The hypothesis of the authors was based on the rationale that a decreased peripheral synthesis of KYNA would allow the relative overrepresentation of other kynurenine metabolites in the brain that are associated with higher BBB-penetrance and/or presumed pathogenic roles in major depression as neurotoxic and neuroinflammatory factors (Brundin et al., 2016), thereby contributing to the development of depressive-like symptoms in animals with muscle-specific PGC-1α deficiency (Agudelo et al., 2014). Here, PPARGC1A is linked to major depressive disorder.