Ketamine enhances ketogenic diet-induced resilience to activity-based anorexia of adult mice through hippocampal synaptic plasticity.
Jun-Di Wang, Olivia Ge, Yiru Dong, Emma Lee, Chiye Aoki
Neuroscience September 1, 2026 DOI: 10.1016/j.neuroscience.2026.08.045 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Observational animal study (mouse model, between-group comparison) Peer reviewed |
|---|---|
| Sample size | 14 |
| Population | Mice in an activity-based anorexia model of anorexia nervosa (7 in the ketamine plus ketogenic diet group, 7 in the ketogenic diet-only group) |
| Interventions | Ketamine Ketogenic diet |
| Duration | More than 28 days |
| Topics | Esketamine Ketamine Neuroplasticity |
| Key findings | Ketamine combined with a ketogenic diet, but not the ketogenic diet alone, sustained suppression of anorexia-like hyperactivity and improved weight retention and anxiety in mice even after return to a standard diet and re-challenge. The authors report that the combined group showed greater correlation between GABAergic inhibition of pyramidal neurons and weight retention, lower areal density of excitatory synapses in the stratum lacunosum-moleculare, and a negative correlation between inhibitory synapses onto GABAergic dendrites and hyperactivity, and propose that sustained plasticity of glutamatergic and GABAergic synapses may underlie the effect. |
Abstract
Ketogenic diet (KGD) combined with ketamine (KET) suppresses food restriction-evoked hyperactivity in activity-based anorexia (ABA) mouse model of anorexia nervosa (AN) for more than 28 days, thereby improving weight retention and reducing anxiety, even after mice return to standard diet (SD) and are re-challenged with ABA (KGD + KET → SD, "KET + KGD group"). Suppression of these AN-like behavior is not sustained in mice fed KGD without KET (KGD → SD, "KGD-only group"). We hypothesized that the sustained efficacy of KET + KGD is associated with altered prevalence of certain synapses in the dorsal hippocampus that influence behavior. We compared the prevalence of excitatory and inhibitory synapses between KET + KGD (N = 7) versus KGD-only (N = 7) groups, using electron microscopy and GAD immunolabeling to distinguish GABAergic inhibitory synapses from non-GABAergic excitatory synapses. Pyramidal cell layer (PCL) was analyzed to assess the contribution by parvalbumin + subtype of GABAergic neurons known to reside there, while stratum lacunosum-molecular (SLM) was analyzed to assess inhibition by non-PV + GABAergic neurons known to reside there. In both PCL and SLM, the KET + KGD group exhibited greater correlation between GABAergic inhibition of PNs and weight retention. In SLM of the KET + KGD group, the areal density of excitatory synapses was less. Inhibitory synapses onto GABAergic dendrites (disinhibition which may also augment excitability) correlated negatively with hyperactivity for the KET + KGD group only. KET + KGD, but not KGD-only, may sustain ABA resilience by enhancing plasticity of both glutamatergic and GABAergic synapses. This jointly sustained plasticity underlying hippocampal excitability may be the cellular bases for KET + KGD treatment's suppression of AN relapses.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |