Nicholas E Bulthuis, Josephine C McGowan, Liliana R Ladner, Christina T LaGamma, Sean C Lim, Claire X Shubeck, Rebecca A Brachman, Ezra Sydnor, Ina P Pavlova, Dong-Oh Seo, Michael R Drew, Christine A Denny
{"title":"小鼠成体颗粒细胞上的 GluN2B 可调节(R,S)-氯胺酮的速效作用。","authors":"Nicholas E Bulthuis, Josephine C McGowan, Liliana R Ladner, Christina T LaGamma, Sean C Lim, Claire X Shubeck, Rebecca A Brachman, Ezra Sydnor, Ina P Pavlova, Dong-Oh Seo, Michael R Drew, Christine A Denny","doi":"10.1093/ijnp/pyae036","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Standard antidepressant treatments often take weeks to reach efficacy and are ineffective for many patients. (R,S)-ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has been shown to be a rapid-acting antidepressant and to decrease depressive symptoms within hours of administration. While previous studies have shown the importance of the GluN2B subunit of the NMDA receptor on interneurons in the medial prefrontal cortex, no study to our knowledge has investigated the influence of GluN2B-expressing adult-born granule cells.</p><p><strong>Methods: </strong>Here, we examined whether (R,S)-ketamine's efficacy depends on adult-born hippocampal neurons using a genetic strategy to selectively ablate the GluN2B subunit of the NMDA receptor from Nestin+ cells in male and female mice, tested across an array of standard behavioral assays.</p><p><strong>Results: </strong>We report that in male mice, GluN2B expression on 6-week-old adult-born neurons is necessary for (R,S)-ketamine's effects on behavioral despair in the forced swim test and on hyponeophagia in the novelty suppressed feeding paradigm, as well on fear behavior following contextual fear conditioning. In female mice, GluN2B expression is necessary for effects on hyponeophagia in novelty suppressed feeding. These effects were not replicated when ablating GluN2B from 2-week-old adult-born neurons. We also find that ablating neurogenesis increases fear expression in contextual fear conditioning, which is buffered by (R,S)-ketamine administration.</p><p><strong>Conclusions: </strong>In line with previous studies, these results suggest that 6-week-old adult-born hippocampal neurons expressing GluN2B partially modulate (R,S)-ketamine's rapid-acting effects. Future work targeting these 6-week-old adult-born neurons may prove beneficial for increasing the efficacy of (R,S)-ketamine.</p>","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":4.5000,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11461768/pdf/","citationCount":"0","resultStr":"{\"title\":\"GluN2B on Adult-Born Granule Cells Modulates (R,S)-Ketamine's Rapid-Acting Effects in Mice.\",\"authors\":\"Nicholas E Bulthuis, Josephine C McGowan, Liliana R Ladner, Christina T LaGamma, Sean C Lim, Claire X Shubeck, Rebecca A Brachman, Ezra Sydnor, Ina P Pavlova, Dong-Oh Seo, Michael R Drew, Christine A Denny\",\"doi\":\"10.1093/ijnp/pyae036\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Standard antidepressant treatments often take weeks to reach efficacy and are ineffective for many patients. (R,S)-ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has been shown to be a rapid-acting antidepressant and to decrease depressive symptoms within hours of administration. While previous studies have shown the importance of the GluN2B subunit of the NMDA receptor on interneurons in the medial prefrontal cortex, no study to our knowledge has investigated the influence of GluN2B-expressing adult-born granule cells.</p><p><strong>Methods: </strong>Here, we examined whether (R,S)-ketamine's efficacy depends on adult-born hippocampal neurons using a genetic strategy to selectively ablate the GluN2B subunit of the NMDA receptor from Nestin+ cells in male and female mice, tested across an array of standard behavioral assays.</p><p><strong>Results: </strong>We report that in male mice, GluN2B expression on 6-week-old adult-born neurons is necessary for (R,S)-ketamine's effects on behavioral despair in the forced swim test and on hyponeophagia in the novelty suppressed feeding paradigm, as well on fear behavior following contextual fear conditioning. In female mice, GluN2B expression is necessary for effects on hyponeophagia in novelty suppressed feeding. These effects were not replicated when ablating GluN2B from 2-week-old adult-born neurons. We also find that ablating neurogenesis increases fear expression in contextual fear conditioning, which is buffered by (R,S)-ketamine administration.</p><p><strong>Conclusions: </strong>In line with previous studies, these results suggest that 6-week-old adult-born hippocampal neurons expressing GluN2B partially modulate (R,S)-ketamine's rapid-acting effects. 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GluN2B on Adult-Born Granule Cells Modulates (R,S)-Ketamine's Rapid-Acting Effects in Mice.
Background: Standard antidepressant treatments often take weeks to reach efficacy and are ineffective for many patients. (R,S)-ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has been shown to be a rapid-acting antidepressant and to decrease depressive symptoms within hours of administration. While previous studies have shown the importance of the GluN2B subunit of the NMDA receptor on interneurons in the medial prefrontal cortex, no study to our knowledge has investigated the influence of GluN2B-expressing adult-born granule cells.
Methods: Here, we examined whether (R,S)-ketamine's efficacy depends on adult-born hippocampal neurons using a genetic strategy to selectively ablate the GluN2B subunit of the NMDA receptor from Nestin+ cells in male and female mice, tested across an array of standard behavioral assays.
Results: We report that in male mice, GluN2B expression on 6-week-old adult-born neurons is necessary for (R,S)-ketamine's effects on behavioral despair in the forced swim test and on hyponeophagia in the novelty suppressed feeding paradigm, as well on fear behavior following contextual fear conditioning. In female mice, GluN2B expression is necessary for effects on hyponeophagia in novelty suppressed feeding. These effects were not replicated when ablating GluN2B from 2-week-old adult-born neurons. We also find that ablating neurogenesis increases fear expression in contextual fear conditioning, which is buffered by (R,S)-ketamine administration.
Conclusions: In line with previous studies, these results suggest that 6-week-old adult-born hippocampal neurons expressing GluN2B partially modulate (R,S)-ketamine's rapid-acting effects. Future work targeting these 6-week-old adult-born neurons may prove beneficial for increasing the efficacy of (R,S)-ketamine.
期刊介绍:
The central focus of the journal is on research that advances understanding of existing and new neuropsychopharmacological agents including their mode of action and clinical application or provides insights into the biological basis of psychiatric disorders and thereby advances their pharmacological treatment. Such research may derive from the full spectrum of biological and psychological fields of inquiry encompassing classical and novel techniques in neuropsychopharmacology as well as strategies such as neuroimaging, genetics, psychoneuroendocrinology and neuropsychology.