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NR2A- and NR2B-NMDA receptors and drebrin within postsynaptic spines of the hippocampus correlate with hunger-evoked exercise

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A Correction to this article was published on 31 January 2020

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Abstract

Hunger evokes foraging. This innate response can be quantified as voluntary wheel running following food restriction (FR). Paradoxically, imposing severe FR evokes voluntary FR, as some animals choose to run rather than eat, even during limited periods of food availability. This phenomenon, called activity-based anorexia (ABA), has been used to identify brain changes associated with FR and excessive exercise (EX), two core symptoms of anorexia nervosa (AN), and to explore neurobiological bases of AN vulnerability. Previously, we showed a strong positive correlation between suppression of FR-evoked hyperactivity, i.e., ABA resilience, and levels of extra-synaptic GABA receptors in stratum radiatum (SR) of hippocampal CA1. Here, we tested for the converse: whether animals with enhanced expression of NMDA receptors (NMDARs) exhibit greater levels of FR-evoked hyperactivity, i.e., ABA vulnerability. Four groups of animals were assessed for NMDAR levels at CA1 spines: (1) ABA, in which 4 days of FR was combined with wheel access to allow voluntary EX; (2) FR only; (3) EX only; and (4) control (CON) that experienced neither EX nor FR. Electron microscopy revealed that synaptic NR2A-NMDARs and NR2B-NMDARs levels are significantly elevated, relative to CONs’. Individuals’ ABA severity, based on weight loss, correlated with synaptic NR2B-NMDAR levels. ABA resilience, quantified as suppression of hyperactivity, correlated strongly with reserve pools of NR2A-NMDARs in spine cytoplasm. NR2A- and NR2B-NMDAR measurements correlated with spinous prevalence of an F-actin binding protein, drebrin, suggesting that drebrin enables insertion of NR2B-NMDAR to and retention of NR2A-NMDARs away from synaptic membranes, together influencing ABA vulnerability.

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  • 31 January 2020

    The title of Fig.��6 in the original article was incorrectly published as "normalized cytoplasmic NR2A".

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Acknowledgements

We thank Gauri Wable, Alisa Liu, Clive Miranda, Jia-Yi Wang, Kei Tateyama, Ruka Aderogba and Barkha Rana for their assistance and Danielle D Mendoca for proof-reading the manuscript. This study was supported by The Klarman Foundation Grant Program in Eating Disorders Research, R21MH091445−01, R21 MH105846, R01NS066019−01A1, R01NS047557−07A1, NEI Core Grant EY13079, NYU’s Research Challenge Fund, NSF-REU 1460880 to CA, YWC, the Fulbright Scholarship to YWC, NYU Dean’s Undergraduate Research Fund to AL and JYW, UL1 TR000038 from the National Center for the Advancement of Translational Science (NCATS) to TGC, T32 MH019524 to GSW, NYU Abu Dhabi Fund to CM and R25GM097634−01 to RA. The brain tissue used for this study is the same as that used for another study (Nedelescu et al. 2016). Therefore, a portion of the ante mortem weight and wheel running data are presented in both manuscripts.

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    1. Center for Neural Science, New York University, 4 Washington PlaceRoom 809, New York, NY, 10003, USA

      Yi-Wen Chen, Hannah Actor-Engel, Ang Doma Sherpa, Lauren Klingensmith, Tara G. Chowdhury & Chiye Aoki

    2. Department of Neuroscience, University of Pittsburgh, Pittsburgh, USA

      Tara G. Chowdhury

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    Y.-W. Chen and H. Actor-Engel contributed equally to the manuscript.

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    Supplementary material 1 Supplemental Figure 1. Group comparison of NR2A immunoreactivity in the vicinity of axo-spinous asymmetric synapses. The upper panel depicts the proportion of spines immunolabeled for the NR2A subunits per-10 synapses. The lower panel depicts the number of PEG particles encountered per-10 synapses. The bars represent the mean ± SEM values of the measurements pooled across animals of the same group. * depicts significance of difference at p < 0.05 by two-way ANOVA, followed by Fisher’s LSD post hoc analysis. Supplemental Figure 2. Group comparison of NR2B immunoreactivity in the vicinity of axo-spinous asymmetric synapses. The upper panel depicts the proportion of spines immunolabeled for the NR2B subunits per-10 synapses. The lower panel depicts the number of PEG particles encountered per-10 synapses. The bars represent the mean ± SEM values of the measurements pooled across animals of the same group. * depicts significance of difference at p < 0.05 by two-way ANOVA, followed by Fisher’s LSD post hoc analysis. (PDF 5879 kb)

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    Chen, YW., Actor-Engel, H., Sherpa, A.D. et al. NR2A- and NR2B-NMDA receptors and drebrin within postsynaptic spines of the hippocampus correlate with hunger-evoked exercise. Brain Struct Funct 222, 2271–2294 (2017). https://doi.org/10.1007/s00429-016-1341-7

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    • DOI: https://doi.org/10.1007/s00429-016-1341-7

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