Knockdown of the CXCL12/CXCR7 chemokine pathway results in learning deficits and neural progenitor maturation impairment in mice.

In adult brain, the chemokine CXCL12 and its receptors CXCR4 and CXCR7 are expressed in neural progenitor and glial cells. Conditional Cxcl12 or Cxcr4 gene knockout in mice leads to severe alterations in neural progenitor proliferation, migration and differentiation. As adult hippocampal neurogenesis is involved in learning and memory processes, we investigated the long-term effects of reduced expression of CXCL12 or CXCR7 in heterozygous Cxcl12+/- and Cxcr7+/- animals (KD mice) on hippocampal neurogenesis, neuronal differentiation and memory processing. In Cxcl12 KD mice, Cxcr4 mRNA expression was reduced, whereas Cxcr7 was slightly increased. Conversely, in Cxcr7 KD mice, both Cxcr4 and Cxcl12 mRNA levels were decreased. Moreover, Cxcl12 KD animals showed marked behavioral and learning deficits that were associated with impaired neurogenesis in the hippocampus. Conversely, Cxcr7 KD animals showed mild learning deficits with normal neurogenesis, but reduced cell differentiation, measured with doublecortin immunolabeling. These findings suggested that a single Cxcl12 or Cxcr7 allele might not be sufficient to maintain the hippocampal niche functionality throughout life, and that heterozygosity might represent a susceptibility factor for memory dysfunction progression.

Haplotypes of TNFα/ß Genes Associated with Sex-Specific Paranoid Schizophrenic Risk in Tunisian Population.

Several medical research findings have announced a strong association between the biology of cytokines and various brain activities. Since growing evidences suggest the crucial and complex role of the tumor necrosis factor in the CNS, we have hypothesized that functional genetic variants of the LTA and TNFA genes (LTA +252A/G (rs909253) and TNFA -857C/T (rs1799724) and TNFA -238G/A (rs361525)) may be involved in the predisposition to schizophrenia. This research is based on a case-control study. The RFLP-PCR genotyping was conducted on a Tunisian population composed of 208 patients and 208 controls. We found a strong significant overrepresentation of the minor alleles (G, T, and A, respectively) in all patients compared with controls (p = 0.003, OR = 1.55; p = 0.005, OR = 1.78; and p = 0.0001, OR = 1.74, respectively). This correlation was confirmed for male but not for female patients. Interestingly, the frequencies of the minor alleles were significantly more common among patients with paranoid schizophrenia when compared with controls (p = 0.003, OR = 1.75; p = 5 · 10-6, OR = 3.04; and p = 4 · 10-6, OR = 2.35, respectively). This potential association was confirmed by a logistic binary regression analysis only for the development of the paranoid form of schizophrenia (p = 0.001/OR = 2.6; p = 0.0002/OR = 3.2; and p = 0.0004/OR = 3.1, respectively) and remained not significant for the other subtypes. Moreover, our study showed an important association between GCA haplotype and the development of this pathological form (p = 10-4, OR = 3.71). In conclusion, our results proved a significant association between the three polymorphisms and paranoid schizophrenia, at least in the Tunisian population, suggesting a substantially increased risk for paranoid schizophrenia with dominant inheritance of these three minor alleles.

IFNGR2 genetic polymorphism associated with sex-specific paranoid schizophrenia risk.

