change in the strength of a particular synapse of the group (e.g., due to Hebbian learning) will affect others' strengths, which has been coined as heterosynaptic plasticity. Classically, Hebbian synaptic plasticity is paired in neuron network models with such mechanisms so as to stabilize the activity and/or the weight structure. Here, we present a review of various concepts from heterosynaptic plasticity to metaplasticity that have been applied to several spiking models of plasticity, either in hippocampus or in cortex, and how they compete with classical Hebbian learning. We list and discuss the different approaches that are nowadays used by state of the art models of plasticity for incorporating those concepts. Making the point that metaplasticity is an ubiquitous mechanism promoting the stability of neural function over multiple timescales and acting on top of classical Hebbian learning, we stress the need for incorporating it as a key element in the framework of plasticity models.

Stress induces several temporally-guided waves of psychobiological responses that differentially influence learning and memory. One way to understand how the temporal dynamics of stress influence these cognitive processes is to consider stress, itself, as a learning experience that influences additional learning and memory. Indeed, research has shown that stress results in electrophysiological and biochemical activity that is remarkably similar to the activity observed as a result of learning. In this mini review, we will present the idea that when a stressful episode immediately precedes or follows learning, such learning is enhanced because the learned information becomes a part of the stress context and is tagged by the emotional memory being formed. In contrast, when a stressful episode is temporally separated from learning or is experienced prior to retrieval, such learning or memory is impaired because the learning or memory is experienced outside the context of the stress episode or subsequent to a saturation of synaptic plasticity, which renders the retrieval of information improbable. The temporal dynamics of emotional memory formation, along with the neurobiological correlates of the stress response, are discussed to support these hypotheses.

A hallmark feature of the neural system controlling breathing is its ability to exhibit plasticity. Less appreciated is the ability to exhibit metaplasticity, a change in the capacity to express plasticity (ie. plastic plasticity). Recent advances in our understanding of cellular mechanisms giving rise to respiratory motor plasticity lay the groundwork for (ongoing) investigations of metaplasticity. This detailed understanding of respiratory metaplasticity will be essential as we harness metaplasticity to restore breathing capacity in clinical disorders that compromise breathing, such as cervical spinal injury, motor neuron disease and other neuromuscular diseases. In this brief review, we discuss key examples of metaplasticity in respiratory motor control, and our current understanding of mechanisms giving rise to spinal plasticity and metaplasticity in phrenic motor output; particularly after pre-conditioning with intermittent hypoxia. Progress in this area has led to the realization that similar mechanisms are operative in other spinal motor networks, including those governing limb movement. Further, these mechanisms can be harnessed to restore respiratory and non-respiratory motor function after spinal injury.

Computational models of metaplasticity have usually focused on the modeling of single synapses (Shouval et al., 2002). In this paper we study the effect of metaplasticity on network behavior. Our guiding assumption is that the primary purpose of metaplasticity is to regulate synaptic plasticity, by increasing it when input is low and decreasing it when input is high. For our experiments we adopt a model of metaplasticity that demonstrably has this effect for a single synapse; our primary interest is in how metaplasticity thus defined affects network-level phenomena. We focus on a network-level phenomenon called polychronicity, that has a potential role in representation and memory. A network with polychronicity has the ability to produce non-synchronous but precisely timed sequences of neural firing events that can arise from strongly connected groups of neurons called polychronous neural groups (Izhikevich et al., 2004; Izhikevich, 2006a). Polychronous groups (PNGs) develop readily when spiking networks are exposed to repeated spatio-temporal stimuli under the influence of spike-timing-dependent plasticity (STDP), but are sensitive to changes in synaptic weight distribution. We use a technique we have recently developed called Response Fingerprinting to show that PNGs formed in the presence of metaplasticity are significantly larger than those with no metaplasticity. A potential mechanism for this enhancement is proposed that links an inherent property of integrator type neurons called spike latency to an increase in the tolerance of PNG neurons to jitter in their inputs.

