TLR4 Polymorphisms (T399I/D299G) Association with Schizophrenia and Bipolar Disorder in a Tunisian Population.

Immune dysregulation has been widely described in the pathophysiology of schizophrenia (SCZ) and bipolar disorder (BD). Particularly, TLR4-altered activation was proposed as one of the underlying processes of psychosis onset. Since TLR4 activation was altered by T399I and D299G polymorphisms, we hypothesized that those variants could present common genetic factors of SCZ and BD. A total of 293 healthy volunteers and 335 psychotic patients were genotyped using PCR-RFLP. Genotype, allele, and haplotype distribution between controls and patients were evaluated according to clinical parameters. Statistical analyses were adjusted by logistic regression. In dominant model, T399I CT + TT and allele frequency were significantly higher in controls compared to psychotic population (p = 0.004, p = 0.002, respectively), SCZ (p = 0.02, p = 0.01, respectively), and BD (p = 0.03, p = 0.02, respectively). Similarly, D299G AG + GG and allele frequency were significantly higher in controls compared to psychotic population (p = 0.04, p = 0.04, respectively) and SCZ (p = 0.04, p = 0.03, respectively). T399I CT + TT and T allele were overrepresented in controls compared to paranoid subgroup (Padjusted = 0.04, p = 0.04, respectively) and type I BD (p = 0.04). Moreover, T399I and D299G were less prevalent in SCZ late-onset age (p = 0.03, p = 0.02, respectively). TA haplotype was associated with protection from psychoses (p = 0.02) and particularly from schizophrenia (p = 0.04). In conclusion, TLR4 polymorphisms could present a preventive genetic background against psychoses onset in a Tunisian population. While T399I could be associated with protection against SCZ and BD, presenting an overlapping genetic factor between those psychoses, D299G was suggested to be associated with protection only from schizophrenia.

A Preventive Role of RANTES Genetic Variation against Undifferentiated Schizophrenia.

AIM: Due to conflicting data from relevant studies, evidence for chemokine alterations in the pathophysiology of schizophrenia (Scz) remains inconclusive. Thus, we aimed to investigate the impact of rs2107538, rs2280788, and rs2280789 polymorphisms in CCL5 gene, as well as rs333 within CCR5 gene and the development of Scz in a Tunisian cohort. METHODS: We performed a case-control study composed of 200 patients and 200 controls using RFLP-PCR. RESULTS: Among the analyzed polymorphisms, only rs2107538 imparted protection against Scz and more specifically to male sex. This protective effect remained valid for the undifferentiated form. Moreover, this SNP had an impact on patients' symptomatology. When focusing on haplotypes, we noticed that the rs2107538-rs2280788-rs2280789 ACT genetic combination, with only one mutated allele rs2107538A, displayed reduced frequency in both Scz (as a whole group) and undifferentiated subtype. The haplotype distribution profile implies that the A allele at rs2107538 could induce a protective effect by increasing RANTES production. CONCLUSION: Additional independent analyses are required to corroborate these findings and elucidate the functional implications of the discovered preventing genotypes and haplotypes in Scz.

Involvement of CXCL10 rs4256246, CXCR4 rs2228014, CCR2 rs1799864 and CXCL16 rs2277680 in the Predisposition to Schizophrenia.

Chemokine ligands and their receptors have acquired less attention than pro- and anti-inflammatory cytokines in schizophrenia (SCZ). Thus, we aimed to examine the impact of functional polymorphisms of the chemokine genes CXCL10, CXCL16, CXCR4, and CCR2 in the development of SCZ. Using PCR-RFLP, we analyzed the selected polymorphisms in a Tunisian cohort composed of 200 patients with SCZ and 200 healthy controls. Our preliminary data suggest that the minor allele A of CXCL10 rs4256246 is significantly associated with likelihood of SCZ (PAdjusted = 0.00002) and more precisely to paranoid patients with late-onset SCZ (PAdjusted = 0.0007). However, the mutated allele T of CXCR4 rs2228014 showed a significant protective impact against SCZ (PAdjusted = 0.000007) and especially to male sex (PAdjusted = 0.000003). This effect persists among the undifferentiated patients with early-onset SCZ (PAdjusted = 0.002). Following the stratified analyses, CCR2 rs1799864 and CXCL16 rs2277680 were significantly correlated with the clinical symptoms among disorganized patients. As regards haplotype analysis, we noted that GATG haplotype was associated with protection against SCZ (PAdjusted = 0.0087) but the AGCG haplotype was correlated with susceptibility to this disease (PAdjusted = 0.014). Our preliminary results suggested that CXCL10 rs4256246 enhanced susceptibility to SCZ, while CXCR4 rs2228014 seemed to be protective factor. Furthermore, we identified a substantial correlation between CCR2 rs1799864 and CXCL16 rs2277680 with the clinical signs of the disorder. To validate these results and clarify the functional significance of the targeted polymorphisms in SCZ, more independent research is needed.

Association of VEGF-A and KDR polymorphisms with the development of schizophrenia.

