Mechanisms underlying sustained resilience against anorexia nervosa from sub-anesthetic ketamine: A review and new research based on electron microscopic analyses of synapses using a mouse model.

Repeated exposure to the activity-based anorexia (ABA) animal model, which mimics key features of anorexia nervosa such as starvation-induced hyperactivity and severe weight loss, can build resilience against relapse through synaptic changes. Sub-anesthetic ketamine given during mid-adolescence enhances this resilience. At medial prefrontal cortex synapses, ketamine increases GluN2B-containing NMDA receptors and the F-actin binding protein drebrin at excitatory synapses on pyramidal cells and GABA-interneurons. These molecular changes occur near 15 days post-injection during relapse in late adolescence. Ketamine treatment in late adolescence also reduces ABA relapse in adulthood, though less effectively. Wheel running promotes inhibitory GABAergic synapse formation on hippocampal pyramidal cells, and ketamine augments this inhibition, suppressing starvation-evoked hyperactivity and increasing food consumption and weight gain.

Study at a glance

Abstract

The activity-based anorexia (ABA) animal model captures key maladaptive behaviors of anorexia nervosa - starvation-evoked hyperactivity, voluntary food restriction, severe weight loss and elevated anxiety-like behavior. By repeating ABA induction, the model reveals an animal's gain of resilience against ABA relapses and concomitant synaptic plasticity. We review findings on the efficacy of sub-anesthetic ketamine administered during ABA in mid-adolescence in gaining resilience against ABA relapses, and the molecular changes evoked at medial prefrontal cortex (mPFC) synapses. GluN2B-containing NMDA receptors are significantly greater at excitatory synapses on dendritic spines of pyramidal cells. Drebrin, an F-actin binding protein that promotes activity-dependent trafficking of NMDA receptors to synaptic membranes, also increases at excitatory synapses on GABA-interneurons and pyramidal cells. These changes are at sites very near (15 days post-injection, during ABA relapse in late adolescence. Ketamine treatment during ABA in late-adolescence ameliorates ABA relapse in adulthood >15 days later but to a lesser extent. A new EM analysis revealed that wheel running promotes GABAergic inhibitory synapse formation on pyramidal cells of the hippocampus and that ketamine augments GABAergic inhibition's contribution towards suppression of the most maladaptive behavior - starvation-evoked hyperactivity - while also augmenting food consumption, as reflected by weight gain at the end of food availability periods.