Skip to main content

Main menu

  • HOME
  • CONTENT
    • Early Release
    • Featured
    • Current Issue
    • Issue Archive
    • Collections
    • Podcast
  • ALERTS
  • FOR AUTHORS
    • Information for Authors
    • Fees
    • Journal Clubs
    • eLetters
    • Submit
    • Special Collections
  • EDITORIAL BOARD
    • Editorial Board
    • ECR Advisory Board
    • Journal Staff
  • ABOUT
    • Overview
    • Advertise
    • For the Media
    • Rights and Permissions
    • Privacy Policy
    • Feedback
    • Accessibility
  • SUBSCRIBE

User menu

  • Log out
  • Log in
  • My Cart

Search

  • Advanced search
Journal of Neuroscience
  • Log out
  • Log in
  • My Cart
Journal of Neuroscience

Advanced Search

Submit a Manuscript
  • HOME
  • CONTENT
    • Early Release
    • Featured
    • Current Issue
    • Issue Archive
    • Collections
    • Podcast
  • ALERTS
  • FOR AUTHORS
    • Information for Authors
    • Fees
    • Journal Clubs
    • eLetters
    • Submit
    • Special Collections
  • EDITORIAL BOARD
    • Editorial Board
    • ECR Advisory Board
    • Journal Staff
  • ABOUT
    • Overview
    • Advertise
    • For the Media
    • Rights and Permissions
    • Privacy Policy
    • Feedback
    • Accessibility
  • SUBSCRIBE
PreviousNext
Journal Club

Integrated Stress Response: Connecting ApoE4 to Memory Impairment in Alzheimer's Disease

Mauricio M. Oliveira and Mychael V. Lourenco
Journal of Neuroscience 27 January 2016, 36 (4) 1053-1055; https://doi.org/10.1523/JNEUROSCI.4110-15.2016
Mauricio M. Oliveira
Biological Chemistry Program, Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21941-902, Brazil
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Mauricio M. Oliveira
Mychael V. Lourenco
Biological Chemistry Program, Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21941-902, Brazil
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF
Loading

There is much evidence to suggest that control of gene expression and protein translation contribute to memory formation and consolidation in the hippocampus (Costa-Mattioli et al., 2007; Cho et al., 2015). Therefore, the intricate coordination of mechanisms that couple extracellular signals to translational regulation is essential for memory stability. Disruption of such pathways might contribute to memory decline in cognitive disorders such as Alzheimer's disease (AD).

Most cases of AD are sporadic, meaning they are not tightly linked to gene mutations. Nonetheless, several genetic risk factors for late-onset, sporadic AD have been reported. The strongest genetic risk factor report is possession of the apolipoprotein E ε4 allele (ApoE4). Compared to the ApoE2 or ApoE3 alleles, ApoE4 appears to promote metabolic impairment, amyloid-β (Aβ) production, and tau aggregation, which are hallmarks of AD (Liu et al., 2013). The debate about the culprits of AD pathology is still open, but mounting evidence indicates that neuronal stress-related mechanisms (initiated by either Aβ, tau, or ApoE4) take place in AD brains to induce synapse dysfunction, memory loss, and neurodegeneration (Lourenco et al., 2015).

Cellular stress signals converge to increase phosphorylation of eukaryotic translation initiation factor 2α (eIF2α-P), resulting in transcriptional changes and protein synthesis attenuation, in a set of mechanisms collectively known as the integrated stress response (ISR). eIF2α can be phosphorylated by four different kinases, namely double-stranded RNA-dependent protein kinase (PKR), PKR-like endoplasmic reticulum kinase (PERK), general control nonderepressible 2 (GCN2), and heme-regulated kinase (HRI). eIF2α-P then acts by blocking its partner, eIF2B, in the translation initiation complex (Buffington et al., 2014). Recent evidence has demonstrated significant roles for ISR elements, including PKR and eIF2α-P, in suppressing memory, in either physiological or AD contexts (for review, see Buffington et al., 2014; Lourenco et al., 2015).

