Suppression of PKR Promotes Network Excitability and Enhanced Cognition by Interferon-γ-Mediated Disinhibition

Zhu, Ping; Huang, Wei; Kalikulov, D; Yoo, Jong W.; Placzek, Andon N.; Stoica, Loredana Elena; Zhou, Hongyi; Bell, John C.; Friedländer, Michael; Krnjević, K.; Noebels, Jeffrey L.; Costa-Mattioli, Mauro

doi:10.1016/j.cell.2011.11.029

Cited by 184 publications

(180 citation statements)

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“…Whereas it remains unknown whether the principles described for the VTA also apply to the hippocampus, we speculate that ISRIB enhances cognitive abilities by blocking LTD and consequently enhancing LTP, thus keeping synaptic connections stronger. Indeed, reduction of eIF2α phosphorylation enhances hippocampal LTP (19,22), but blocks mGluR-LTD (33). By contrast, induction of eIF2α phosphorylation in hippocampal neurons impairs LTP (19,25) and induces mGluR-LTD (33).…”

Section: Discussionmentioning

confidence: 97%

“…Electrophysiological recordings were performed as previously described (22,72,73). Briefly, hippocampal slices (350 μm) were cut from brains of sham and TBI (focal injury; n = 7-9 per group) mice in 4°C artificial cerebrospinal fluid (ACSF), kept in ACSF at room temperature for at least 1 hr before recording, and maintained in an interface-type chamber perfused with oxygenated ACSF (95% O 2 and 5% CO 2 ) containing in millimoles: 124 NaCl, 2.0 KCl, 1.3 MgSO 4 , 2.5 CaCl 2 , 1.2 KH 2 PO 4 , 25 NaHCO 3 , and 10 glucose (2-3 mL/min).…”

Section: Discussionmentioning

confidence: 99%

“…In the brain, phosphorylation of eIF2α regulates the formation of long-term memory (19)(20)(21). Briefly, animals with reduced phosphorylation of eIF2α show enhanced long-term memory storage (19,(22)(23)(24), and increased phosphorylation of eIF2α in the brain prevents the formation of long-term memory (19,24,25).…”

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confidence: 99%

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Inhibition of the integrated stress response reverses cognitive deficits after traumatic brain injury

Chou

Krukowski

Jopson

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Traumatic brain injury (TBI) is a leading cause of long-term neurological disability, yet the mechanisms underlying the chronic cognitive deficits associated with TBI remain unknown. Consequently, there are no effective treatments for patients suffering from the long-lasting symptoms of TBI. Here, we show that TBI persistently activates the integrated stress response (ISR), a universal intracellular signaling pathway that responds to a variety of cellular conditions and regulates protein translation via phosphorylation of the translation initiation factor eIF2α. Treatment with ISRIB, a potent drug-like small-molecule inhibitor of the ISR, reversed the hippocampaldependent cognitive deficits induced by TBI in two different injury mouse models-focal contusion and diffuse concussive injury. Surprisingly, ISRIB corrected TBI-induced memory deficits when administered weeks after the initial injury and maintained cognitive improvement after treatment was terminated. At the physiological level, TBI suppressed long-term potentiation in the hippocampus, which was fully restored with ISRIB treatment. Our results indicate that ISR inhibition at time points late after injury can reverse memory deficits associated with TBI. As such, pharmacological inhibition of the ISR emerges as a promising avenue to combat head traumainduced chronic cognitive deficits.brain trauma | memory deficits | translational control | eIF2α | hippocampus T raumatic brain injury (TBI) represents a major mental health problem (1-4). Even a mild TBI can elicit cognitive deficits, including permanent memory dysfunction (2, 4). Moreover, TBI is one of the most predictive environmental risk factors for the development of Alzheimer's disease and other forms of dementia (5-9). Current treatments have focused primarily on reducing the risk of TBI incidence, immediate neurosurgical intervention, or broad behavioral rehabilitation (10-13). Despite posing a huge societal problem, there are currently no pharmacological treatment options for patients that suffer from TBIinduced cognitive deficits.The integrated stress response (ISR) is an evolutionarily conserved pathway that controls cellular homeostasis and function (14). The central ISR regulatory step is the phosphorylation of the α-subunit of the eukaryotic translation initiation factor 2 (eIF2α) by a family of four eIF2α kinases (15, 16). Phosphorylation of eIF2α leads to inhibition of general protein synthesis, but also, to the translational up-regulation of a select subset of mRNAs (17, 18). In the brain, phosphorylation of eIF2α regulates the formation of long-term memory (19)(20)(21). Briefly, animals with reduced phosphorylation of eIF2α show enhanced long-term memory storage (19,(22)(23)(24), and increased phosphorylation of eIF2α in the brain prevents the formation of long-term memory (19,24,25).Similar to other chronic cognitive disorders (21, 26), TBI leads to a persistent activation of the ISR. TBI induces eIF2α phosphorylation even in brain regions that are distal to the injury site (27, 28). How...

