Ketamine may exert antidepressant effects via suppressing NLRP3 inflammasome to upregulate AMPA receptors

Abstract

Recent studies have indicated that sub-anesthetic dose of ketamine exerts rapid antidepressant effects. Upregulation of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors contributes to rapid antidepressant effects of ketamine. A recent study indicated that the increasing expression of AMPARs is related to the inhibition of NLRP3 inflammasome. Thus, we postulated that NLRP3 inflammasome might play an important role in ketamine's antidepressant effects. We found that sub-anesthesia dose of ketamine (10 ml/kg) ameliorated LPS-induced depressive-like behaviors, including decreased sucrose preference and increased immobility times in the tail suspension test. Ketamine also abrogated LPS-induced over expression of IL-1β and NLRP3 and reversed LPS-induced down-regulation of AMPA GluA1 subunits in hippocampi. The selective NLRP3 inflammasome inhibitor Ac-YVAD-CMK exhibited similar anti-inflammatory and antidepressant effects like ketamine. Combination of ketamine and Ac-YVAD-CMK showed no enhanced anti-inflammatory and antidepressant effects than ketamine or Ac-YVAD-CMK administration alone. These results indicated that the NLRP3 inflammasome might be an important mediator, through which ketamine could regulate AMPA receptors to exert rapid antidepressant effects.

Keywords: AMPA; Antidepressant; Ketamine; LPS; NLRP3.