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.

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 (<1 μm) but clearly not at the post-synaptic plasma membrane of excitatory synapses, enabling rapid strengthening of synapses through receptor trafficking to the plasma membrane without increasing steady-state excitability. We propose that these changes underlie the ketamine-evoked gain of resilience against anorexia-like behaviors >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.