In a recent paper in The Journal of Neuroscience, Segev, Barrera et al. (2015) addressed whether PKR could mediate the deleterious impact of ApoE4 on memory. They used a mouse model harboring two genomic copies of either human ApoE3 or ApoE4 alleles in place of the murine homologs. They initially found that ApoE4 mice exhibited impaired contextual memory in the fear conditioning paradigm, in agreement with their previous observations (Segev et al., 2013). They further demonstrated that young (∼3-month-old) ApoE4 mice had higher hippocampal levels of mRNA encoding activating transcription factor 4 (ATF4) than age-matched ApoE3 or wild-type mice (Segev, Barrera et al., 2015).

This increase in ATF4 levels is interesting for several reasons. ATF4 mRNA translation is selectively induced when eIF2α-P increases, despite general translational attenuation, and this drives ISR-related transcriptional reprogramming (Buffington et al., 2014). Recently, ATF4 was described as essential for synapse development and morphogenesis (Liu et al., 2014), and hippocampal silencing of ATF4 impaired synapse plasticity and spatial memory formation in mice (Pasini et al., 2015). However, ATF4 overexpression has been shown to mediate oxidative stress-induced cell death (Lange et al., 2008) and alter expression of several ISR factors, including chaperones and the pro-apoptotic transcription factor C/EBP-homologous protein (CHOP) in neurons (Galehdar et al., 2010). Earlier reports have also indicated that ATF4 could negatively impact memory, as it was shown to oppose the actions of the cAMP response element binding (CREB) transcription factor in the hippocampus (Chen et al., 2003). Thus, fine tuning of ATF4 signaling appears essential for proper synapse and cognitive function. Furthermore, increased ATF4 levels have been observed in the brains of both AD patients (Baleriola et al., 2014) and mouse models (Ma et al., 2013). A recent study by Baleriola and colleagues (2014) identified ATF4 as a retrograde neurodegenerative signal that propagates from neurons exposed to toxic Aβ oligomers (AβOs), known for their central role in AD. Hence, ATF4 has the potential to explain, at least in part, how AD pathology spreads throughout brain regions.

Segev, Barrera et al. (2015) next demonstrated that PKR inhibition alleviates memory impairment and hippocampal ATF4 upregulation in ApoE4 mice. This is consistent with previous reports that blocking eIF2α kinases is effective in impeding AD-related memory impairment in different animal models (Lourenco et al., 2013; Ma et al., 2013) and further extends the notion that metabolic stress and ISR are integral components of AD pathogenesis.

Neuroinflammation has been linked to AD pathogenesis, and some evidence suggests that inflammatory mechanisms drive synapse and cognitive impairment through ISR and metabolic stress (Lourenco et al., 2015). Human ApoE4 carriers have elevated plasma levels of inflammatory markers (Ringman et al., 2012), and ApoE4 has been shown to exacerbate central inflammatory responses that coincide with decreased levels of synaptic markers in mice (Maezawa et al., 2006; Tai et al., 2015). A similar phenomenon is thought to underlie AβO-induced cognitive dysfunction in AD models (Lourenco et al., 2013). Therefore, current evidence suggests that ApoE4 and AβOs may contribute to a toxic process that includes brain inflammation and ISR and impairs synapse and memory (Fig. 1).

Figure 1.
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 1.

ISR mediates synaptic and memory impairment triggered by ApoE4 and AβOs. ISR comprises the activation of PKR, GCN2, or PERK, resulting in abnormal eIF2α-P. ApoE4 and AβOs promote an inflammatory process, which likely enhances ISR through PKR-dependent eIF2α-P. PERK and GCN2 may further contribute to the increase eIF2α-P levels. This process favors upregulation of ATF4, whose nuclear actions antagonize CREB activity and facilitate stress-related gene transcription, including CHOP and molecular chaperones. Such transcriptional changes result in defective synaptic plasticity and cognition, and may further stimulate ISR. Aberrant ISR may thus comprise a common ground to explain memory loss in AD, possibly offering novel targets for therapeutic intervention.

