Lack of CASP1, IFNGR and NOS2 Genes Alter Depressive-, Anxiety-Like Behavior and Gut Microbiota

Background
Mounting evidence implicates neuroinflammatory pathways in the development and treatment response of MDD. Pre-clinical and clinical studies suggest that decreasing pro-inflammatory signaling may be beneficial to MDD. Dysregulation of three major inflammatory systems is evident in this condition: A) increased oxidative stress by means of nitric oxide (NO) overproduction, driven by NOS2 (NO synthase 2), B) low-grade chronic pro-inflammatory status driven by caspase 1 (CASP1) overproduction, and C) interferon gamma (INFG) over production driven by type 1 T helper (Th1) cells.

Methods
The chronic unpredictable mild stress (CUMS) paradigm was used to evaluate whether triple knockout male mice lacking the pro-inflammatory CASP1, INFG receptor, and NOS2 (Casp1, Ifngr, Nos2)-/- display altered depressive- and anxiety-like behavior. Gut microbiome studies were performed at baseline after CUMS; we also measured plasma adrenocorticotropic hormone (ACTH) and corticosterone (CORT) levels using ELISA.

Results
Triple knockout mice exhibit decreased depressive- and anxiety-like behavior and increased hedonic-like behavior and locomotor activity at baseline, and resistance to developing anhedonic-like behavior and a heightened emotional state following stress compared to wild-type (wt) mice. Plasma ACTH and CORT levels did not differ between the triple knockout and wt mice following CUMS. The triple knockout mice fecal microbiota differed from that of wt mice at baseline and displayed reduced changes in response to chronic stress.

Conclusions
Simultaneous deficit in multiple pro-inflammatory pathways has antidepressant-like effects at baseline and confers resilience to stress-induced anhedonic-like behavior. Concomitant changes in the gut microbiome composition suggest that CASP1, IFNGR and NOS2 play a role in maintaining microbiome homeostasis.