Abstract
Anorexia nervosa (AN) is a mental illness with high rates of mortality and relapse, and no approved pharmacotherapy. Using the activity-based anorexia (ABA) model of AN, we previously showed that a single sub-anesthetic intraperitoneal injection of ketamine (30 mg/kg-KET, but not 3 mg/kg-KET), has an immediate and long-lasting effect of reducing anorexia-like behavior among adolescent female mice. We also showed previously that excitatory outflow from medial prefrontal cortex (mPFC) engages hunger-evoked hyperactivity, leading to the ABA condition of severe weight loss. Ketamine is known to target GluN2B-containing NMDARs (NR2B). Might synaptic plasticity involving NR2B in mPFC contribute to ketamine’s ameliorative effects? We addressed this question through electron microscopic immunocytochemical quantification of GluN2B at excitatory synapses of pyramidal neurons (PN) and GABAergic interneurons (IN) in mPFC layer 1 of animals that underwent recovery from a second ABA induction (ABA2), 22 days after ketamine injection during the first ABA induction. The 30 mg/kg-KET evoked synaptic plasticity that differed for PN and IN, with changes revolving the cytoplasmic reserve pool of NR2B more than the postsynaptic membrane pool. Those individuals that suppressed hunger-evoked wheel running the most and increased food consumption during recovery from ABA2 the most showed the greatest increase of NR2B at PN and IN excitatory synapses. We hypothesize that 30 mg/kg-KET promotes long-lasting changes in the reserve cytoplasmic pool of NR2B that enables activity-dependent rapid strengthening of mPFC circuits underlying the more adaptive behavior of suppressed running and enhanced food consumption, in turn supporting better weight restoration.
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Acknowledgements
We thank Dr. Yi-Wen Chen for her input in animal handling and data collection and analysis of body weights, wheel counts, food consumption and EPM. This study was supported by The Klarman Family Foundation Grant Program in Eating Disorders Research, NIH grants R21 MH105846, R01NS066019-01A1, R01NS047557-07A1, EY13079, and BP-ENDURE R25NS080686, NYU's Research Challenge Fund, NSF Grants NSF-REU 1460880, NSF-REU 1950649 and NYU Langone’s Vulnerable Brain Project to CA; the Fulbright Scholarship to YWC; Dean’s Undergraduate Research Fund of New York University in May 2020 and November 2021 to JL. The mice used in this study were the same as those from another study (Chen et al. 2018), which is why some behavioral data from that publication re-appear in this manuscript in analyses correlating behavior to anatomical features.
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The project was supported by grants from The Klarman Family Foundation Grant Program in Eating Disorders Research, the National Institutes of Health of the US, the National Science Foundation of the US, NYU’s Research Challenge Fund, NYU Langone’s Vulnerable Brain Project, NYU’s Dean’s Undergraduate Research Fund, and the Fulbright Scholarship.
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Behavioral data were collected by Y-WC. Electron microscopic data were collected by JL and CA. JL, RT and CA analyzed the raw EM data, wrote the main manuscript text and prepared figures. All authors reviewed and approve the manuscript.
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Li, J., Temizer, R., Chen, YW. et al. Ketamine ameliorates activity-based anorexia of adolescent female mice through changes in GluN2B-containing NMDA receptors at postsynaptic cytoplasmic locations of pyramidal neurons and interneurons of medial prefrontal cortex. Brain Struct Funct 229, 323–348 (2024). https://doi.org/10.1007/s00429-023-02740-w
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DOI: https://doi.org/10.1007/s00429-023-02740-w