The precise mechanisms by which ApoE4 acts to increase AD risk remain to be determined, and inflammation-dependent cellular stress pathways might offer a consistent explanation for ApoE4-linked AD cases. The description of higher ATF4 levels in brains of ApoE4 carriers than in noncarriers, and in AD subjects compared to cognitively healthy controls, offers additional support for this possibility (Baleriola et al., 2014; Segev, Barrera et al., 2015). Still, further investigation is required to establish a causal role for ATF4 in ApoE4-induced memory defects.

In addition to upregulation of ATF4, eIF2α-P-dependent disruption of translation appears to mediate memory impairment in AD (Ma et al., 2013), which is consistent with the notion that protein synthesis is essential for synaptic plasticity and memory consolidation (Buffington et al., 2014). One might thus envision that targeting aberrant translational regulation could offer therapeutic benefit for cognitive decline. In fact, ISRIB, a pharmacological agent that counteracts eIF2α-P signaling through eIF2B binding (Sekine et al., 2015), reduces ATF4-dependent gene expression while sustaining protein synthesis and enhancing memory in mice (Sidrauski et al., 2013). Nonetheless, further efforts in preclinical research and drug development are needed to support the promising possibility that ISR could become an effective target in neurodegenerative disorders.

In conclusion, Segev, Barrera et al. (2015) provide evidence that ISR mediates memory impairment caused by the ApoE4 allele, whose carriers are at higher risk of developing AD. This opens the possibility that modulating ISR could represent a potential preventive strategy against ApoE4-related cognitive impairment. Furthermore, such findings offer a novel perspective in which similar mechanisms may drive memory loss induced by different AD-associated agents.

Footnotes

  • Editor's Note: These short, critical reviews of recent papers in the Journal, written exclusively by graduate students or postdoctoral fellows, are intended to summarize the important findings of the paper and provide additional insight and commentary. For more information on the format and purpose of the Journal Club, please see http://www.jneurosci.org/misc/ifa_features.shtml.

  • M.M.O. was supported by the Brazilian research funding agencies Coordenação de Aperfeiçoamento de Pessoal de Ensino Superior (CAPES). M.V.L. was supported by Fundação Carlos Chagas Filho de Amparo à Pesquisa no Estado do Rio de Janeiro (FAPERJ), respectively.

  • The authors declare no competing financial interests.

  • Correspondence should be addressed to Maurício M. Oliveira or Mychael V. Lourenco, Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21941-902, Brazil. mmoliveira{at}bioqmed.ufrj.br or mychael{at}bioqmed.ufrj.br

