Suppression of food restriction‐evoked hyperactivity in activity‐based anorexia animal model through glutamate transporters GLT‐1 at excitatory synapses in the hippocampus

Severe voluntary food restriction is the defining symptom of anorexia nervosa (AN), but anxiety and excessive exercise are maladaptive symptoms that contributes significantly to the severity of AN and which individuals with AN have difficulty suppressing. We hypothesized that excitability of hippocampal pyramidal neurons, known to contribute to anxiety, leads to the maladaptive behavior of excessive exercise. Conversely, since glutamate transporter GLT-1, dampens excitability of hippocampal pyramidal neurons through uptake of ambient glutamate and suppression of the GluN2B-subunit containing NMDA receptors (GluN2B-NMDARs), GLT-1 may contribute towards dampening excessive exercise. This hypothesis was tested using the mouse model of AN, called activity-based anorexia (ABA), whereby food restriction evokes the maladaptive behavior of excessive wheel running (FRER) exercise. We tested whether individual differences in ABA vulnerability of mice, quantified based on FRER, correlated with individual differences in the levels of GLT-1 at excitatory synapses of the hippocampus. Electron microscopic immunocytochemistry (EM-ICC) was used to quantify GLT-1 levels at excitatory synapses of the hippocampus. FRER varied more than 10-fold and Pearson correlation analyses revealed a strong negative correlation (p=0.02) between FRER and GLT-1 levels at axon terminals forming excitatory synapses and at the surrounding astrocytic plasma membranes. Moreover, synaptic levels of GluN2B-NMDARs correlated strongly with GLT-1 levels at peri-synaptic astrocytic plasma membranes. There is at present no accepted pharmacotherapy for AN and little known about the etiology of this deadly illness. Current findings suggest that drugs increasing GLT-1 expression may reduce AN severity through reduction of GluN2B-NMDAR activity.