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

Gil-Pisa I, Cebrián C, Ortega JE, Meana JJ, Sulzer D - J Neuroinflammation (2014)

Bottom Line: 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.Together, these data suggest a possible role for an immune imbalance in this disorder.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Neurology, Columbia University Medical Center, 710 W, 168th Street, New York, NY 10032, USA. itziar.gil@ehu.es.

ABSTRACT

Background: An 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.

Methods: Cytokines 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.

Results: Each 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.

Conclusions: The 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.

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Immunodensities of (a) CD11b, (b) GFAP and (c) NF-κB (p65) proteins with representative immunoblots in striatum from Munc18-OE (n = 5) and wild-type (n = 5) mice. Bar graphs are ratios of optical densities of our proteins of interest to β-actin (42 kDa band), expressed as immunoreactivity in percentage of mean value of the WT group (100%). No differences were detected between groups for any of the analyzed proteins. Right panels are representative immunoblots for target proteins and β-actin which included Munc18-OE (OE) and wild-type (WT) mice samples. The molecular masses were estimated from referenced standards.
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Figure 4: Immunodensities of (a) CD11b, (b) GFAP and (c) NF-κB (p65) proteins with representative immunoblots in striatum from Munc18-OE (n = 5) and wild-type (n = 5) mice. Bar graphs are ratios of optical densities of our proteins of interest to β-actin (42 kDa band), expressed as immunoreactivity in percentage of mean value of the WT group (100%). No differences were detected between groups for any of the analyzed proteins. Right panels are representative immunoblots for target proteins and β-actin which included Munc18-OE (OE) and wild-type (WT) mice samples. The molecular masses were estimated from referenced standards.

Mentions: In the cortical samples, we observed lower CD11b expression (Figure 3a) in Munc18-OE mice than WT mice (t = 3.01, P <0.05), whereas no differences were detected in the levels of GFAP between both groups (Figure 3b). Although no statistically significant changes were obtained in the NF-κB transcription factor p65 subunit between both groups of mice, a trend of lower levels in Munc18-OE mice was observed (Figure 3c).None of these inflammatory parameters protein levels differed in the striatum of Munc18-OE from those quantified in WT mice (Figure 4).


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

Gil-Pisa I, Cebrián C, Ortega JE, Meana JJ, Sulzer D - J Neuroinflammation (2014)

Immunodensities of (a) CD11b, (b) GFAP and (c) NF-κB (p65) proteins with representative immunoblots in striatum from Munc18-OE (n = 5) and wild-type (n = 5) mice. Bar graphs are ratios of optical densities of our proteins of interest to β-actin (42 kDa band), expressed as immunoreactivity in percentage of mean value of the WT group (100%). No differences were detected between groups for any of the analyzed proteins. Right panels are representative immunoblots for target proteins and β-actin which included Munc18-OE (OE) and wild-type (WT) mice samples. The molecular masses were estimated from referenced standards.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4128549&req=5

Figure 4: Immunodensities of (a) CD11b, (b) GFAP and (c) NF-κB (p65) proteins with representative immunoblots in striatum from Munc18-OE (n = 5) and wild-type (n = 5) mice. Bar graphs are ratios of optical densities of our proteins of interest to β-actin (42 kDa band), expressed as immunoreactivity in percentage of mean value of the WT group (100%). No differences were detected between groups for any of the analyzed proteins. Right panels are representative immunoblots for target proteins and β-actin which included Munc18-OE (OE) and wild-type (WT) mice samples. The molecular masses were estimated from referenced standards.
Mentions: In the cortical samples, we observed lower CD11b expression (Figure 3a) in Munc18-OE mice than WT mice (t = 3.01, P <0.05), whereas no differences were detected in the levels of GFAP between both groups (Figure 3b). Although no statistically significant changes were obtained in the NF-κB transcription factor p65 subunit between both groups of mice, a trend of lower levels in Munc18-OE mice was observed (Figure 3c).None of these inflammatory parameters protein levels differed in the striatum of Munc18-OE from those quantified in WT mice (Figure 4).

Bottom Line: 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.Together, these data suggest a possible role for an immune imbalance in this disorder.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Neurology, Columbia University Medical Center, 710 W, 168th Street, New York, NY 10032, USA. itziar.gil@ehu.es.

ABSTRACT

Background: An 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.

Methods: Cytokines 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.

Results: Each 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.

Conclusions: The 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.

Show MeSH
Related in: MedlinePlus