AIM: Several approaches indicate different blood flow disturbances in schizophrenia. VEGF-A is widely recognized as one of the key molecules involved in the angiogenesis process through mainly its receptor KDR. The current work was designed to investigate the potential association between three polymorphisms (rs699947; rs833061 and rs3025039) in VEGF-A gene and two SNPs (rs2305948 and rs1870377) within KDR gene and predisposition to schizophrenia among the Tunisian cohort. METHODS: We carried-out a case-control study composed of 200 patients with schizophrenia and 200 healthy subjects using PCR-RFLP. RESULTS: Of all analyzed polymorphisms, only rs833061, rs3025039 and rs1870377) showed a significant risk for schizophrenia (PAdjusted = 0.04, PAdjusted=<0.001, PAdjusted = 0.005 respectively). Following the stratified analysis, rs3025039 was more prevalent among undifferentiated form (PAdjusted=<0.001) and more specifically with male sex (PAdjusted=<0.001). Yet, rs1870377 was correlated with paranoid subtype (PAdjusted = 0.002) and particularly with male sex (PAdjusted = 0.005). We found also that rs699947 is associated to negative symptoms before and after treatment (P = 0.004; P = 0.001 respectively) and rs3025039 had an impact on positive and negative symptoms only after treatment (P = 0.03; P = 0.008 respectively). Haplotype analysis revealed a strong LD between rs833061 and rs3025039 only for controls and undifferentiated patients (P = 0.005). Moreover, the rs699947*C âˆ¼ rs833061*T âˆ¼ rs3025039*T haplotype, with only one mutated allele rs3025039*T, conferred a high risk to schizophrenia (P = 0.016) and, in particular, to undifferentiated and paranoid forms (P = 0.03; P = 0.02 respectively). Among the last-mentioned subgroup, we noticed another overrepresented haplotype (rs699947*A âˆ¼ rs833061*T âˆ¼ rs3025039*T; P = 0.01). Furthermore, the rs2305948*G âˆ¼ rs1870377*T haplotype carrying the minor allele rs1870377*T displayed increased frequencies in the whole group of patients and particularly among paranoid subtype (P = 0.013; P=<0.001 respectively). CONCLUSION: Our results show that all SNPs associated with the development or the severity of schizophrenia, were subsequently correlated with a decrease in the VEGF-A levels or influence KDR binding affinity. These data need to be strengthened by further independent analyses.

MK-801-induced behavioral and dopaminergic responses in the shell part of the nucleus accumbens in adult male rats are disrupted after neonatal blockade of the ventral subiculum.

The present study was conducted in the context of animal modeling of schizophrenia. It investigated in adult male rats, after transient neonatal blockade of the ventral subiculum (VSub), the impact of a very specific non-competitive antagonist of NMDA receptors (MK-801) on locomotor activity and dopaminergic (DAergic) responses in the dorsomedial shell part of the nucleus accumbens (Nacc), a striatal subregion described as the common target region for antipsychotics. The functional neonatal inactivation of the VSub was achieved by local microinjection of tetrodotoxin (TTX) at postnatal day 8 (PND8). Control pups were microinjected with the solvent phosphate buffered saline (PBS). Locomotor responses and DAergic variations in the dorsomedial shell part of the Nacc were measured simultaneously using in vivo voltammetry in awake, freely moving male animals after sc administration of MK-801. The following results were obtained: 1) a dose-dependent increase in locomotor activity in PBS and TTX animals, greater in TTX rats/PBS rats; and 2) divergent DAergic responses for PBS and TTX animals. A decrease in DA levels with a return to around basal values was observed in PBS animals. An increase in DA levels was obtained in TTX animals. The present data suggest that neonatal blockade of the VSub results in disruption in NMDA glutamatergic transmission, causing a disturbance in DA release in the dorsomedial shell in adults male rats. In the context of animal modeling of schizophrenia using the same approach it would be interesting to investigate possible changes in postsynaptic NMDA receptors-related proteins in the dorsomedial shell region in the Nacc.

Association between TLR2 polymorphisms (- 196-174 Ins/Del, R677W, R753Q, and P631H) and schizophrenia in a Tunisian population.

Since immune dysregulation has been well studied in schizophrenia pathophysiology, recent studies showed a potent role of TLR2 in neuroinflammation process underlying schizophrenia pathogenesis. However, the genetic predisposition is still unclear. Thus, we hypothesized that TLR2 polymorphisms - 196-174 Ins/Del (rs111200466), R753Q (rs5743708), R677W (rs121917864), and P631H (rs5743704) could be involved in schizophrenia predisposition. A case-control study was performed on a Tunisian population composed of 250 healthy controls and 250 patients genotyped by PCR-RFLP. Genotype and allele distribution were evaluated with sex, schizophrenia subtypes, and other clinical features. We also assessed a haplotype analysis for TLR2 polymorphisms with schizophrenia. Our results showed higher ins/del genotype frequency in healthy women compared to patients (p = 0.006; OR = 0.2). In the other hand, logistic regression showed higher ins/del genotype frequency in controls compared to paranoid patients (p = 0.05; OR = 0.48, adjusted). Frequencies of CT and T allele of R677W were significantly higher in patients compared to controls (p < 10-4, OR = 10.39; p < 10-4, OR = 4, adjusted, respectively). R753Q polymorphism was exclusively detected in patients (GA + AA = 2.5%) particularly in men with disorganized subtype. P631H did not show any association with schizophrenia. Finally, haplotype analysis showed that InsGTC and delGTC were associated with higher risk of schizophrenia (p = 0.0001, OR = 8.58; p = 0.04, OR = 5.01, respectively). In the Tunisian population, our results suggested that TLR2 R677W could be associated with susceptibility for schizophrenia, while - 196-174 Ins/Del suggested a trend of protection in women. Otherwise, R753Q could have an effect on schizophrenia especially for disorganized subgroup.

