Article

mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists

Yale University, New Haven, Connecticut, United States
Science (Impact Factor: 33.61). 08/2010; 329(5994):959-64. DOI: 10.1126/science.1190287
Source: PubMed

ABSTRACT

The rapid antidepressant response after ketamine administration in treatment-resistant depressed patients suggests a possible
new approach for treating mood disorders compared to the weeks or months required for standard medications. However, the mechanisms
underlying this action of ketamine [a glutamate N-methyl-d-aspartic acid (NMDA) receptor antagonist] have not been identified. We observed that ketamine rapidly activated the mammalian
target of rapamycin (mTOR) pathway, leading to increased synaptic signaling proteins and increased number and function of
new spine synapses in the prefrontal cortex of rats. Moreover, blockade of mTOR signaling completely blocked ketamine induction
of synaptogenesis and behavioral responses in models of depression. Our results demonstrate that these effects of ketamine
are opposite to the synaptic deficits that result from exposure to stress and could contribute to the fast antidepressant
actions of ketamine.

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    • "The first set of experiments examined whether systemic ketamine would modify behavioral and neurochemical effects of IS. Ketamine (10 mg/kg, i.p.; Li et al., 2010) was administered 2 weeks, 1 week, or 2 h before IS, and anxiety was evaluated by the JSI test 24 h after the stressor. BLA extracellular 5-HT levels induced by IS were assessed in a separate set of rats using in vivo microdialysis. "
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    ABSTRACT: Recent interest in the antidepressant and anti-stress effects of subanesthetic doses of ketamine, an NMDA receptor antagonist, has identified mechanisms whereby ketamine reverses the effect of stress, but little is known regarding the prophylactic effect ketamine might have on future stressors. Here we investigate the prophylactic effect of ketamine against neurochemical and behavioral changes that follow inescapable, uncontrollable tail shocks (ISs) in Sprague Dawley rats. IS induces increased anxiety, which is dependent on activation of serotonergic (5-HT) dorsal raphe nucleus (DRN) neurons that project to the basolateral amygdala (BLA). Ketamine (10 mg/kg, i.p.) administered 2 h, 1 week, or 2 weeks before IS prevented the increased extracellular levels of 5-HT in the BLA typically produced by IS. In addition, ketamine administered at these time points blocked the decreased juvenile social investigation produced by IS. Microinjection of ketamine into the prelimbic (PL) region of the medial prefrontal cortex duplicated the effects of systemic ketamine, and, conversely, systemic ketamine effects were prevented by pharmacological inhibition of the PL. Although IS does not activate DRN-projecting neurons from the PL, IS did so after ketamine, suggesting that the prophylactic effect of ketamine is a result of altered functioning of this projection.
    Full-text · Article · Jan 2016 · The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
    • "This finding may be due to the unique mechanism of action of ketamine that, in this region, might reduce glutamate neurotransmission, which is known to tonically regulate basal expression of Zif-268[51]. In fact, a similar dose of IV ketamine infusion, equivalent to those inducing both anti-depressant effects[6,52]and hippocampal-mediated spatial memory impairment[53]was shown to have a predicted NMDA receptor occupancy of 40% at 30 min and 14% at 60 min during infusion time[52]. We could therefore speculate that, in our study, the single ketamine infusion could block hippocampal NMDA activation , considering however that receptor occupancy may depend on different regional NMDA expression levels and use-dependency binding affinities. "
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    ABSTRACT: Ketamine is a drug of abuse with a unique profile, which besides its inherent mechanism of action as a non-competitive antagonist of the NMDA glutamate receptor, displays both antidepressant and reinforcing properties. The major aim of our study was to find a molecular signature of ketamine that may help in discriminating between its reinforcing and antidepressant effects. To this end, we focused our attention on BDNF, a neurotrophin that has been shown to play a role in both antidepressant and reinforcing properties of several drugs. Rats were exposed to self-administer intravenous (IV) ketamine (S/A) for 43 days or to receive a single IV ketamine 0.5mg/kg, or vehicle infusion. Although the dose we employed is lower than that reported by the literature, it however yields Cmax values that correspond to those achieved in humans after antidepressant treatment. Our results show that while the single infusion of ketamine increased the neurotrophin expression in the hippocampus while reducing it in the ventral striatum, a feature shared with other antidepressants, the repeated self-administration reduced mBDNF expression and its downstream signalling in both ventral striatum and hippocampus. Further, we here show that phosphorylation of Akt is oppositely regulated by ketamine, pointing to this pathway as central to the different actions of the drug. Taken together, we here point to BDNF and its downstream signalling pathway as a finely tuned mechanism whose modulation might subserve the different features of ketamine.
    No preview · Article · Dec 2015 · Pharmacological Research
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    • "These morphological changes appeared to be a more transient effect, as 24 h ketamine treatment did not produce spine enlargement (Table 2). However, 24 h treatment did promote a significant increase in the number of spines in contact with presynaptic terminals (Table 2), consistent with the delayed increase in synapsin I expression and other synaptic markers following ketamine administration (Li et al., 2010). Thus, ketamine promotes alterations in spine size similar to that seen with vortioxetine treatment. "
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    ABSTRACT: Cognitive dysfunction is prevalent in patients with major depressive disorder (MDD), and cognitive impairments can persist after relief of depressive symptoms. The multimodal-acting antidepressant vortioxetine is an antagonist at 5-HT3, 5-HT7, and 5-HT1D receptors, a partial agonist at 5-HT1B receptors, an agonist at 5-HT1A receptors, and an inhibitor of the serotonin (5-HT) transporter (SERT) and has pro-cognitive properties. In preclinical studies, vortioxetine enhances long-term potentiation (LTP), a cellular correlate of neuroplasticity, and enhances memory in various cognitive tasks. However, the molecular mechanisms by which vortioxetine augments LTP and memory remain unknown. Dendritic spines are specialized, actin-rich microdomains on dendritic shafts and are major sites of most excitatory synapses. Since dendritic spine remodeling is implicated in synaptic plasticity and spine size dictates the strength of synaptic transmission, we assessed if vortioxetine, relative to other antidepressants including ketamine, duloxetine, and fluoxetine, plays a role in the maintenance of dendritic spine architecture in vitro. We show that vortioxetine, ketamine, and duloxetine induce spine enlargement. However, only vortioxetine treatment increased the number of spines in contact with presynaptic terminals. In contrast, fluoxetine had no effect on spine remodeling. These findings imply that the various 5-HT receptor mechanisms of vortioxetine may play a role in its effect on spine dynamics and in increasing the proportion of potentially functional synaptic contacts.
    Full-text · Article · Dec 2015 · Neuropharmacology
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