In a mouse model of activity‑based anorexia, the combination of a ketogenic diet and a single ketamine administration prolonged suppression of hyperactivity, preserved body weight and reduced anxiety for more than four weeks, an effect that was not observed with the diet alone. Electron‑microscopic analysis linked these behavioral benefits to altered densities of excitatory and inhibitory hippocampal synapses.
Study and findings
The authors used the activity‑based anorexia (ABA) paradigm in adult mice, a model that reproduces key features of anorexia nervosa such as food‑restriction‑induced hyperactivity and weight loss. Mice received either a ketogenic diet (KGD) alone or a ketogenic diet together with a single ketamine injection (KET + KGD). After 28 days on the diet, both groups were returned to a standard diet and re‑exposed to the ABA protocol. The KET + KGD group retained more body weight, displayed lower anxiety‑like behavior, and continued to show reduced hyperactivity during the re‑challenge, whereas the KGD‑only group lost the protective effect. Electron microscopy with GAD immunolabeling was used to quantify excitatory and GABAergic inhibitory synapses in two hippocampal sub‑regions: the pyramidal cell layer (PCL) and the stratum lacunosum‑molecular (SLM). In the KET + KGD mice, a stronger correlation between GABAergic inhibition of pyramidal neurons and weight retention was observed in both regions. Additionally, the SLM of KET + KGD mice showed a lower areal density of excitatory synapses, and inhibitory synapses onto GABAergic dendrites (a form of disinhibition) correlated negatively with hyperactivity only in this group.
Clinical interpretation
These data suggest that ketamine may augment the long‑term behavioral benefits of a ketogenic diet in this preclinical model by promoting coordinated plasticity of both glutamatergic and GABAergic hippocampal circuits. The observed association between enhanced inhibitory tone and weight maintenance aligns with the notion that hippocampal excitability influences feeding‑related motivation and anxiety. While the findings are limited to mice, they raise the possibility that a combined pharmacological‑nutritional approach could modulate neural substrates implicated in relapse‑like behaviors of anorexia nervosa.
Limitations and open questions
The study relied on a single ketamine dose and a specific ketogenic formulation; dose‑response relationships remain undefined. The sample size (n = 7 per group) limits statistical power and generalizability. Electron‑microscopic quantification provides a snapshot of synaptic density but does not directly demonstrate functional changes in neurotransmission. Moreover, the translational relevance to human anorexia nervosa is uncertain because the ABA model captures only selected aspects of the disorder. Future work should test whether repeated ketamine dosing, alternative diet compositions, or timing of intervention affect the durability of the effect, and whether similar synaptic adaptations occur in higher‑order brain regions involved in reward and cognition.
Source
Wang J, Ge O, Dong Y, Lee E, Aoki C. Ketamine enhances ketogenic diet-induced resilience to activity-based anorexia of adult mice through hippocampal synaptic plasticity. Neuroscience. 2026:S0306-4522(26)00588-9. doi: 10.1016/j.neuroscience.2026.08.045. PMID: 42679921.