Essential role of microglial transforming growth factor-β1 in antidepressant actions of (R)-ketamine and the novel antidepressant TGF-β1

Abstract

In rodent models of depression, (R)-ketamine has greater potency and longer-lasting antidepressant effects than (S)ketamine; however, the precise molecular mechanisms underlying the antidepressant actions of (R)-ketamine remain unknown. Using RNA-sequencing analysis, we identified novel molecular targets that contribute to the different antidepressant effects of the two enantiomers. Either (R)-ketamine (10 mg/kg) or (S)-ketamine (10 mg/kg) was administered to susceptible mice after chronic social defeat stress (CSDS). RNA-sequencing analysis of prefrontal cortex (PFC) and subsequent GSEA (gene set enrichment analysis) revealed that transforming growth factor (TGF)-β signaling might contribute to the different antidepressant effects of the two enantiomers. (R)-ketamine, but not (S)-ketamine, ameliorated the reduced expressions of Tgfb1 and its receptors (Tgfbr1 and Tgfbr2) in the PFC and hippocampus of CSDS susceptible mice. Either pharmacological inhibitors (i.e., RepSox and SB431542) or neutralizing antibody of TGF-β1 blocked the antidepressant effects of (R)-ketamine in CSDS susceptible mice. Moreover, depletion of microglia by the colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX3397 blocked the antidepressant effects of (R)-ketamine in CSDS susceptible mice. Similar to (R)-ketamine, the recombinant TGF-β1 elicited rapid and long-lasting antidepressant effects in animal models of depression. Our data implicate a novel microglial TGF-β1-dependent mechanism underlying the antidepressant effects of (R)-ketamine in rodents with depression-like phenotype. Moreover, TGF-β1 and its receptor agonists would likely constitute a novel rapid-acting and sustained antidepressant in humans.

Ingestion of Lactobacillus intestinalis and Lactobacillus reuteri causes depression- and anhedonia-like phenotypes in antibiotic-treated mice via the vagus nerve

“…Behavioral tests, including the locomotion test, TST, FST, and 1% SPT, were performed as previously reported [ 15 , 17 – 19 , 33 – 37 ].…”

“…The CSDS procedure was performed as previously reported [15,[17][18][19][33][34][35][36][37]. C57BL/6 mice were exposed to a different CD1 aggressor mouse for 10 min per day for 10 consecutive days (days 1-10).…”

Antidepressant Drugs and Physical Activity: A Possible Synergism in the Treatment of Major Depression?

“…Furthermore, the ability of some antidepressant drugs to induce the synthesis and the release of BDNF and TGF-β1 has been demonstrated both in vitro and in vivo studies (Caraci et al, 2010), suggesting that the long time required for BDNF restore could, at least in part, contributes to explain the therapeutic latency (2-4 weeks) of these drugs (Racagni and Popoli, 2010). Recent studies have demonstrated the rapid and long-lasting antidepressant effects of TGF-β1 as well as the key role of TGF-β1 released from microglia in mediating the antidepressant activity of (R)-ketamine (10 mg/kg) in a mouse model of depression (Zhang et al, 2020). (R)ketamine is a novel drug under study for treatment-resistant MDD patients.…”

Can Intraoperative Low-Dose R,S-Ketamine Prevent Depressive Symptoms After Surgery? The First Meta-Analysis of Clinical Trials

“…Variations in patient baseline conditions may also have contributed to the differing results. The antidepressant effect of (R,S)-ketamine is affected by baseline inflammation levels, metabolic pathway activation levels (Ionescu et al, 2014;Zhou et al, 2020), immune status (Zhang et al, 2020), baseline depression levels (Pal et al, 2015;Stoker et al, 2019), baseline functional connectivity of the brain , family drinking history (Pennybaker et al, 2017), gender (Picard et al, 2019), and age. Moreover, (R,S)-ketamine may reduce depression scores by alleviating pain (Riddell et al, 2019;Thompson et al, 2019).…”