1-methyltryptophan treatment ameliorates high-fat diet induced depression in mice through reversing perineuronal nets changes

Abstract

Abstract Depression and obesity are prevalent disorders that have significant public health implications. To investigate the mechanism underlying high-fat diet (HFD)-induced depression-like behaviors, we used a mouse model of HFD-induced obesity. The HFD-induced obese mouse exhibited a depression-like phenotype in behavioral assays, as well as a reduction in hippocampus volume. These phenotypes were reversed by treating HFD mice with the indoleamine 2,3-dioxygenase (IDO) inhibitor 1-methyltryptophan (1-MT). Interestingly, no changes in IDO levels were observed post 1-MT treatment, suggesting that the anti-depressive effect of 1-MT has an IDO-independent mechanism. To clarify the mechanism of 1-MT in reversing HFD-induced depression-like behaviors, we conducted RNA sequencing analysis which showed a significant enrichment of shared differential genes in the extracellular matrix (ECM) organization pathway between the 1-MT-treated and untreated HFD-induced depression mice. Therefore, we hypothesized that changes in ECM play a crucial role in the anti-depressive effect of 1-MT. To this end, we investigated perineuronal nets (PNNs), which are ECM assemblies that preferentially ensheath parvalbumin (PV)-positive interneurons and are involved in many abnormalities. We found that HFD is associated with excessive accumulation of PV-positive neurons and the upregulation of PNNs, which, in turn, affect synaptic transmission in PV-positive neurons and lead to glutamate-gamma-aminobutyric acid imbalances in the hippocampus. 1-MT effectively reversed these changes, highlighting an IDO-independent mechanism by which 1-MT exerts its anti-depressive effect.