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

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-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.

Repeated social defeat-induced neuroinflammation, anxiety-like behavior and resistance to fear extinction were attenuated by the cannabinoid receptor agonist WIN55,212-2

“…Behavior was determined using the open field and elevated plus maze (EPM) paradigms as reported [13,28] and described in Supplementary Methods. For the open field test, mice were placed in the corner of the test apparatus and activity was recorded and analyzed using an automated system (VersaMax).…”

Affective and cognitive behavior is not altered by chronic constriction injury in B7-H1 deficient and wildtype mice

“…In a recent study IL-18 deficient mice showed a schizophrenia-like phenotype (higher impulsivity and aggression), but no relevant behavioral changes in tests for anxiety- (EPM) or depression-like behavior (FST) [43]. Also, tumor necrosis factor ko mice did not show alterations in anxiety- and depression-related behavior in the EPM and FST [44].…”

Impaired function of aorta and perivascular adipose tissue in IL-18-deficient mice

“…For example, IL-18KO mice have been shown to become obese and to present with hepatosteatosis, probably because of impaired metabolism of glucose/fatty acids (41,42,64). In addition, IL-18KO mice display altered behaviors that may be related to impaired neurons and damaged mitochondria (34,63). Furthermore, we have previously shown dysfunctions of the heart in IL-18KO mice, probably related to impaired mitochondrial functions (33).…”