We review the plastic changes of the prefrontal cortex of the rat in response to a wide range of experiences including sensory and motor experience, gonadal hormones, psychoactive drugs, learning tasks, stress, social experience, metaplastic experiences, and brain injury. Our focus is on synaptic changes (dendritic morphology and spine density) in pyramidal neurons and the relationship to behavioral changes. The most general conclusion we can reach is that the prefrontal cortex is extremely plastic and that the medial and orbital prefrontal regions frequently respond very differently to the same experience in the same brain and the rules that govern prefrontal plasticity appear to differ for those of other cortical regions.

It is well established that selective activation of group I metabotropic glutamate (mGlu) receptors induces LTD of synaptic transmission at Schaffer collateral-CAl synapses. In contrast, application of 1S,3R-ACPD, a mixed agonist at group I and group II mGlu receptors, induces LTP. Using whole-cell recordings from CA1 pyramidal cells and field recordings in the hippocampal CA1 region, we investigated the specific contribution of group II mGlu receptors to synaptic plasticity at Schaffer collateral-CAl synapses in acute slices of adult mice. Pharmacological activation of group II mGlu receptors (mGlu2 and mGlu3 receptors) with the specific agonist LY354740 in conjunction with electrical stimulation induced postsynaptic LTP. This form of plasticity requires coactivation of NMDA receptors (NMDARs). Group II mGlu receptor activation led to PKC-dependent phosphorylation of the GluN 1 subunit. We found that both synaptic and extrasynaptic NMDARs, which are differentially modulated by mGlu2 and mGlu3 receptors, contribute to LTP induction. Furthermore, LTP initiated by activation of group II mGlu receptors was not occluded by LTP induced with high-frequency trains of stimuli. However, the phosphorylation of NMDARs mediated by group II mGlu receptor activation led to a priming effect that enhanced subsequent high-frequency stimulation-induced LTP. These findings reveal a novel metaplastic mechanism through which group II mGlu receptors modulate synaptic function at the Schaffer collateral input to CA1 pyramidal cells, thereby lowering the threshold to induce plasticity. [ABSTRACT FROM AUTHOR]

Shortly after stress, basolateral amygdala neurons are exposed to sequential yet partly overlapping waves of hormones. We examined how these hormonal waves can change activity of basolateral amygdala neurons such that emotional aspects of stress become so deeply ingrained. To this end, spontaneous glutamatergic transmission was recorded during and up to several hours after combined adrenergic and corticosteroid waves, targeting the time-window relevant for encoding of stress-related information. Hormonal waves mimicking moderately stressful conditions cause a transient enhancement followed by later suppression of glutamatergic transmission. However, this late phase flips from suppressed to enhanced glutamatergic transmission with conditions mimicking severe stress. Such a prolonged window of enhanced excitability may contribute to the excessively strong encoding seen after the experience of highly stressful or traumatic events. [ABSTRACT FROM AUTHOR]

This brief review summarizes 60 years of conceptual advances that have demonstrated a role for active changes in neuronal connectivity as a controller of behavior and behavioral change. Seminal studies in the first phase of the six-decade span of this review firmly established the cellular basis of behavior - a concept that we take for granted now, but which was an open question at the time. Hebbian plasticity, including long-term potentiation and long-term depression, was then discovered as being important for local circuit refinement in the context of memory formation and behavioral change and stabilization in the mammalian central nervous system. Direct demonstration of plasticity of neuronal circuit function in vivo, for example, hippocampal neurons forming place cell firing patterns, extended this concept. However, additional neurophysiologic and computational studies demonstrated that circuit development and stabilization additionally relies on non-Hebbian, homoeostatic, forms of plasticity, such as synaptic scaling and control of membrane intrinsic properties. Activity-dependent neurodevelopment was found to be associated with cell-wide adjustments in post-synaptic receptor density, and found to occur in conjunction with synaptic pruning. Pioneering cellular neurophysiologic studies demonstrated the critical roles of transmembrane signal transduction, NMDA receptor regulation, regulation of neural membrane biophysical properties, and back-propagating action potential in critical time-dependent coincidence detection in behavior-modifying circuits. Concerning the molecular mechanisms underlying these processes, regulation of gene transcription was found to serve as a bridge between experience and behavioral change, closing the 'nature versus nurture' divide. Both active DNA (de)methylation and regulation of chromatin structure have been validated as crucial regulators of gene transcription during learning. The discovery of protein synthesis dependence on the acquisition of behavioral change was an influential discovery in the neurochemistry of behavioral modification. Higher order cognitive functions such as decision making and spatial and language learning were also discovered to hinge on neural plasticity mechanisms. The role of disruption of these processes in intellectual disabilities, memory disorders, and drug addiction has recently been clarified based on modern genetic techniques, including in the human. [ABSTRACT FROM AUTHOR]

