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 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.
"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; "
[Show abstract][Hide abstract] 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.
"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). "
[Show abstract][Hide abstract] 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.
"Other studies showing mGluR 2/3 antagonists, that also lead to an increased release of presynaptic glutamate, produce ketamine-like biochemical and behavioral effects which are blocked by AMPA receptor blockade (Dwyer et al, 2012; Karasawa et al, 2005), provide additional support to this model. In addition, it has also been proposed that ketamine is capable of increasing AMPA neurotransmission through suppression of spontaneous NMDAR-mediated neurotransmission that elicits a rapid eEF2-and BDNF-dependent potentiation mediated through increased surface expression of AMPA receptors (Autry et al, 2011; Nosyreva et al, 2013). "
[Show abstract][Hide abstract] ABSTRACT: Large 'real world' studies demonstrating the limited effectiveness and slow onset of clinical response associated with our existing antidepressant medications has highlighted need for the development of new therapeutic strategies for major depression and other mood disorders. Yet, despite intense research efforts, the field has had little success in developing antidepressant treatments with fundamentally novel mechanisms of action over the past six decades, leaving the field wary and skeptical about any new developments. However, a series of relatively small proof of concept studies conducted over the last 15 years has gradually gained great interest by providing strong evidence that a unique, rapid onset of sustained, but still temporally limited, antidepressant effects can be achieved with a single administration of ketamine. We are now left with several questions regarding the true clinical meaningfulness of the findings and the mechanisms underlying the antidepressant action. In this Circumspectives piece, Dr. Sanacora and Schatzberg share their opinions on these issues and discuss paths to move the field forward.Neuropsychopharmacology accepted article preview online, 26 September 2014; doi:10.1038/npp.2014.261.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 09/2014; 40(5). DOI:10.1038/npp.2014.261 · 7.05 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.