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.