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

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Inhibition of the integrated stress response reverses cognitive deficits after traumatic brain injury

Chou

Krukowski

Jopson

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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208

213

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“…Previously, it was shown that reduction of eIF2a phosphorylation in mice lacking the eIF2a kinase general control nonderepressible 2 (GCN2) and in heterozygous knockin mice with a mutation on serine 51 of eIF2a results in a lowered threshold for inducing long-lasting late-phase long-term potentiation (L-LTP) (Costa-Mattioli et al 2005. In addition, mice harboring a deletion of the double-stranded (ds) RNA-activated protein kinase (PKR) show a similar decrease in threshold for inducing L-LTP (Zhu et al 2011). Conversely, increased eIF2a phosphorylation in transgenic mice overexpressing PKR causes increased expression of ATF4 and impaired L-LTP (Jiang et al 2010).…”

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confidence: 99%

The eIF2α kinase PERK limits the expression of hippocampal metabotropic glutamate receptor-dependent long-term depression

Trinh

Kaphzan

et al. 2014

Learn. Mem.

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The proper regulation of translation is required for the expression of long-lasting synaptic plasticity. A major site of translational control involves the phosphorylation of eukaryotic initiation factor 2 a (eIF2a) by PKR-like endoplasmic reticulum (ER) kinase (PERK). To determine the role of PERK in hippocampal synaptic plasticity, we used the Cre-lox expression system to selectively disrupt PERK expression in the adult mouse forebrain. Here, we demonstrate that in hippocampal area CA1, metabotropic glutamate receptor (mGluR)-dependent long-term depression (LTD) is associated with increased eIF2a phosphorylation, whereas stimulation of early-and late-phase long-term potentiation (E-LTP and L-LTP, respectively) is associated with decreased eIF2a phosphorylation. Interesting, although PERK-deficient mice exhibit exaggerated mGluR-LTD, both E-LTP and L-LTP remained intact. We also found that mGluR-LTD is associated with a PERK-dependent increase in eIF2a phosphorylation. Our findings are consistent with the notion that eIF2a phosphorylation is a key site for the bidirectional control of persistent forms of synaptic LTP and LTD and suggest a distinct role for PERK in mGluR-LTD.

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“…However, in some cases, it is clear that the gene causing the epileptic phenotype is also partially or totally responsible for the cognitive impairment (Bender et al 2013). Indeed, in some single-gene models, there is evidence that a gain in cognitive function may coexist with epilepsy, suggesting that seizures are not always destructive and that the pathways for cognition and epilepsy can occasionally be dissected (Zhu et al 2011).…”

Section: Epileptic Encephalopathiesmentioning

confidence: 99%

The Epilepsy Spectrum: Targeting Future Research Challenges

Holmes

Noebels

2016

Cold Spring Harb Perspect Med

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There have been tremendous recent advances in our understanding of the biological underpinnings of epilepsy and associated comorbidities that justify its representation as a spectrum disorder. Advances in genetics, electrophysiology, and neuroimaging have greatly improved our ability to differentiate, diagnose, and treat individuals with epilepsy. However, we have made little overall progress in preventing epilepsy, and the number of patients who are cured remains small. Likewise, the comorbidities of epilepsy are often underdiagnosed or not adequately treated. In this article, we suggest a few areas in which additional research will likely pay big dividends for patients and their families.T he pace of recent advances in epilepsy has been explosive, driven by our increasing understanding of the disorder's inextricable links to development, excitability, and plasticity in the central nervous system, and by the steady emergence of techniques to analyze these properties at high resolution in both human and animal models. As shown in Figure 1, there has been a near doubling in published articles dealing with epilepsy over the last 15 years. Experimental research has produced a threefold increase in peer-reviewed papers since 1970. Subareas within epilepsy research that have shown nearly exponential increases in activity include genetic models, epileptogenesis, comorbidities, and mortality.Although it is gratifying that epilepsy is now receiving the attention it deserves based on its prevalence, the new knowledge comes at a cost; the more we learn about the complex biology of epilepsy, the further away we appear to be from the therapeutic goalposts. Despite our advances in more precisely defining seizure phenotypes, isolating causative genes, and developing specific therapies, much more work needs to be done before we can hope to prevent epilepsy in vulnerable populations, reduce comorbidities associated with epilepsy, and effectively eliminate seizures without causing adverse side effects. However, clinical heterogeneity and molecular complexity are features of all human disease, and serve to position the field of epilepsy research alongside that of cancer in allowing the opportunity to make steady inroads in curing certain forms (Noebels 2015). In the future, rather than measuring our progress by the prevalence of the disorder as a whole, we will be monitoring research progress within the many

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Suppression of PKR Promotes Network Excitability and Enhanced Cognition by Interferon-γ-Mediated Disinhibition

Cited by 184 publications

References 62 publications

Inhibition of the integrated stress response reverses cognitive deficits after traumatic brain injury

Inhibition of the integrated stress response reverses cognitive deficits after traumatic brain injury

The eIF2α kinase PERK limits the expression of hippocampal metabotropic glutamate receptor-dependent long-term depression

The Epilepsy Spectrum: Targeting Future Research Challenges

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