Acute Suppression of Spontaneous Neurotransmission Drives Synaptic Potentiation
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; "
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.eLife Sciences 07/2015; 4. DOI:10.7554/eLife.09262 · 8.52 Impact Factor
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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). "
ABSTRACT: Acute low-dose administration of the N-methyl-D-aspartate (NMDA) receptor antagonist, ketamine, produces rapid and sustained antidepressant-like effects in humans and rodents. Recently, we found that the long-lasting effect of ketamine on the forced swim test requires ventral hippocampal (vHipp) activity at the time of drug administration. The medial prefrontal cortex (mPFC), a target of the vHipp dysregulated in depression, is important for cognitive flexibility and response strategy selection. Deficits in cognitive flexibility, the ability to modify thoughts and behaviors in response to changes in the environment, are associated with depression. We have shown that chronic stress impairs cognitive flexibility on the attentional set-shifting test (AST) and induces a shift from active to passive response strategies on the shock-probe defensive burying test (SPDB). In this study, we tested the effects of ketamine on chronic stress-induced changes in cognitive flexibility and coping behavior on the AST and SPDB, respectively. Subsequently, we investigated vHipp-mPFC plasticity as a potential mechanism of ketamine's therapeutic action. Ketamine reversed deficits in cognitive flexibility and restored active coping behavior in chronically stressed rats. Further, high frequency stimulation in the vHipp replicated ketamine's antidepressant-like effects on the forced swim test and AST, but not on the SPDB. These results show that ketamine restores cognitive flexibility and coping response strategy compromised by stress. Activity in the vHipp-mPFC pathway may represent a neural substrate for some of the antidepressant-like behavioral effects of ketamine, including cognitive flexibility, but other circuits may mediate the effects of ketamine on coping response strategy.Psychopharmacology 05/2015; DOI:10.1007/s00213-015-3957-3 · 3.99 Impact Factor
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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. "
ABSTRACT: Neuronal activity results in long lasting changes in synaptic structure and function by regulating mRNA translation in dendrites. These activity dependent events yield the synthesis of proteins known to be important for synaptic modifications and diverse forms of synaptic plasticity. Worthy of note, there is accumulating evidence that the eukaryotic Elongation Factor 2 Kinase (eEF2K)/eukaryotic Elongation Factor 2 (eEF2) pathway may be strongly involved in this process. Upon activation, eEF2K phosphorylates and thereby inhibits eEF2, resulting in a dramatic reduction of mRNA translation. eEF2K is activated by elevated levels of calcium and binding of Calmodulin (CaM), hence its alternative name calcium/CaM-dependent protein kinase III (CaMKIII). In dendrites, this process depends on glutamate signaling and N-methyl-D-aspartate receptor (NMDAR) activation. Interestingly, it has been shown that eEF2K can be activated in dendrites by metabotropic glutamate receptor (mGluR) 1/5 signaling, as well. Therefore, neuronal activity can induce local proteomic changes at the postsynapse by altering eEF2K activity. Well-established targets of eEF2K in dendrites include brain-derived neurotrophic factor (BDNF), activity-regulated cytoskeletal-associated protein (Arc), the alpha subunit of calcium/CaM-dependent protein kinase II (αCaMKII), and microtubule-associated protein 1B (MAP1B), all of which have well-known functions in different forms of synaptic plasticity. In this review we will give an overview of the involvement of the eEF2K/eEF2 pathway at dendrites in regulating the translation of dendritic mRNA in the context of altered NMDAR- and neuronal activity, and diverse forms of synaptic plasticity, such as metabotropic glutamate receptor-dependent-long-term depression (mGluR-LTD). For this, we draw on studies carried out both in vitro and in vivo.Frontiers in Cellular Neuroscience 02/2014; 8:35. DOI:10.3389/fncel.2014.00035 · 4.18 Impact Factor