Aberrant NMDA receptor (NMDAR) activity contributes to several neurological disorders, but direct antagonism is poorly tolerated therapeutically. The GluN2B cytoplasmic C-terminal domain (CTD) represents an alternative therapeutic target since it potentiates excitotoxic signaling. The key GluN2B CTD-centred event in excitotoxicity is proposed to involve its phosphorylation at Ser-1303 by DAPK1, that is blocked by a neuroprotective cell-permeable peptide mimetic of the region. Contrary to this model, we find that excitotoxicity can proceed without increased Ser-1303 phosphorylation, and is unaffected by DAPK1 deficiency in vitro or following ischemia in vivo. Pharmacological analysis of the aforementioned neuroprotective peptide revealed that it acts in a sequence-independent manner as an open-channel NMDAR antagonist at or near the Mg2+ site, due to its high net positive charge. Thus, GluN2B-driven excitotoxic signaling can proceed independently of DAPK1 or altered Ser-1303 phosphorylation.
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: All experiments using live animals were conducted under the authority of UK Home Office project and personal licences and adhered to regulations specified in the Animals (Scientific Procedures) Act (1986) and Directive 2010/63/EU and were approved by both The Roslin Institute's and the University of Edinburgh's Animal Welfare and Ethics Committees. Experimental design, analysis and reporting followed the ARRIVE guidelines (https://www.nc3rs.org.uk/arrive-guidelines) where possible. Animal experimentation: Animals used in this study were treated in accordance with UK Animal Scientific Procedures Act (1986) . The relevant Home Office project licences are P1351480E and 60/4407, and the use of genetically modified organisms approved by local committee reference SBMS 13_007.
© 2017, McQueen et al.
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Prey must balance predator avoidance with feeding, a central dilemma in prey refuge theory. Additionally, prey must assess predatory imminence—how close threats are in space and time. Predatory imminence theory classifies defensive behaviors into three defense modes: pre-encounter, post-encounter, and circa-strike, corresponding to increasing levels of threat—–suspecting, detecting, and contacting a predator. Although predatory risk often varies in spatial distribution and imminence, how these factors intersect to influence defensive behaviors is poorly understood. Integrating these factors into a naturalistic environment enables comprehensive analysis of multiple defense modes in consistent conditions. Here, we combine prey refuge and predatory imminence theories to develop a model system of nematode defensive behaviors, with Caenorhabditis elegans as prey and Pristionchus pacificus as predator. In a foraging environment comprised of a food-rich, high-risk patch and a food-poor, low-risk refuge, C. elegans innately exhibits circa-strike behaviors. With experience, it learns post- and pre-encounter behaviors that proactively anticipate threats. These defense modes intensify with predator lethality, with only life-threatening predators capable of eliciting all three modes. SEB-3 receptors and NLP-49 peptides, key stress regulators, vary in their impact and interdependence across defense modes. Overall, our model system reveals fine-grained insights into how stress-related signaling regulates defensive behaviors.
Several recent theoretical accounts have posited that interoception, the perception of internal bodily signals, plays a vital role in early human development. Yet, empirical evidence of cardiac interoceptive sensitivity in infants to date has been mixed. Furthermore, existing evidence does not go beyond the perception of cardiac signals and focuses only on the age of 5–7 mo, limiting the generalizability of the results. Here, we used a modified version of the cardiac interoceptive sensitivity paradigm introduced by Maister et al., 2017 in 3-, 9-, and 18-mo-old infants using cross-sectional and longitudinal approaches. Going beyond, we introduce a novel experimental paradigm, namely the iBREATH, to investigate respiratory interoceptive sensitivity in infants. Overall, for cardiac interoceptive sensitivity (total n=135) we find rather stable evidence across ages with infants on average preferring stimuli presented synchronously to their heartbeat. For respiratory interoceptive sensitivity (total n=120) our results show a similar pattern in the first year of life, but not at 18 mo. We did not observe a strong relationship between cardiac and respiratory interoceptive sensitivity at 3 and 9 mo but found some evidence for a relationship at 18 mo. We validated our results using specification curve- and mega-analytic approaches. By examining early cardiac and respiratory interoceptive processing, we provide evidence that infants are sensitive to their interoceptive signals.