NLRP3 deficiency-induced hippocampal dysfunction and anxiety-like behavior in mice

Brain Res. 2021 Feb 1:1752:147220. doi: 10.1016/j.brainres.2020.147220. Epub 2020 Dec 23.


Neuroinflammation has been classified as a trigger of behavioral alterations and cognitive impairments in many neurological conditions, including Alzheimer's disease, major depression, anxiety and others. Regardless of the cause of neuroinflammation, key molecules, which sense neuropathological conditions, are intracellular multiprotein signaling inflammasomes. Increasing evidence shows that the inflammatory response, mediated by activated nucleotide-binding oligomerization domain-, leucine-rich repeat- and pyrin domain-containing 3 (NLRP3) inflammasomes, is associated with the onset and progression of a wide range of diseases of the CNS. However, whether the NLRP3 inflammasome in the CNS is involved in the learning, development of anxiety and adult neurogenesis remains elusive. Therefore, the present study was designed to assess NLRP3 inflammasome contribution in anxiety and reveal its potential involvement in the experimental acquisition of fear responses and hippocampal neurogenesis. Behavioral, immunohistochemical and electrophysiological alterations were measured to evaluate role of neuroinflammation in the limbic system of mice. In this study, we describe interrelated neurophysiological mechanisms, which culminate in absence of NLRP3 inflammasome in young 4 months mice. These include the following: anxious behavior and deterioration in learning and memory of fear conditioning; impairment of adult neurogenesis; reduction and altered morphology of astrocytes in the brain; hyperexcitability in basolateral amygdala (BLA); impaired activation in axons of pyramidal cells of CA1 hippocampal zone in NLRP3 KO mice particularly via the Schaffer collateral pathway; and impaired synaptic transduction in pyramidal cells mediated by an embarrassment of neurotransmitter release from presynaptic site in CA3 hippocampal zone. The present study has demonstrated the novel findings that basal level of NLRP3 inflammasome in the brain of young mice is required for conditioning-induced plasticity in the ventral hippocampus and the basolateral amygdala. The deletion of NLRP3 impair synaptic transduction and caused anxiety-like behavior and labored fear learning, suggesting that low grade inflammation, mediated by NLRP3 expression, play a key role in memory consolidation.

Keywords: Anxiety; Astrocyte; Fear conditioning; NLRP3 inflammasome; Neurogenesis; Neuroinflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anxiety / physiopathology*
  • Encephalitis / physiopathology*
  • Hippocampus / physiopathology*
  • Inflammasomes / physiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
  • NLR Family, Pyrin Domain-Containing 3 Protein / physiology*
  • Neuroglia / metabolism
  • Neurons / metabolism


  • Inflammasomes
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse