Single dose S-ketamine rescues transcriptional dysregulation of Mtor and Nrp2 in the prefrontal cortex of FSL rats 1 hour but not 14 days post dosing

Abstract

There is a pressing need to identify biological indicators of major depression to help guide proper diagnosis and optimize treatment. Animal models mimicking aspects of depression constitute essential tools for early-stage exploration of relevant pathways. In this study, we used the Flinders Sensitive and Resistant Line (FSL/FRL) to explore central and peripheral transcriptional changes in vascular endothelial growth factor (VEGF) pathway genes and their temporal regulation after a single dose of S-ketamine (15 mg/kg). We found that S-ketamine induced both rapid (1 hour) and sustained (2 and 14 days) antidepressant-like effects in the FSL rats. Analysis of mRNA expression revealed significant strain effects of Vegf, Vegf164, Vegfr-1, Nrp1, Nrp2, Rictor, and Raptor in the prefrontal cortex (PFC) and of Vegf164, GbetaL, and Tsc1 in the hippocampus (HIP), which indicates suppression of VEGF signaling in the FSL rats compared to FRL rats. This notion was further substantiated by reduced expression of Vegf and Mtor in plasma from FSL rats. In the brain, S-ketamine induced transcriptional changes in the acute phase, not the sustained phase. There were significant treatment effects of S-ketamine on Vegfr-2 in both PFC and HIP and on Vegf and Vegfr-1 in HIP. Moreover, we found that S-ketamine specifically restored reduced levels of Nrp2 and Mtor in the PFC of the FSL rats. In conclusion, this study substantiates the use of the FRL/FSL rats to explore the depressive-like behavior at the transcriptional level of the VEGF pathway genes and study their regulation in response to various treatment paradigms.