BACKGROUND: Considering current scientific evidence about the significant role of chronic low grade inflammation in the physiopathology of schizophrenia, it has been hypothesized that changes in pro-inflammatory cytokines such as interferon gamma may have a significant role in the predisposition to schizophrenia. AIM: This study focuses on identifying whether the functional polymorphism of interferon gamma receptor 2 (IFNGR2) is a risk factor for the development of schizophrenia. METHODS: This study was conducted by the RFLP-PCR on a Tunisian population composed of 225 patients with different sub-types of schizophrenia and 166 controls. RESULTS: The IFNGR2 (Q64R) polymorphism analysis showed higher frequencies of minor homozygous genotype (RR) and allele (R) in all patients compared to controls (21.8% vs 10.2%; p = .006, OR = 2.54) and (44% vs 34.9%; p = .01; OR = 1.46), respectively. This correlation was confirmed only for males. This study also noted a significant increase of the mutated homozygous (RR) genotype and (R) allele frequencies of IFNGR2 in paranoid schizophrenics compared to controls (31.4% vs 10.2%; p = .001; OR = 3.34 and 47.2% vs 34.9%; p = .009; OR = 1.66, respectively). This increase remains significant after using binary logistic regression to eliminate confounding factors such as age and sex. Additionally, carriers of RR genotype have significant lower scores on the Scale of Assessment of Positive (SAPS) and negative (SANS) symptoms comparatively to the carrier of the QQ + QR genotypes, suggesting that the R recessive allele carriers could have milder symptoms. CONCLUSION: The IFNGR2Q64R polymorphism is correlated with male sex and paranoid schizophrenia. It is suggested that a chronic neuroinflammation may predispose to the paranoid schizophrenia development in men.

Association of the IFN-γ (+874A/T) Genetic Polymorphism with Paranoid Schizophrenia in Tunisian Population.

Since growing evidence suggests a significant role of chronic low-grade inflammation in the physiopathology of schizophrenia, we have hypothesized that functional genetic variant of the IFN gamma (IFN-γ; +874A/T; rs2430561) gene may be involved in the predisposition to schizophrenia. This research is based on a case-control study which aims to identify whether polymorphism of the IFN-γ gene is a risk factor for the development of schizophrenia. The RFLP-PCR genotyping of the IFN-γ gene was conducted on a Tunisian population composed of 218 patients and 162 controls. The IFN-γ (+874A/T) polymorphism analysis showed higher frequencies of minor homozygous genotype (TT) and allele (T) in all patients compared with controls (11.5 vs. 4.9%; p = 0.03, OR = 2.64 and 30.7 vs. 24.1%, p = 0.04, OR = 1.4, respectively). This correlation was confirmed for male but not for female patients. Also, the T allele was significantly more common among patients with paranoid schizophrenia when compared with controls (25.8 vs. 4.9%, p = 0.0001; OR = 6.7). Using the binary regression analysis to eliminate confounding factors as age and sex, only this last association remained significant (p = 0.03; OR = 1.76, CI = 1.05-2.93). In conclusion, our results showed a significant association between +874A/T polymorphism of IFN-γ and paranoid schizophrenia, suggesting that this single nucleotide polymorphism (SNP) or another at proximity could predispose to paranoid schizophrenia. Since the minor allele of this polymorphism was correlated with an increased expression of their product, our study validates the hypothesis of excessive pro-inflammatory cytokine in the physiopathology of paranoid schizophrenia.

Toxoplasma gondii infection in schizophrenia and associated clinical features.

The belief that latent toxoplasmosis is asymptomatic has been questioned, in particular due to the repeated highlighted link between the Toxoplasma gondii infection and an increased incidence of schizophrenia. However, to understand this relationship, the effect of infection with Toxoplasma gondii on the severity of schizophrenia has been poorly studied. Our work focused on comparing the prevalence of Toxoplasma infection between schizophrenic patients and healthy controls, as well as comparing the clinical features and the demographic characteristics between Toxoplasma-seronegative and Toxoplasma-seropositive patients with schizophrenia. The rate of IgG antibody in the schizophrenia patients was 74.8% compared 53.8% in controls. Patients with schizophrenia had a significantly higher mean of serum IgG antibodies to T. gondii compared to controls. The seropositive male patients had a higher age of disease onset, a higher BPRS score, a greater negative PANSS score and a lower GAF score than the seronegative male patients. These results suggest a higher severity of clinical symptoms in the male patients with schizophrenia. This study provides further evidence to the hypothesis that exposure to Toxoplasma may be a risk factor for schizophrenia. Moreover, toxoplasmosis in men with schizophrenia may lead to more severe negative and cognitive symptoms and a less favorable course of schizophrenia.