Cytokine pathway disruption in a mouse model of schizophrenia induced by Munc18-1a overexpression in the brain

Abstract

BackgroundAn accumulating body of evidence points to the significance of neuroinflammation and immunogenetics in schizophrenia, and an imbalance of cytokines in the central nervous system (CNS) has been suggested to be associated with the disorder. Munc18-overexpressing mice (Munc18-OE) have provided a model for the study of the alterations that may underlie the symptoms of subjects with schizophrenia. The aim of the present study was to elucidate the involvement of neuroinflammation and cytokine imbalance in this model.MethodsCytokines were evaluated in the cortex and the striatum of Munc18-OE and wild-type (WT) mice by enzyme-linked immunosorbent assay (ELISA). Protein levels of specific microglia and macrophage, astrocytic and neuroinflammation markers were quantified by western blot in the cortex and the striatum of Munc18-OE and WT mice.ResultsEach cytokine evaluated (Interferon-gamma (IFN-γ), Tumor Necrosis Factor-alpha (TNF-α), Interleukin-2 (IL-2) and CCL2 chemokine) was present at higher levels in the striatum of Munc18-OE mice than WT. Cortical TNF-α and IL-2 levels were significantly lower in Munc18-OE mice than WT mice. The microglia and macrophage marker CD11b was lower in the cortexes of Munc18-OE mice than WT, but no differences were observed in the striatum. Glial Fibrillary Acidic Protein (GFAP) and Nuclear Factor-kappaB (NF-κB)p65 levels were not different between the groups. Interleukin-1beta (IL-1β) and IL-6 levels were beneath detection limits.ConclusionsThe disrupted levels of cytokines detected in the brain of Munc18-OE mice was found to be similar to clinical reports and endorses study of this type for analysis of this aspect of the disorder. The lower CD11b expression in the cortex but not in the striatum of the Munc18-OE mice may reflect differences in physiological activity. The cytokine expression pattern observed in Munc18-OE mice is similar to a previously published model of schizophrenia caused by maternal immune activation. Together, these data suggest a possible role for an immune imbalance in this disorder.

Astroglial correlates of neuropsychiatric disease: From astrocytopathy to astrogliosis

“…Although these studies suggest a correlation between possible astrogliosis and the presence of schizophrenic symptoms, numerous other preclinical studies have reported no changes in GFAP expression associated with schizophrenia. For example, mouse models of schizophrenia with overexpression of Munc-18a or mutant DISC-1 show no changes in cortical or hippocampal GFAP expression, respectively [149, 150].…”

Immune synaptopathies: how maternal immune activation impacts synaptic function during development

“…The same was described for the overexpression of Munc18‐1a , a presynaptic protein that mainly regulates synaptic vesicle fusion by interacting with the SNARE complex (Fig 2 ) and whose mutations or abnormal expression occurs in various neurological diseases, including epileptic encephalopathy, ASD, and schizophrenia. Munc18‐1a overexpression results in immune and inflammatory dysfunctions in distinct brain regions (Gil‐Pisa et al , 2014 ). Interferon‐gamma (IFN‐γ), TNF‐α, IL‐2, and CCL2 chemokine are present at higher levels in the striatum of Munc18‐1a‐overexpressing mice than in WT, while TNF‐α and IL‐2 levels, together with the microglial marker CD11b, are significantly lower in the neocortex.…”

Equivalent change enrichment analysis: assessing equivalent and inverse change in biological pathways between diverse experiments

“…For example, Shen, et al studied whether similar pathways were perturbed in smokers vs. users of e-cigarettes [9]. Gil-Pisa, et al justified the use of their mouse model of schizophrenia based on its similarity in cytokine expression to a previously published model [10]. Martins-de-Souza, et al showed that responders showed the same pathways were affected, but in opposite directions, in poor vs. good responders to anti-psychotics [11].…”