Peripheral effects of central serotonin depletion in a mouse model for sub sickness behavior

Abstract

Major Depression Disorders (MDD) are the most frequent psychiatric disorders in the Western civilization. The most popular theory highlights the depletion of serotonin (5-HT) and epinephrine in the central nervous system (CNS) as major factors contributing to the development of MDD, while other theories stress the influence of peripheral immune-activation. Here we used tryptophan hydoxylase2 (TPH2)-deficient mice, that lack the rate-limiting enzyme of 5-HT synthesis in the CNS. We established a model of mild-stimulation of the peripheral immune system by lipopolysaccharide (LPS)-treatment at a dose of 0.02 mg/kg and analyzed the physiological and behavioral responses during four hours after intraperitoneal injection of LPS or saline in Tph2-deficient (Tph2−/−) and wildtype (Tph+/+) mice. Both Tph2−/− and Tph2+/+ animals displayed typical hypoglycemia and total white blood cell depletion, but no signs of sickness behavior after LPS-administration. However, the increase in corticosterone levels was blunted in Tph2−/− mice. FACS analysis showed identical changes in T- and B-cell amounts in blood, bone marrow, and spleen of Tph2+/+ and Tph2−/− animals. Surprisingly, LPS-treated Tph2−/− mice were not able to recruit the same amount of Ly6Ghigh/CD115+/CD11b+/Gr1+ progenitor cells from bone marrow as Tph2+/+ mice and also showed no reduction of these cells in the blood. Both genotypes showed no signs of sickness or changes in exploration behavior after 4 h of injection. Evaluation of a depression-like state in the tail suspension test 2 h after the LPS administration revealed no change in wildtype animals due to treatment, but a decreased level of struggling activity in Tph2−/− mice.