Alzheimer's disease (AD) and type 2 diabetes appear to share similar pathogenic mechanisms. dsRNA-dependent protein kinase (PKR) underlies peripheral insulin resistance in metabolic disorders. PKR phosphorylates eukaryotic translation initiation factor 2α (eIF2α-P), and AD brains exhibit elevated phospho-PKR and eIF2α-P levels. Whether and how PKR and eIF2α-P participate in defective brain insulin signaling and cognitive impairment in AD are unknown. We report that β-amyloid oligomers, AD-associated toxins, activate PKR in a tumor necrosis factor α (TNF-α)-dependent manner, resulting in eIF2α-P, neuronal insulin receptor substrate (IRS-1) inhibition, synapse loss, and memory impairment. Brain phospho-PKR and eIF2α-P were elevated in AD animal models, including monkeys given intracerebroventricular oligomer infusions. Oligomers failed to trigger eIF2α-P and cognitive impairment in PKR(-/-) and TNFR1(-/-) mice. Bolstering insulin signaling rescued phospho-PKR and eIF2α-P. Results reveal pathogenic mechanisms shared by AD and diabetes and establish that proinflammatory signaling mediates oligomer-induced IRS-1 inhibition and PKR-dependent synapse and memory loss.

Summary:Purpose: The physiologic role of the cellular prion protein (PrP') is unknown. Mice devoid of PrPC develop normally and show only minor deficits. However, electrophysiologic and histologic alterations found in these mice suggest a possible role for PrP" in seizure threshold andor epilepsy.Methods: We tested the sensitivity of PrP" knockout mice to seizures induced by single convulsant or repeated subconvulsant (kindling) doses of pentylenetetrazol (PTZ), and to status epilepticus (SE) induced by kainic acid or pilocarpine.Results: In PTZ kindling, seizure severity progressed faster in the PrP' knockout group, in which 92.8% reached stage 5 or death after 4 days of stimulation, as opposed to 38.4% in wildtype animals. After 10 injections, mortality was 85.7% among knockouts and 15.3% among controls. After a single PTZ injection (60 mgkg), overall mortality due to seizures was 91 % in knockout mice, but only 33% among wild-type animals. Pilocarpine-induced SE (320 mgkg) caused an 86.7% mortality in knockouts, as opposed to 40% in wild-type animals. Finally, after kainic acid injections (10 mgkg), 70% of the knockouts developed at least one severe seizure, and 50% showed repetitive seizures, whereas no wild-type animal exhibited observable seizures.Conclusions: Animals lacking cellular prion protein expression are more susceptible to seizures induced by various convulsant agents. This is perhaps the most striking alteration yet found in PrP'-null mice, who at first analysis appeared to be completely normal. A possible role for PrP' in chronic and idiopathic (familial), secondary, or cryptogenic epilepsies in humans remains to be investigated. Key Words: PrionPrP"--Seizure-Epileps y-Kindling.Prions have long been known as the causative agents of spongiform encephalopathies, which can be transmitted through infection in livestock and humans but also by genetic inheritance in the latter (1). Their composition has been firmly established as consisting of a single protein termed scrapie prion protein (PrP'"). It has been shown that there are no differences between the amino acid sequences of PrP" and of its physiologic counterpart, cellular prion protein (PrP"). The only relevant difference between PrP"" and PrP" concerns their secondary structures, with the former displaying a much higher proportion of p-sheet conformational domains than the latter, which is mostly a-helical (2,3).The physiological function of PrP", however, remains unclear ( 1 4 ) . As it is located in the outer surface of cells, anchored by phosphatidylinositol glycolipid, it is a candidate for a signaling or, less likely, a transport function (3). Mice devoid of PrP" develop normally, showing normal learning (3,4), but have aberrant sleep patterns (3,5); moreover, one line of mice lacking PrP" developed cerebellar degeneration in old age (6). Mossy fiber alterations resembling those seen in temporal lobe epilepsy have recently been described in PrP" knockout mice (7). Moreover, one study has shown that y-aminobutyric acid type A (GABA,) rece...

The processes of memory reconsolidation and extinction have received increasing attention in recent experimental research, as their potential clinical applications begin to be uncovered. A number of studies suggest that amnestic drugs injected after reexposure to a learning context can disrupt either of the two processes, depending on the behavioral protocol employed. Hypothesizing that reconsolidation represents updating of a memory trace in the hippocampus, while extinction represents formation of a new trace, we have built a neural network model in which either simple retrieval, reconsolidation or extinction of a stored attractor can occur upon contextual reexposure, depending on the similarity between the representations of the original learning and reexposure sessions. This is achieved by assuming that independent mechanisms mediate Hebbian-like synaptic strengthening and mismatch-driven labilization of synaptic changes, with protein synthesis inhibition preferentially affecting the former. Our framework provides a unified mechanistic explanation for experimental data showing (a) the effect of reexposure duration on the occurrence of reconsolidation or extinction and (b) the requirement of memory updating during reexposure to drive reconsolidation.