Short-term immobilization that reduces muscle use for 8–10 h is known to influence cortical excitability and motor performance. However, the mechanisms through which this is achieved, and whether these changes can be used to modify cortical plasticity and motor skill learning, are not known. The purpose of this study was to investigate the influence of short-term immobilization on use-dependent cortical plasticity, motor learning and retention. Twenty-one adults were divided into control and immobilized groups, both of which underwent two experimental sessions on consecutive days. Within each session, transcranial magnetic stimulation (TMS) was used to assess motor-evoked potential (MEP) amplitudes, short- (SICI) and long-interval intracortical inhibition (LICI), and intracortical facilitation (ICF) before and after a grooved pegboard task. Prior to the second training session, the immobilized group underwent 8 h of left hand immobilization targeting the index finger, while control subjects were allowed normal limb use. Immobilization produced a reduction in MEP amplitudes, but no change in SICI, LICI or ICF. While motor performance improved for both groups in each session, the level of performance was greater 24-h later in control, but not immobilized subjects. Furthermore, training-related MEP facilitation was greater after, compared with before, immobilization. These results indicate that immobilization can modulate use-dependent plasticity and the retention of motor skills. They also suggest that changes in intracortical excitability are unlikely to contribute to the immobilization-induced modification of cortical excitability. [ABSTRACT FROM AUTHOR]

Anodal transcranial direct current stimulation (tDCS) is known to increase the force-generating capacity of the skeletal muscles. However, when tDCS is concurrently combined with a motor task, interference may occur that hinders tDCS effects. Here, we tested the interaction and time course of tDCS effects on force production when paired with a low-level force-matching task. Twenty-two subjects were randomized into two groups: tDCS-Matching and tDCS-Resting. Each group received tDCS and a sham stimulation, separated by one week. Maximal knee extensor and flexor torques were measured before and up to twenty-five minutes following the stimulation. The tDCS-Matching group produced greater knee extension torques relative to sham when compared with the tDCS-Resting group. There was no significant effect for knee flexion. This suggests that interference does not occur for force production tasks when tDCS is combined with a motor task. Rather, the task appears to aid and isolate the effects to the muscle groups involved in the task. [ABSTRACT FROM AUTHOR]

Electroconvulsive therapy (ECT) is an effective treatment for depression, but it can induce learning and memory impairment. Our previous study found propofol (γ-aminobutyric acid (GABA) receptor agonist) could ameliorate electroconvulsive shock (ECS, an analog of ECT to animals)-induced cognitive impairment, however, the underlying molecular mechanisms remain unclear. This study aimed to investigate the effects of propofol on metaplasticity and autophosphorylation of CaMKIIa in stressed rats receiving ECS. Depressive-like behavior and learning and memory function were assessed by sucrose preference test and Morris water test respectively. LTP were tested by electrophysiological experiment, the expression of CaMKIIa, p-T305-CaMKII in hippocampus and CaMKIIα in hippocampal PSD fraction were evaluated by western blot. Results suggested ECS raised the baseline fEPSP and impaired the subsequent LTP, increased the expression of p-T305-CaMKII and decreased the expression of CaMKIIα in hippocampal PSD fraction, leading to cognitive dysfunction in stressed rats. Propofol could down-regulate the baseline fEPSP and reversed the impairment of LTP partly, decreased the expression of p-T305-CaMKII and increased the expression of CaMKIIα in hippocampal PSD fraction and alleviated ECS-induced learning and memory impairment. In conclusion, propofol ameliorates ECS-induced learning and memory impairment, possibly by regulation of synaptic metaplasticity via p-T305-CaMKII. [ABSTRACT FROM AUTHOR]