Postnatal functional inactivation of the ventral subiculum enhances dopaminergic responses in the core part of the nucleus accumbens following ketamine injection in adult rats.

For almost two decades schizophrenia has been considered to be a functional disconnection disorder. This functional disconnectivity between several brain regions could have a neurodevelopmental origin. Various approaches suggest the ventral subiculum (SUB) is a particular target region for neurodevelopemental disturbances in schizophrenia. It is also commonly acknowledged that there is a striatal dopaminergic (DA) dysregulation in schizophrenia which may depend on a subiculo-striatal disconnection involving glutamatergic NMDA receptors. The present study was designed to investigate, in adult rats, the effects of the non-competitive NMDA receptor antagonist ketamine on DA responses in the ventral striatum, or, more specifically, the core part of the nucleus accumbens (Nacc), following postnatal functional inactivation of the SUB. Functional inactivation of the left SUB was carried out by local tetrodotoxin (TTX) microinjection at postnatal day 8 (PND8), i.e. at a critical point in the neurodevelopmental period. DA variations were recorded using in vivo voltammetry in freely moving adult rats (11 weeks). Locomotor activity was recorded simultaneously with the extracellular levels of DA in the core part of the Nacc. Data obtained during the present study showed that after administration of ketamine, the two indexes were higher in TTX animals than PBS animals, the suggestion being that animals microinjected with TTX in the left SUB at PND8 present greater reactivity to ketamine than animals microinjected with PBS. These findings could provide new information regarding the involvement of NMDA glutamatergic receptors in the core part of the Nacc in the pathophysiology of schizophrenia.

Inteurleukin-8 gene variations and the susceptibility to schizophrenia.

The relevance of Interleukin-8 (IL-8) cytokine alteration in the peripheral and central system has been widely shown in psychosis while variation in the IL-8 gene remains largely unexplored and to the best of our knowledge, IL-8 polymorphisms have never been specifically targeted in Schizophrenia (Scz). Thus, we set out to search a potential correlation between rs4073, rs2227306 and rs1126647 polymorphisms in IL-8 gene and the development of Scz in a sample of the Tunisian population in a candidate gene approach. Targeted polymorphisms were analysed in 206 patients and 195 controls using PCR-RFLP method. Among all analysed polymorphisms, only rs1126647 showed a significant risk for Scz. After stratification analysis, we noted a significant association of TT genotype and T allele at rs1126647 with paranoid form, and more specifically with female sex. We find that the rare haplotypes at rs4073-rs2227306-rs1126647 of TTT, ACT and TCT, each containing the risk allele rs1126647T, were associated with increased risk for paranoid Scz while only the TCT combination constituted a risk factor for Scz more generally. Our findings support that IL-8 gene may be involved in susceptibility to Scz but this still preliminary and needs to be strengthened by further independent analyses.

Protective Effect of the MCP-1 Gene Haplotype against Schizophrenia.

While cytokines and their genetic variants have been intensively studied in schizophrenia, little attention has been focused on chemokines in the last years. The monocyte chemoattractant protein 1 (MCP-1) is known to attract peripheral monocytes to the brain during an inflammatory reaction and to affect the T helper (Th) cell development by stimulating Th2 polarization. Owing to the neuroinflammation in schizophrenia and the variable level of MCP-1 in these patients' sera, we proposed to analyze the impact of functional genetic variants of the MCP-1 gene (MCP-1-2518A/G (rs1024611), MCP-1-362G/C (rs2857656), and MCP-1 int1del554-567 (rs3917887)) in schizophrenic patients. We conducted a case-control study on a Tunisian population composed of 200 patients and 200 controls using RFLP-PCR. Our results indicated that the minor alleles (-2518G and Del554-567) were significantly more prevalent in controls than in patients (P=0.001/adjusted OR = 0.42, P=0.04/adjusted OR = 0.64), whereas, for -362C minor allele, increased risk of schizophrenia was revealed (P=0.001, adjusted OR = 2.38). In conclusion, we have identified the haplotype combination -2581G/-362G/int1del554-567 that could mediate protection against schizophrenia (P=0.0038, OR = 0.19) and the effect could result more strongly from the MCP-1 -2582G with -362G variants, whereas the effect of int1del554-567 may in part be explained by its LD with -362.