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Acute Suppression of Spontaneous Neurotransmission Drives Synaptic Potentiation

Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9111, Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9111, and The Department of Pharmacology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.75). 04/2013; 33(16):6990-7002. DOI: 10.1523/JNEUROSCI.4998-12.2013
Source: PubMed

ABSTRACT The impact of spontaneous neurotransmission on neuronal plasticity remains poorly understood. Here, we show that acute suppression of spontaneous NMDA receptor-mediated (NMDAR-mediated) neurotransmission potentiates synaptic responses in the CA1 regions of rat and mouse hippocampus. This potentiation requires protein synthesis, brain-derived neurotrophic factor expression, eukaryotic elongation factor-2 kinase function, and increased surface expression of AMPA receptors. Our behavioral studies link this same synaptic signaling pathway to the fast-acting antidepressant responses elicited by ketamine. We also show that selective neurotransmitter depletion from spontaneously recycling vesicles triggers synaptic potentiation via the same pathway as NMDAR blockade, demonstrating that presynaptic impairment of spontaneous release, without manipulation of evoked neurotransmission, is sufficient to elicit postsynaptic plasticity. These findings uncover an unexpectedly dynamic impact of spontaneous glutamate release on synaptic efficacy and provide new insight into a key synaptic substrate for rapid antidepressant action.

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    • "Under these conditions, anisomycin completely abolished the increase in AMPAmEPSC amplitudes as no significant differences were seen in their distribution after TTX + ryanodine treatment compared to treatment with TTX alone (Figure 5D–F). Previous studies have also shown that a key regulator of protein synthesis, eukaryotic elongation factor 2 (eEF2), is phosphorylated and inactivated by the Ca 2+ -dependent eEF2 kinase thus blocking protein synthesis under resting conditions (Sutton et al., 2007; Autry et al., 2011; Nosyreva et al., 2013; "
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    ABSTRACT: Spontaneous glutamate release-driven NMDA receptor activity exerts a strong influence on synaptic homeostasis. However, the properties of Ca(2+) signals that mediate this effect remain unclear. Here, using hippocampal neurons labeled with the fluorescent Ca(2+) probes Fluo-4 or GCAMP5, we visualized action potential-independent Ca(2+) transients in dendritic regions adjacent to fluorescently labeled presynaptic boutons in physiological levels of extracellular Mg(2+). These Ca(2+) transients required NMDA receptor activity, and their propensity correlated with acute or genetically induced changes in spontaneous neurotransmitter release. In contrast, they were insensitive to blockers of AMPA receptors, L-type voltage-gated Ca(2+) channels, or group I mGluRs. However, inhibition of Ca(2+)-induced Ca(2+) release suppressed these transients and elicited synaptic scaling, a process which required protein translation and eukaryotic elongation factor-2 kinase activity. These results support a critical role for Ca(2+)-induced Ca(2+) release in amplifying NMDA receptor-driven Ca(2+) signals at rest for the maintenance of synaptic homeostasis.
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    • "Furthermore, our present study found that high frequency stimulation in the vHipp of non-stressed rats was sufficient to recapitulate ketamine's antidepressant-like effects on the forced swim test (Fig. 3). Enhanced plasticity in the hippocampal-prefrontal cortical circuitry is commonly associated with antidepressant efficacy (Ohashi et al. 2002; Li et al. 2011; Cornwell et al. 2012; Carlson et al. 2013; Nosyreva et al. 2013). Additionally, imaging studies in humans and rodents suggest that ketamine enhances connectivity in hippocampal and cortical regions (Cornwell et al. 2012; Carlson et al. 2013; Gass et al. 2014). "
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    • "synaptic transmission. In line with this fact, knockout mice for an AMPAR called GluA2 do not exhibit the antidepressive response induced by ketamin (Nosyreva et al., 2013). Interestingly, the finding that the (dendritically localized) eEF2K/eEF2 pathway leads to an activity-dependent upregulation of AMPAR currents also suggests that the activity of the eEF2K/eEF2 pathway may not only be dependent on network activity, but may itself determine the extent of network activity. "
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