The emergence of the human mind is a topic that has been of considerable interest to the disciplines of archaeology, cognitive archaeology and neuroscience in recent years. Most research in this regard has tended to focus on what material culture associated with early Homo sapiens might reflect in terms of the timing and nature of early cognitive capacities and ‘behavioural modernity’. In recent years, however, both the concept of ‘behavioural modernity’ and its passive treatment of material culture have become highly criticised. Yet, until now, there has remained some confusion as to where to turn in its absence. Recently, Lambros Malafouris outlined the theoretical frameworks of Material Engagement Theory and Metaplasticity as a means to understand the active role of material culture in the constitution of the human mind. However, despite Malafouris' application of these theoretical frameworks to a series of case studies previously associated with human cognitive ‘modernity’ (including tool manufacture, early body ornamentation, and ritual art), the Late Pleistocene archaeological community has done little to engage with this work. In this paper I outline and then apply MET and Metaplasticity to two further case studies often considered pertinent to the development of human cognition in the Late Pleistocene – namely, long-distance resource sourcing and/or exchange and the development of composite technologies. In doing so, I hope to demonstrate that there is somewhere to turn in the wake of the statement ‘we have never been behaviourally modern’. [ABSTRACT FROM AUTHOR]

Homeostatic plasticity mechanisms dynamically adjust synaptic strengths to promote stability that is crucial for memory storage. Metaplasticity is an example of these forms of plasticity that modify the capacity of synapses to experience subsequent Hebbian modifications. In particular, training in several behavioral tasks modifies the ability to induce long-term potentiation (LTP). Recently, we have reported that prior training in conditioned taste aversion (CTA) prevents the subsequent induction of LTP generated by high frequency stimulation in the projection from the basolateral nucleus of the amygdala (Bla) to the insular cortex (IC). One of the key molecular players that underlie long-term synaptic plasticity is brain-derived neurotrophic factor (BDNF). Previous studies from our group reported that acute microinfusion of BDNF in the IC induces a lasting potentiation of synaptic efficacy at the Bla-IC projection. Thus, the aim of the present study was to analyze whether CTA training modifies the ability to induce subsequent BDNF-induced potentiation of synaptic transmission in the Bla-IC projection in vivo. Accordingly, CTA trained rats received intracortical microinfusion of BDNF in order to induce lasting potentiation 48 h after the aversion test. Our results show that CTA training prevents the induction of in vivo BDNF-LTP in the Bla-IC projection. The present results provide evidence that CTA modulates BDNF-dependent changes in IC synaptic strength. [ABSTRACT FROM AUTHOR]

Objective Contractions of the target muscle influence the aftereffects of repetitive transcranial magnetic stimulation (rTMS). The aim of this paper is to investigate whether or not voluntary hand movement influences the aftereffects of quadripulse stimulation (QPS) on the hand motor area. Methods Thirteen healthy volunteers participated in this study. After QPS-5 or QPS-50 intervention over the motor hot spot for the right first dorsal interosseous muscle (FDI), the subjects performed voluntary motor tasks (opening–closing right hand movements at 1 Hz for 1 min). We compared the time courses of MEP size between the conditions with and without voluntary movement. Results When the subjects moved their hands immediately after QPS, both QPS-5 and QPS-50 aftereffects were abolished. However, if they moved their hands at 20 min after QPS, the long-term aftereffects were preserved. Conclusions Voluntary hand movement applied after intervention influences QPS aftereffects, but the magnitude of the influence depends on the delay between QPS and the voluntary movement. Significance In the plasticity induction experiments, we should always be mindful of the fact that voluntary movement, including the target muscle, seriously influences the induced long-term effects of QPS. [ABSTRACT FROM AUTHOR]

After several decades of study, the dynamics of synaptic plasticity in neurons still remains somewhat a mystery. By conducting a series of simulations on a simulated version of an in-vivo experiment on the rat dentate gyrus granule cell, using the Izhikevich spiking neuron model, we compare and contrast several potential synaptic plasticity rules׳ applicability to the same experiment. Our simulations reveal that spike timing dependent plasticity (STDP), a more recent theory of synaptic plasticity, is insufficient to replicate the heterosynaptic LTD shown in the experiment without including aspects of the significantly older Bienenstock–Cooper–Munro (BCM) theory. The STDP rule modified by including the history of postsynaptic spiking seems most likely to be an accurate candidate for reproducing the heterosynaptic plasticity dynamics. [ABSTRACT FROM AUTHOR]

