PMID- 29195684 OWN - NLM STAT- MEDLINE DCOM- 20190705 LR - 20190705 IS - 1872-8421 (Electronic) IS - 0165-5728 (Linking) VI - 314 DP - 2018 Jan 15 TI - Mice lacking interleukin-18 gene display behavioral changes in animal models of psychiatric disorders: Possible involvement of immunological mechanisms. PG - 58-66 LID - S0165-5728(17)30278-3 [pii] LID - 10.1016/j.jneuroim.2017.11.008 [doi] AB - 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-1beta levels in the hippocampus and TNF-alpha 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 naive 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. CI - Copyright (c) 2017 Elsevier B.V. All rights reserved. FAU - Lisboa, S F AU - Lisboa SF AD - Department of Pharmacology, Medical School of Ribeirao Preto, University of Sao Paulo (FMRP/USP), Brazil; Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), University of Sao Paulo, Brazil. Electronic address: sabrinalisboa@usp.br. FAU - Issy, A C AU - Issy AC AD - Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), University of Sao Paulo, Brazil; Dental School of Ribeirao Preto, University of Sao Paulo (FOR/USP), Brazil. FAU - Biojone, C AU - Biojone C AD - Neuroscience Center, University of Helsinki, Finland. FAU - Montezuma, K AU - Montezuma K AD - Department of Pharmacology, Medical School of Ribeirao Preto, University of Sao Paulo (FMRP/USP), Brazil; Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), University of Sao Paulo, Brazil. FAU - Fattori, V AU - Fattori V AD - Department of General Pathology, Biological Sciences Center, Londrina State University (CCB/UEL), Brazil. FAU - Del-Bel, E A AU - Del-Bel EA AD - Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), University of Sao Paulo, Brazil; Dental School of Ribeirao Preto, University of Sao Paulo (FOR/USP), Brazil. FAU - Guimaraes, F S AU - Guimaraes FS AD - Department of Pharmacology, Medical School of Ribeirao Preto, University of Sao Paulo (FMRP/USP), Brazil; Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), University of Sao Paulo, Brazil. FAU - Cunha, F Q AU - Cunha FQ AD - Department of Pharmacology, Medical School of Ribeirao Preto, University of Sao Paulo (FMRP/USP), Brazil. FAU - Verri, W A AU - Verri WA AD - Department of General Pathology, Biological Sciences Center, Londrina State University (CCB/UEL), Brazil. FAU - Joca, S R L AU - Joca SRL AD - Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), University of Sao Paulo, Brazil; Department of Physics and Chemistry, School of Pharmaceutical Sciences of Ribeirao Preto (FCFRP/USP), University of Sao Paulo, Brazil; Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Denmark. Electronic address: samia@usp.br. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20171110 PL - Netherlands TA - J Neuroimmunol JT - Journal of neuroimmunology JID - 8109498 RN - 0 (Cytokines) RN - 0 (Interleukin-18) SB - IM MH - Animals MH - Behavior, Animal/physiology MH - Brain/*immunology MH - Cytokines/biosynthesis/immunology MH - Disease Models, Animal MH - Interleukin-18/*deficiency/*immunology MH - Male MH - Mental Disorders MH - Mice MH - Mice, Inbred BALB C MH - Mice, Knockout MH - Schizophrenia/genetics/*immunology EDAT- 2017/12/03 06:00 MHDA- 2019/07/06 06:00 CRDT- 2017/12/03 06:00 PHST- 2017/06/23 00:00 [received] PHST- 2017/10/22 00:00 [revised] PHST- 2017/11/09 00:00 [accepted] PHST- 2017/12/03 06:00 [pubmed] PHST- 2019/07/06 06:00 [medline] PHST- 2017/12/03 06:00 [entrez] AID - S0165-5728(17)30278-3 [pii] AID - 10.1016/j.jneuroim.2017.11.008 [doi] PST - ppublish SO - J Neuroimmunol. 2018 Jan 15;314:58-66. doi: 10.1016/j.jneuroim.2017.11.008. Epub 2017 Nov 10.