Inhibition of Indoleamine 2,3-Dioxygenase in the Prelimbic and Infralimbic Cortices Exerts Antidepressant Effects through Different Pathways in ICV-STZ Rats

Abstract

An intracerebroventricular injection of streptozotocin (ICV-STZ) is used to simulate sporadic alzheimer’s disease (sAD) in rats. Rats exhibit depression-like behaviors at the beginning of this model. Indoleamine 2,3-dioxygenase (IDO), a rate-limiting enzyme catalyzing the conversion of tryptophan to kynurenine, is closely related to AD and depression. Present study investigated the neurophysiological mechanism of depression-like behaviors in ICV-STZ rats with a focus on IDO-related kynurenine pathways. IDO was activated in both the prelimbic cortex (PrL) and infralimbic cortex (IL), but abnormalities in downstream metabolic pathways were dramatically different and associated with separate secondary biological effects. In the PrL, the neuroprotective branch of the kynurenine pathway was attenuated, as evidenced by a decrease in kynurenic acid and kynurenine aminotransferase II accompanied by defects in astrocytes, reflected by decreases in GFAP-positive cells and glial transporters and morphological damage. In the IL, the neurotoxic branch of the kynurenine pathway was enhanced, as evidenced by an increase in 3-hydroxy-kynurenine and kynurenine 3-monooxygenase paralleled by the overactivation of microglia, reflected by an increase in Iba1-positive cells and cytokines with morphological alterations. Synaptic plasticity was attenuated in both subregions. Additionally, a microinjection of the selective IDO inhibitor 1-MT in the PrL or IL alleviated depression-like behaviors by reversing these different abnormalities in the PrL and IL. These results suggest that the antidepressant effects of IDO inhibition in the PrL and IL occur through different pathways, namely by enhancing neuroprotective effects in the PrL and attenuating neurotoxic responses in the IL.