References

  1. ↵
    1. Baleriola J,
    2. Walker CA,
    3. Jean YY,
    4. Crary JF,
    5. Troy CM,
    6. Nagy PL,
    7. Hengst U
    (2014) Axonally synthesized ATF4 transmits a neurodegenerative signal across brain regions. Cell 158:1159–1172, doi:10.1016/j.cell.2014.07.001, pmid:25171414.
    OpenUrlCrossRefPubMed
  2. ↵
    1. Buffington SA,
    2. Huang W,
    3. Costa-Mattioli M
    (2014) Translational control in synaptic plasticity and cognitive dysfunction. Annu Rev Neurosci 37:17–38, doi:10.1146/annurev-neuro-071013-014100, pmid:25032491.
    OpenUrlCrossRefPubMed
  3. ↵
    1. Chen A,
    2. Muzzio IA,
    3. Malleret G,
    4. Bartsch D,
    5. Verbitsky M,
    6. Pavlidis P,
    7. Yonan AL,
    8. Vronskaya S,
    9. Grody MB,
    10. Cepeda I,
    11. Gilliam TC,
    12. Kandel ER
    (2003) Inducible enhancement of memory storage and synaptic plasticity in transgenic mice expressing an inhibitor of ATF4 (CREB-2) and C/EBP proteins. Neuron 39:655–669, doi:10.1016/S0896-6273(03)00501-4, pmid:12925279.
    OpenUrlCrossRefPubMed
  4. ↵
    1. Cho J,
    2. Yu NK,
    3. Choi JH,
    4. Sim SE,
    5. Kang SJ,
    6. Kwak C,
    7. Lee SW,
    8. Kim JI,
    9. Choi DI,
    10. Kim VN,
    11. Kaang BK
    (2015) Multiple repressive mechanisms in the hippocampus during memory formation. Science 350:82–87, doi:10.1126/science.aac7368, pmid:26430118.
    OpenUrlAbstract/FREE Full Text
  5. ↵
    1. Costa-Mattioli M,
    2. Gobert D,
    3. Stern E,
    4. Gamache K,
    5. Colina R,
    6. Cuello C,
    7. Sossin W,
    8. Kaufman R,
    9. Pelletier J,
    10. Rosenblum K,
    11. Krnjević K,
    12. Lacaille JC,
    13. Nader K,
    14. Sonenberg N
    (2007) eIF2α phosphorylation bidirectionally regulates the switch from short- to long-term synaptic plasticity and memory. Cell 129:195–206, doi:10.1016/j.cell.2007.01.050, pmid:17418795.
    OpenUrlCrossRefPubMed
  6. ↵
    1. Galehdar Z,
    2. Swan P,
    3. Fuerth B,
    4. Callaghan SM,
    5. Park DS,
    6. Cregan SP
    (2010) Neuronal apoptosis induced by endoplasmic reticulum stress is regulated by ATF4-CHOP-mediated induction of the Bcl-2 homology 3-only member PUMA. J Neurosci 30:16938–16948, doi:10.1523/JNEUROSCI.1598-10.2010, pmid:21159964.
    OpenUrlAbstract/FREE Full Text
  7. ↵
    1. Lange PS,
    2. Chavez JC,
    3. Pinto JT,
    4. Coppola G,
    5. Sun CW,
    6. Townes TM,
    7. Geschwind DH,
    8. Ratan RR
    (2008) ATF4 is an oxidative stress-inducible, prodeath transcription factor in neurons in vitro and in vivo. J Exp Med 205:1227–1242, doi:10.1084/jem.20071460, pmid:18458112.
    OpenUrlAbstract/FREE Full Text
  8. ↵
    1. Liu CC,
    2. Kanekiyo T,
    3. Xu H,
    4. Bu G
    (2013) Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol 9:106–118, doi:10.1038/nrneurol.2012.263, pmid:23296339.
    OpenUrlCrossRefPubMed
  9. ↵
    1. Liu J,
    2. Pasini S,
    3. Shelanski ML,
    4. Greene LA
    (2014) Activating transcription factor 4 (ATF4) modulates post-synaptic development and dendritic spine morphology. Front Cell Neurosci 8:177, doi:10.3389/fncel.2014.00177, pmid:25071442.
    OpenUrlCrossRefPubMed
  10. ↵
    1. Lourenco MV,
    2. Clarke JR,
    3. Frozza RL,
    4. Bomfim TR,
    5. Forny-Germano L,
    6. Batista AF,
    7. Sathler LB,
    8. Brito-Moreira J,
    9. Amaral OB,
    10. Silva CA,
    11. Freitas-Correa L,
    12. Espírito-Santo S,
    13. Campello-Costa P,
    14. Houzel JC,
    15. Klein WL,
    16. Holscher C,
    17. Carvalheira JB,
    18. Silva AM,
    19. Velloso LA,
    20. Munoz DP,
    21. et al.
    (2013) TNF-α mediates PKR-dependent memory impairment and brain IRS-1 inhibition induced by Alzheimer's β-amyloid oligomers in mice and monkeys. Cell Metab 18:831–843, doi:10.1016/j.cmet.2013.11.002, pmid:24315369.
