Nitric Oxide Is an Activity-Dependent Regulator of Target Neuron Intrinsic Excitability

Steinert, Joern R.; Robinson, Susan W.; Tong, Huaxia; Haustein, Martin D.; Kopp-Scheinpflug, Cornelia; Forsythe, Ian D.

doi:10.1016/j.neuron.2011.05.037

Cited by 102 publications

(128 citation statements)

References 80 publications

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“…PrP Sc was detected after proteinase K digestion 7 . Whole-cell recordings were done in acute hippocampal slices to measure synaptic transmission 31 . Global translation levels were detected using [ 35 S]methionine incorporation in acute hippocampal slices; translations of specific transcripts in polysomal fractions from hippocampi were analysed by northern blotting 32 .…”

Section: Methodsmentioning

confidence: 99%

Sustained translational repression by eIF2α-P mediates prion neurodegeneration

Moreno

Radford

Peretti

et al. 2012

Nature

551

617

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The mechanisms leading to neuronal death in neurodegenerative disease are poorly understood. Many of these disorders, including Alzheimer's, Parkinson's and prion diseases, are associated with the accumulation of misfolded disease-specific proteins. The unfolded protein response is a protective cellular mechanism triggered by rising levels of misfolded proteins. One arm of this pathway results in the transient shutdown of protein translation, through phosphorylation of the a-subunit of eukaryotic translation initiation factor, eIF2. Activation of the unfolded protein response and/or increased eIF2a-P levels are seen in patients with Alzheimer's, Parkinson's and prion diseases 1-4 , but how this links to neurodegeneration is unknown. Here we show that accumulation of prion protein during prion replication causes persistent translational repression of global protein synthesis by eIF2a-P, associated with synaptic failure and neuronal loss in prion-diseased mice. Further, we show that promoting translational recovery in hippocampi of prion-infected mice is neuroprotective. Overexpression of GADD34, a specific eIF2a-P phosphatase, as well as reduction of levels of prion protein by lentivirally mediated RNA interference, reduced eIF2a-P levels. As a result, both approaches restored vital translation rates during prion disease, rescuing synaptic deficits and neuronal loss, thereby significantly increasing survival. In contrast, salubrinal, an inhibitor of eIF2a-P dephosphorylation 5 , increased eIF2a-P levels, exacerbating neurotoxicity and significantly reducing survival in priondiseased mice. Given the prevalence of protein misfolding and activation of the unfolded protein response in several neurodegenerative diseases, our results suggest that manipulation of common pathways such as translational control, rather than disease-specific approaches, may lead to new therapies preventing synaptic failure and neuronal loss across the spectrum of these disorders.Neurodegenerative diseases pose an ever-increasing challenge for society and health care systems worldwide, but their molecular pathogenesis is still largely unknown and no curative treatments exist. Alzheimer's (AD), Parkinson's (PD) and prion diseases are separate clinical and pathological conditions, but it is likely they share common mechanisms leading to neuronal death. Mice with prion disease show misfolded prion protein (PrP) accumulation and develop extensive neurodegeneration (with profound neurological deficits), in contrast to mouse models of AD or PD, in which neuronal loss is rare. Uniquely therefore, prion-infected mice allow access to mechanisms linking protein misfolding with neuronal death. Prion replication involves the conversion of cellular PrP, PrP C , to its misfolded, aggregating conformer, PrP Sc , a process leading ultimately to neurodegeneration 6 . We have previously shown rescue of neuronal loss and reversal of early cognitive and morphological changes in prion-infected mice by depleting PrP in neurons, preventing prion replication and ab...

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Section: Methodsmentioning

confidence: 99%

Sustained translational repression by eIF2α-P mediates prion neurodegeneration

Moreno

Radford

Peretti

et al. 2012

Nature

551

617

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“…The activity of the delayed rectifying K+ channels is an important determinant of the activation threshold in dendrites and is thought to have a major impact on neuronal plasticity (Sjostrom et al, 2008). Kv channels have been shown to participate in the regulation of the neuronal excitability of CA3 hippocampal neurons in response to synaptic activity through a NO-dependent mechanism (Steinert et al, 2011). Previously, we have reported that Wnt-5a induces NO production in hippocampal neurons to regulate the surface expression of NMDARs (Muñoz et al, 2014); our results suggest a potential common mechanism underlying Wnt-5a-dependent changes in post-synaptic excitability and plasticity.…”

Section: Effect Of Wnt-5a Upon Hippocampal Synaptic Potentials Is Supmentioning

confidence: 52%

“…NO signaling also contributes to the fine tuning of ion channel activity and therefore neuron excitability (Steinert et al, 2011). The family of Kv channels, when deregulated, has been linked to CNS diseases including hereditary epilepsy (Otto et al, 2009), episodic ataxia and Alzheimer's disease (Colom et al, 1998;Shieh et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Wnt5a inhibits K+ currents in hippocampal synapses through nitric oxide production

Parodí

Montecinos-Oliva

Varas

et al. 2015

Molecular and Cellular Neuroscience

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Hippocampal synapses play a key role in memory and learning processes by inducing longterm potentiation and depression. The growth of adult synapses is regulated by the Wnt signaling pathway, in addition to other pathways. Wnt may also regulate the activity of the postsynaptic terminal. We have previously found that Wnt-5a induces nitric oxide (NO) production, which modulates NMDA expression in the postsynaptic regions of hippocampal neurons. Because the activity of Kv3.2 channels can be inhibited by NO, we investigated whether Wnt-5a can regulate potassium currents in rat hippocampal neurons.Wnt-5a activates non-canonical Wnt/Ca 2+ signaling; triggering NO production, which in turn inhibits a sustained voltage-dependent K + current. The inhibition of the potassium current is mediated at least in part by ROR2, one of the three previously identified Wnt-5areceptors. Preincubation with the soluble Frizzled receptor protein (sFRP-2), which is a Wnt antagonist, and 7-nitroindazole (7-NI), which is a specific inhibitor of neuronal NO synthase, eliminates the inhibitory effect on the K + current. We conclude that Wnt-5aproduces NO and decreases potassium amplitude currents via NO, demonstrating a novel mechanism by which Wnt-5a may regulate the excitability of hippocampal neurons.

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“…In peripheral tissues this enzyme is mainly, but not exclusively, expressed in macrophages. In the CNS, NOS-2 is 25 expressed in microglia and astroglia, and its generation of NO has been implicated in the pathogenesis of various insults as well as in neurological disorders (Brown and Neher 2010, Murphy 2000, Steinert et al 2011. Upregulation of iNOS has been implicated in tissue damage in MS and EAE (Raivich and Banati 2004).…”

Section: Nitric Oxide Synthasesmentioning

confidence: 99%

Mechanisms Involved in the Remyelinating Effect of Sildenafil

Díaz-Lucena

Gutièrrez‐Mecinas

Moreno

et al. 2017

J Neuroimmune Pharmacol

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Nitric Oxide Is an Activity-Dependent Regulator of Target Neuron Intrinsic Excitability

Cited by 102 publications

References 80 publications

Sustained translational repression by eIF2α-P mediates prion neurodegeneration

Sustained translational repression by eIF2α-P mediates prion neurodegeneration

Wnt5a inhibits K+ currents in hippocampal synapses through nitric oxide production

Mechanisms Involved in the Remyelinating Effect of Sildenafil

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