Mice lacking interleukin-18 gene display behavioral changes in animal models of psychiatric disorders: Possible involvement of immunological mechanisms

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

  • S F Lisboa, Department of Pharmacology, Medical School of Ribeirão Preto, University of São Paulo (FMRP/USP), Brazil; Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), University of São Paulo, Brazil. Electronic address: sabrinalisboa@usp.br.
  • ,
  • A C Issy, Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), University of São Paulo, Brazil; Dental School of Ribeirão Preto, University of São Paulo (FOR/USP), Brazil.
  • ,
  • C Biojone, Neuroscience Center, University of Helsinki, Finland. Electronic address: plinio@gmx.com.
  • ,
  • K Montezuma, Department of Pharmacology, Medical School of Ribeirão Preto, University of São Paulo (FMRP/USP), Brazil; Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), University of São Paulo, Brazil.
  • ,
  • V Fattori, Department of General Pathology, Biological Sciences Center, Londrina State University (CCB/UEL), Brazil.
  • ,
  • E A Del-Bel, Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), University of São Paulo, Brazil; Dental School of Ribeirão Preto, University of São Paulo (FOR/USP), Brazil.
  • ,
  • F S Guimarães, Department of Pharmacology, Medical School of Ribeirão Preto, University of São Paulo (FMRP/USP), Brazil; Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), University of São Paulo, Brazil.
  • ,
  • F Q Cunha, Department of Pharmacology, Medical School of Ribeirão Preto, University of São Paulo (FMRP/USP), Brazil.
  • ,
  • W A Verri, Department of General Pathology, Biological Sciences Center, Londrina State University (CCB/UEL), Brazil.
  • ,
  • S R L Joca

Preclinical and clinical evidence suggests pro-inflammatory cytokines might play an important role in the neurobiology of schizophrenia and stress-related psychiatric disorders. Interleukin-18 (IL-18) is a member of the IL-1 family of cytokines and it is widely expressed in brain regions involved in emotional regulation. Since IL-18 involvement in the neurobiology of mental illnesses, including schizophrenia, remains unknown, this work aimed at investigating the behavior of IL-18 null mice (KO) in different preclinical models: 1. the prepulse inhibition test (PPI), which provides an operational measure of sensorimotor gating and schizophrenic-like phenotypes; 2. amphetamine-induced hyperlocomotion, a model predictive of antipsychotic activity; 3. resident-intruder test, a model predictive of aggressive behavior. Furthermore, the animals were submitted to models used to assess depressive- and anxiety-like behavior. IL-18KO mice showed impaired baseline PPI response, which was attenuated by d-amphetamine at a dose that did not modify PPI response in wild-type (WT) mice, suggesting a hypodopaminergic prefrontal cortex function in those mice. d-Amphetamine, however, induced hyperlocomotion in IL-18KO mice compared to their WT counterparts, suggesting hyperdopaminergic activity in the midbrain. Moreover, IL-18KO mice presented increased basal levels of IL-1β levels in the hippocampus and TNF-α in the prefrontal cortex, suggesting an overcompensation of IL-18 absence by increased levels of other proinflammatory cytokines. Although no alteration was observed in the forced swimming or in the elevated plus maze tests in naïve IL-18KO mice, these mice presented anxiogenic-like behavior after exposure to repeated forced swimming stress. In conclusion, deletion of the IL-18 gene resembled features similar to symptoms observed in schizophrenia (positive and cognitive symptoms, aggressive behavior), in addition to increased susceptibility to stress. The IL-18KO model, therefore, could provide new insights into how changes in brain immunological homeostasis induce behavioral changes related to psychiatric disorders, such as schizophrenia.

Original languageEnglish
JournalJournal of Neuroimmunology
Volume314
Pages (from-to)58-66
Number of pages9
ISSN0165-5728
DOIs
Publication statusPublished - 15 Jan 2018

    Research areas

  • Journal Article

See relations at Aarhus University Citationformats

ID: 120578866