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

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Lisboa , S F , Issy , A C , Biojone , C , Montezuma , K , Fattori , V , Del-Bel , E A , Guimaraes , F S , Cunha , F Q , Verri , W A & Joca , S R L 2018 , ' Mice lacking interleukin-18 gene display behavioral changes in animal models of psychiatric disorders : Possible involvement of immunological mechanisms ' , Journal of Neuroimmunology , vol. 314 , pp. 58-66 . https://doi.org/10.1016/j.jneuroim.2017.11.008

Title: Mice lacking interleukin-18 gene display behavioral changes in animal models of psychiatric disorders : Possible involvement of immunological mechanisms
Author: Lisboa, S. F.; Issy, A. C.; Biojone, C.; Montezuma, K.; Fattori, V.; Del-Bel, E. A.; Guimaraes, F. S.; Cunha, F. Q.; Verri, W. A.; Joca, S. R. L.
Other contributor: University of Helsinki, Neuroscience Center

Date: 2018-01-15
Language: eng
Number of pages: 9
Belongs to series: Journal of Neuroimmunology
ISSN: 0165-5728
DOI: https://doi.org/10.1016/j.jneuroim.2017.11.008
URI: http://hdl.handle.net/10138/299472
Abstract: 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-1 beta 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.
Subject: CENTRAL-NERVOUS-SYSTEM
NITRIC-OXIDE SYNTHASE
NECROSIS-FACTOR-ALPHA
PREPULSE INHIBITION
PROINFLAMMATORY CYTOKINE
MICROGLIAL ACTIVATION
MAJOR DEPRESSION
TNF-ALPHA
CHRONIC-SCHIZOPHRENIA
COGNITIVE IMPAIRMENT
3112 Neurosciences
3124 Neurology and psychiatry
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