BACKGROUND: Neurogenic dysphagia is a difficulty in swallowing induced by nervous system disease. It often causes serious complications, which are preventable if dysphagia is properly managed. There is growing debate concerning the usefulness of non-invasive neuromuscular electrical stimulation (NMES) in treating swallowing dysfunction. OBJECTIVE: Aim of this study was to assess the effectiveness of Vitalstim© device, and to investigate the neurophysiological mechanisms underlying functional recovery. METHODS: A 34-year-old man, affected by severe chronic dysphagia following traumatic brain injury, underwent two different intensive rehabilitation trainings, including either conventional rehabilitation alone or coupled to Vitalstim training. We evaluated patient swallowing function in two separate sessions (i.e. before and after the two trainings) by means of ad hoc swallowing function scales and electrophysiological parameters (rapid paired associative stimulation). The overall Vitalstim program was articulated in 6 weekly sessions for 6 weeks. RESULTS: The patient did not report any side-effect either during or following both the intensive rehabilitation trainings. We observed an important improvement in swallowing function only after Vitalstim training. In fact, the patient was eventually able to safely eat even solid food. CONCLUSIONS: This is the first report objectively suggesting (by means of rPAS) a correlation between the brain neuro-plastic changes induced by Vitalstim and the swallowing function improvement. It is hypothesizable that Vitalstim may have targeted cortical (and maybe subcortical) brain areas that are recruited during the highly coordinated function of swallowing, and it may have thus potentiated the well-known neuroplastic changes induced by repetitive and intensive swallowing exercises, probably thanks to metaplasticity phenomena. [ABSTRACT FROM AUTHOR]

The second messenger cyclic GMP affects synaptic transmission and modulates synaptic plasticity and certain types of learning and memory processes. The impact of the natriuretic peptide receptor B (NPR-B) and its ligand C-type natriuretic peptide (CNP), one of several cGMP producing signalling systems, on hippocampal synaptic plasticity and learning is, however, less well understood. We have previously shown that the NPR-B ligand CNP increases the magnitude of long-term depression (LTD) in hippocampal area CA1, while reducing the induction of long-term potentiation (LTP). We have extended this line of research to show that bidirectional plasticity is affected in the opposite way in rats expressing a dominant-negative mutant of NPR-B (NSE-NPR-BdeltaKC) lacking the intracellular guanylyl cyclase domain under control of a promoter for neuron-specific enolase. The brain cells of these transgenic rats express functional dimers of the NPR-B receptor containing the dominant-negative NPR-BdeltaKC mutant, and therefore show decreased CNP-stimulated cGMP-production in brain membranes. The NPR-B transgenic rats display enhanced LTP but reduced LTD in hippocampal slices. When the frequency-dependence of synaptic modification to afferent stimulation in the range of 1-100 Hz was assessed in transgenic rats the threshold for LTP induction was raised, but LTD induction was facilitated. In parallel, NPR-BdeltaKC rats exhibited an enhancement in exploratory and learning behavior. These results indicate that bidirectional plasticity and learning and memory mechanism are affected in transgenic rats expressing a dominant-negative mutant of NPR-B. Our data substantiate the hypothesis that NPR-B-dependent cGMP signalling has a modulatory role for synaptic information storage and learning.

Major depressive disorder (MDD) remains a huge personal and societal encumbrance. Particularly burdensome is a virulent subtype of MDD, treatment resistant major depression (TMRD), which afflicts 15–30% of MDD patients. There has been recent interest in N-methyl-d-aspartate receptors (NMDARs) as targets for treatment of MDD and perhaps TMRD. To date, most pre-clinical and clinical studies have focused on ketamine, although psychotomimetic and other side effects may limit ketamine's utility. These considerations prompted a recent promising pilot clinical trial of nitrous oxide, an NMDAR antagonist that acts through a mechanism distinct from that of ketamine, in patients with severe TRMD. In this paper, we review the clinical picture of TRMD as a subtype of MDD, the evolution of ketamine as a fast-acting antidepressant, and clinical and basic science studies supporting the possible use of nitrous oxide as a rapid antidepressant. [ABSTRACT FROM AUTHOR]