LPS-Induced Inflammation Reduces GABAergic Interneuron markers and Brain-derived Neurotrophic Factor in Mouse Prefrontal Cortex and Hippocampus

Inflammation, reduced gamma-aminobutyric acidergic (GABAergic) function and altered neuroplasticity are co-occurring pathophysiologies in major depressive disorder (MDD). However, the link between these biological changes remains unclear. We hypothesized that inflammation induces deficits in GABAergic interneuron markers and that this effect is mediated by brain-derived neurotrophic factor (BDNF). We report here that systemic inflammation induced by intraperitoneal injection of lipopolysaccharide (LPS) (0.125, 0.25, 0.5, 1, 2mg/kg) in the first cohort of C57BL/6 mice (n=72; 9-12 weeks; 50% female) resulted in increased interleukin 1-beta and interleukin-6 in prefrontal cortex (PFC) and hippocampus (HPC), as measured using enzyme-linked immunosorbent assay (ELISA). Quantitative real-time polymerase reaction (qPCR) was used to explore the effect of LPS on the expression of GABAergic interneuron markers. In the PFC of the second cohort (n=39; 9-12 weeks; 50% female), 2mg/kg of LPS decreased the expression of somatostatin (Sst) (p=0.0014), parvalbumin (Pv) (p=0.0257), cortistatin (Cort) (p=0.0003), neuropeptide Y (Npy) (p=0.0033) and cholecystokinin (Cck) (p=0.0041), and did not affect corticotropin-releasing hormone (Crh) and vasoactive intestinal peptide (Vip) expression. In the HPC, 2mg/kg of LPS decreased the expression of Sst (P=0.0543), Cort (p=0.0011), Npy (p=0.0001), and Cck (p<0.0001), and did not affect Crh, Pv, and Vip expression. LPS decreased the expression of Bdnf in the PFC (P<0.0001) and HPC (P=0.0003), which significantly correlated with affected markers (Sst, Pv, Cort, Cck, and Npy). Collectively, these results suggest that inflammation may causally contribute to cortical cell microcircuit GABAergic deficits observed in MDD.