    OpenUrlCrossRefPubMed
  11. ↵
    1. Lourenco MV,
    2. Ferreira ST,
    3. De Felice FG
    (2015) Neuronal stress signaling and eIF2alpha phosphorylation as molecular links between Alzheimer's disease and diabetes. Prog Neurobiol 129:37–57, doi:10.1016/j.pneurobio.2015.03.003, pmid:25857551.
    OpenUrlCrossRefPubMed
  12. ↵
    1. Ma T,
    2. Trinh MA,
    3. Wexler AJ,
    4. Bourbon C,
    5. Gatti E,
    6. Pierre P,
    7. Cavener DR,
    8. Klann E
    (2013) Suppression of eIF2α kinases alleviates Alzheimer's disease-related plasticity and memory deficits. Nat Neurosci 16:1299–1305, doi:10.1038/nn.3486, pmid:23933749.
    OpenUrlCrossRefPubMed
  13. ↵
    1. Maezawa I,
    2. Nivison M,
    3. Montine KS,
    4. Maeda N,
    5. Montine TJ
    (2006) Neurotoxicity from innate immune response is greatest with targeted replacement of ε4 allele of apolipoprotein E gene and is mediated by microglial p38MAPK. FASEB J 20:797–799, doi:10.1096/fj.05-5423fje, pmid:16481366.
    OpenUrlAbstract/FREE Full Text
  14. ↵
    1. Pasini S,
    2. Corona C,
    3. Liu J,
    4. Greene LA,
    5. Shelanski ML
    (2015) Specific downregulation of hippocampal ATF4 reveals a necessary role in synaptic plasticity and memory. Cell Rep 11:183–191, doi:10.1016/j.celrep.2015.03.025, pmid:25865882.
    OpenUrlCrossRefPubMed
  15. ↵
    1. Ringman JM,
    2. Elashoff D,
    3. Geschwind DH,
    4. Welsh BT,
    5. Gylys KH,
    6. Lee C,
    7. Cummings JL,
    8. Cole GM
    (2012) Plasma signaling proteins in persons at genetic risk for Alzheimer disease: influence of APOE genotype. Arch Neurol 69:757–764, doi:10.1001/archneurol.2012.277, pmid:22689192.
    OpenUrlCrossRefPubMed
  16. ↵
    1. Segev Y,
    2. Michaelson DM,
    3. Rosenblum K
    (2013) ApoE ε4 is associated with eIF2α phosphorylation and impaired learning in young mice. Neurobiol Aging 34:863–872, doi:10.1016/j.neurobiolaging.2012.06.020, pmid:22883908.
    OpenUrlCrossRefPubMed
  17. ↵
    1. Segev Y,
    2. Barrera I,
    3. Ounallah-Saad H,
    4. Wibrand K,
    5. Sporild I,
    6. Livne A,
    7. Rosenberg T,
    8. David O,
    9. Mints M,
    10. Bramham CR,
    11. Rosenblum K
    (2015) PKR inhibition rescues memory deficit and ATF4 overexpression in ApoE epsilon4 human replacement mice. J Neurosci 35:12986–12993, doi:10.1523/JNEUROSCI.5241-14.2015, pmid:26400930.
    OpenUrlAbstract/FREE Full Text
  18. ↵
    1. Sekine Y,
    2. Zyryanova A,
    3. Crespillo-Casado A,
    4. Fischer PM,
    5. Harding HP,
    6. Ron D
    (2015) Mutations in a translation initiation factor identify the target of a memory-enhancing compound. Science 348:1027–1030, doi:10.1126/science.aaa6986, pmid:25858979.
    OpenUrlAbstract/FREE Full Text
  19. ↵
    1. Sidrauski C,
    2. Acosta-Alvear D,
    3. Khoutorsky A,
    4. Vedantham P,
    5. Hearn BR,
    6. Li H,
    7. Gamache K,
    8. Gallagher CM,
    9. Ang KK,
    10. Wilson C,
    11. Okreglak V,
    12. Ashkenazi A,
    13. Hann B,
    14. Nader K,
    15. Arkin MR,
    16. Renslo AR,
    17. Sonenberg N,
    18. Walter P
    (2013) Pharmacological brake-release of mRNA translation enhances cognitive memory. eLife 2:e00498, doi:10.7554/eLife.00498, pmid:23741617.
    OpenUrlAbstract/FREE Full Text
  20. ↵
    1. Tai LM,
    2. Ghura S,
    3. Koster KP,
    4. Liakaite V,
    5. Maienschein-Cline M,
    6. Kanabar P,
    7. Collins N,
    8. Ben-Aissa M,
    9. Lei AZ,
    10. Bahroos N,
    11. Green SJ,
    12. Hendrickson B,
    13. Van Eldik LJ,
    14. LaDu MJ
    (2015) APOE-modulated Abeta-induced neuroinflammation in Alzheimer's disease: current landscape, novel data, and future perspective. J Neurochem 133:465–488, doi:10.1111/jnc.13072, pmid:25689586.
    OpenUrlCrossRefPubMed
Back to top