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Despite some caveats, G protein-coupled receptor oligomerization is a phenomenon that is becoming largely accepted. Within these oligomers, however, stoichiometry remains to be elucidated. Here, by using bimolecular fluorescence complementation, we visualized adenosine A 2A receptor homodimers in living cells, showing no apparent difference in the subcellular distribution when compared to the YFP-labelled adenosine A 2A receptor protomer. Interestingly, the combination of bimolecular fluorescence complementation and bioluminescence resonance energy transfer techniques allowed us to detect the occurrence of adenosine A 2A receptors oligomers containing more than two protomers. These results provide new insights into the molecular composition of G protein-coupled receptor oligomers.

Journal impact factors have become an important criterion to judge the quality of scientific publications over the years, influencing the evaluation of institutions and individual researchers worldwide. However, they are also subject to a number of criticisms. Here we point out that the calculation of a journal’s impact factor is mainly based on the date of publication of its articles in print form, despite the fact that most journals now make their articles available online before that date. We analyze 61 neuroscience journals and show that delays between online and print publication of articles increased steadily over the last decade. Importantly, such a practice varies widely among journals, as some of them have no delays, while for others this period is longer than a year. Using a modified impact factor based on online rather than print publication dates, we demonstrate that online-to-print delays can artificially raise a journal’s impact factor, and that this inflation is greater for longer publication lags. We also show that correcting the effect of publication delay on impact factors changes journal rankings based on this metric. We thus suggest that indexing of articles in citation databases and calculation of citation metrics should be based on the date of an article’s online appearance, rather than on that of its publication in print.

Retrieval of an associative memory can lead to different phenomena. Brief reexposure sessions tend to trigger reconsolidation, whereas more extended ones trigger extinction. In appetitive and fear cued Pavlovian memories, an intermediate "null point" period has been observed where neither process seems to be engaged. Here we investigated whether this phenomenon extends to contextual fear memory. Adult rats were subjected to a contextual fear conditioning paradigm, reexposed to the context 2 d later for 3, 5, 10, 20, or 30 min, with immediate injections of MK-801 or saline following reexposure, and tested on the following day. We observed a significant effect of MK-801 with the 3-and 30-min sessions, impairing reconsolidation and extinction, respectively. However, it did not have significant effects with 5-, 10-, or 20-min sessions, even though freezing decreased from reexposure to test. Further analyses indicated that this is not likely to be due to a variable transition point at the population level. In conclusion, the results show that in contextual fear memories there is a genuine "null point" between the parameters that induce reconsolidation and extinction, as defined by the effects of MK-801, although NMDA receptor-independent decreases in freezing can still occur in these conditions.[Supplemental material is available for this article.]The retrieval of an associative memory can result in different outcomes. Retrieval in the absence of further reinforcement can destabilize a memory, requiring a process of reconsolidation (Nader and Hardt 2009), or can cause memory extinction through new inhibitory learning (Giustino and Maren 2015). The balance between destabilization and extinction appears to be influenced by the relative strength of learning and extent of nonreinforced retrieval (Eisenberg et al. 2003;Suzuki et al. 2004;Lee et al. 2006;de la Fuente et al. 2011;Flavell and Lee 2013). More extensive stimulus reexposure (i.e., extinction training), or weaker initial conditioning is more likely to result in extinction, whereas more restricted stimulus reexposure preferentially engages memory destabilization. This apparent competition between destabilization and extinction manifests as a bidirectional effect of amnestic treatment, depending of the parameters of conditioning and retrieval. Either reconsolidation is impaired to reduce subsequent memory expression, or extinction is disrupted to maintain expression of the original memory (Eisenberg et al. 2003;Suzuki et al. 2004;Lee et al. 2006;de la Fuente et al. 2011;Flavell and Lee 2013).In both appetitive Pavlovian and conditioned fear memories, recent evidence has indicated that extinction per se does not prevent memory destabilization and reconsolidation. In cue-sucrose, cue-fear, and context-fear settings, there appears to be a reexposure period between the parameters that engage destabilization and extinction, in which there is no behavioral effect of amnestic treatment (Flavell and Lee 2013;Merlo et al. 2014;Alfei et al. 2015). This "limbo" or "null poin...

Environmental enrichment is known to induce plastic changes in the brain, including morphological changes in hippocampal neurons, with increases in synaptic and spine densities. In recent years, the evidence for a role of astrocytes in regulating synaptic transmission and plasticity has increased, and it is likely that morphological and functional changes in astrocytes play an important role in brain plasticity. Our study was designed to evaluate changes in astrocytes induced by environmental enrichment in the CA1 region of the hippocampus, focusing on astrocytic density and on morphological changes in astrocytic processes. After 8 weeks of environmental enrichment starting at weaning, male CF-1 mice presented no significant changes in astrocyte number or in the density of glial fibrillary acidic protein (GFAP) immunoreactivity in the stratum radiatum. However, they did present changes in astrocytic morphology in the same region, as expressed by a significant increase in the ramification of astrocytic processes measured by the Sholl concentric circles method, as well as by an increase in the number and length of primary processes extending in a parallel orientation to CA1 nerve fibers. This led astrocytes to acquire a more stellate morphology, a fact which could be related to the increase in hippocampal synaptic density observed in previous studies. These findings corroborate the idea that structural changes in astrocytic networks are an integral part of plasticity processes occurring in the brain.