Abstract
Dysregulation of the immune system contributes to the pathogenesis of neuropsychiatric disorders including schizophrenia. Here, we demonstrated that toll-like receptor (TLR)-2, a family of pattern-recognition receptors, is involved in the pathogenesis of schizophrenia-like symptoms. Psychotic symptoms such as hyperlocomotion, anxiolytic-like behaviors, prepulse inhibition deficits, social withdrawal, and cognitive impairments were observed in TLR-2 knock-out (KO) mice. Ventricle enlargement, a hallmark of schizophrenia, was also observed in TLR-2 KO mouse brains. Levels of p-Akt and p-GSK-3α/β were markedly higher in the brain of TLR-2 KO than wild-type (WT) mice. Antipsychotic drugs such as haloperidol or clozapine reversed behavioral and biochemical alterations in TLR-2 KO mice. Furthermore, p-Akt and p-GSK-3α/β were decreased by treatment with a TLR-2 ligand, lipoteichoic acid, in WT mice. Thus, our data suggest that the dysregulation of the innate immune system by a TLR-2 deficiency may contribute to the development and/or pathophysiology of schizophrenia-like behaviors via Akt-GSK-3α/β signaling.
Highlights
Dysregulation of the immune system contributes to the pathogenesis of neuropsychiatric disorders including schizophrenia
We found that only toll-like receptor (TLR)-2 KO mice exhibited abnormal and aggressive behavior; whereas these effects were not observed in TLR-3 and 4 KO mice (Supplementary Fig. 1a, b)
TLR-2 KO mice did not show any change in immobility in the forced swimming test (Supplementary Fig. 3), which is used to detect anti-depressant-like activity
Summary
Dysregulation of the immune system contributes to the pathogenesis of neuropsychiatric disorders including schizophrenia. We demonstrated that toll-like receptor (TLR)-2, a family of pattern-recognition receptors, is involved in the pathogenesis of schizophrenia-like symptoms Psychotic symptoms such as hyperlocomotion, anxiolytic-like behaviors, prepulse inhibition deficits, social withdrawal, and cognitive impairments were observed in TLR-2 knock-out (KO) mice. Levels of p-Akt and p-GSK-3a/b were markedly higher in the brain of TLR-2 KO than wild-type (WT) mice Antipsychotic drugs such as haloperidol or clozapine reversed behavioral and biochemical alterations in TLR-2 KO mice. Our data suggest that the dysregulation of the innate immune system by a TLR-2 deficiency may contribute to the development and/or pathophysiology of schizophrenia-like behaviors via Akt-GSK-3a/b signaling. Dysregulation of the immune system, along with genetic and environmental factors, is known to contribute to abnormal neurodevelopment processes, which leads to the pathogenesis of schizophrenia[5]. We showed in this study that the deletion of the TLR-2 gene in mice causes the typical behavioral, histological, and pathophysiological characteristics observed in schizophrenia patients
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