In this issue

The Journal of Neuroscience: 36 (4)
Journal of Neuroscience
Vol. 36, Issue 4
27 Jan 2016
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
  • Advertising (PDF)
  • Ed Board (PDF)
Email

Thank you for sharing this Journal of Neuroscience article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
Integrated Stress Response: Connecting ApoE4 to Memory Impairment in Alzheimer's Disease
(Your Name) has forwarded a page to you from Journal of Neuroscience
(Your Name) thought you would be interested in this article in Journal of Neuroscience.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Print
View Full Page PDF
Citation Tools
Integrated Stress Response: Connecting ApoE4 to Memory Impairment in Alzheimer's Disease
Mauricio M. Oliveira, Mychael V. Lourenco
Journal of Neuroscience 27 January 2016, 36 (4) 1053-1055; DOI: 10.1523/JNEUROSCI.4110-15.2016

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Respond to this article
Request Permissions
Share
Integrated Stress Response: Connecting ApoE4 to Memory Impairment in Alzheimer's Disease
Mauricio M. Oliveira, Mychael V. Lourenco
Journal of Neuroscience 27 January 2016, 36 (4) 1053-1055; DOI: 10.1523/JNEUROSCI.4110-15.2016
Twitter logo Facebook logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Responses to this article

Respond to this article

Jump to comment:

  • Author Response to Oliveira et al. Journal Club
    Yifat Segev, Dr. Iliana Barrera and Prof. Kobi Rosenblum
    Published on: 27 July 2017
  • Published on: (27 July 2017)
    Page navigation anchor for Author Response to Oliveira et al. Journal Club
    Author Response to Oliveira et al. Journal Club
    • Yifat Segev, Author, University of Haifa
    • Other Contributors:
      • Dr. Iliana Barrera
      • Prof. Kobi Rosenblum

    A response to this article may be found here.

    Competing Interests: None declared.

Related Articles

Cited By...

More in this TOC Section

  • Obesity and Gut–Brain Communication: The Cholinergic-Endocannabinoid Link
  • Unraveling Pallido-Retrorubral Circuits Linking the Basal Ganglia to Limbic Areas
  • µ-Opioid Receptor Control of Glutamate/GABA Coreleasing SUM and VTA Projections to the Dentate Gyrus
Show more Journal Club
  • Home
  • Alerts
  • Follow SFN on BlueSky
  • Visit Society for Neuroscience on Facebook
  • Follow Society for Neuroscience on Twitter
  • Follow Society for Neuroscience on LinkedIn
  • Visit Society for Neuroscience on Youtube
  • Follow our RSS feeds

Content

  • Early Release
  • Current Issue
  • Issue Archive
  • Collections

Information

  • For Authors
  • For Advertisers
  • For the Media
  • For Subscribers

About

  • About the Journal
  • Editorial Board
  • Privacy Notice
  • Contact
  • Accessibility
(JNeurosci logo)
(SfN logo)

Copyright © 2025 by the Society for Neuroscience.
JNeurosci Online ISSN: 1529-2401

The ideas and opinions expressed in JNeurosci do not necessarily reflect those of SfN or the JNeurosci Editorial Board. Publication of an advertisement or other product mention in JNeurosci should not be construed as an endorsement of the manufacturer’s claims. SfN does not assume any responsibility for any injury and/or damage to persons or property arising from or related to any use of any material contained in JNeurosci.