Disruption of microglial homeostasis and synaptic stabilization in the Activity-Based Anorexia rat model

Anorexia nervosa (AN) is a severe psychiatric disease primarily affecting young women. Despite its clear symptomatology, its etiology remains poorly understood. Severe dietary restrictions and physical activity, the core symptoms of AN, lead to multiorgan dysfunction involving the immune system. Microglia, the brain’s resident immune cells, are highly sensitive to microenvironmental changes and crucial for synaptic plasticity and circuit refinement. We hypothesized that AN compromises the delicate interplay between microglia and neurons, leading to synaptic changes that contribute to the disease progression, particularly within the hippocampus, a central hub of the limbic system. To test this, we utilized the activity-based anorexia (ABA) rat model: female rats were exposed to the combination of food restriction and wheel access during adolescence (from postnatal day (P)38 to P42). Animals were sacrificed at P42, at the acute phase, or at P49, after a 7-day recovery. Structural analyses at P42 revealed reduced dendritic spine density and PSD95 protein levels in the hippocampus. While spine density recovered by P49, the reduction in PSD95 protein levels persisted. Molecular analyses in the ventral hippocampus at P42 revealed increased Tnf-a mRNA levels and a downregulation of Iba1, Trem2 and P2yr12, alongside reduced protein levels of iC3b, Cd11b and Cx3cl1 (with unchanged Cx3cr1) and increased SIRPα (with unchanged CD47). At P49 Tnf-a mRNA levels were reduced while Iba1 and Trem2 expression was upregulated. However, iC3b, Cd11b and Cx3cl1 (with unchanged Cx3cr1) protein levels remained reduced and SIRPα (with unchanged CD47) remained increased. These data suggest that ABA causes an early shift from homeostatic to reactive microglia states, potentially resulting in dendritic spine loss. The subsequent phase of spine regrowth is characterized by improper synaptic stabilization, likely due to the delayed recovery of microglial homeostasis. These alterations may contribute to the long-term neurobiological signatures of AN.