The role of selected postsynaptic scaffolding proteins at glutamatergic synapses in autism-related animal models.

Pathological changes in synapse formation, plasticity, and development are caused by altered trafficking and assembly of postsynaptic scaffolding proteins at sites of glutamatergic and gamma-aminobutyric acid (GABA)ergic synapses, suggesting their involvement in the etiology of neurodevelopmental disorders, including autism. Several autism-related mouse models have been developed in recent years for studying molecular, cellular, and behavioural defects in order to understand the etiology of autism and test the potential treatment strategies. In this review, we explain the role of alterations in selected postsynaptic scaffolding proteins in relevant transgene autism-like mouse models. We also provide a summary of selected animal models by paying special attention to interactions between guanylate kinases or membrane-associated guanylate kinases (MAGUKs), as well as other synapse protein components which form functional synaptic networks. The study of early developmental stages of autism-relevant animal models can help us understand the origin and development of diverse autistic symptomatology.

Deoxyribonuclease partially ameliorates thioacetamide-induced hepatorenal injury.

Several recent studies have shown that liver injury is associated with the release of DNA from hepatocytes. This DNA stimulates innate immunity and induces sterile inflammation, exacerbating liver damage. Similar mechanisms have been described for acute renal injury. Deoxyribonuclease degrades cell-free DNA and can potentially prevent some of the induced tissue damage. This study analyzed the effects of thioacetamide-induced hepatorenal injury on plasma DNA in rats. Plasma DNA of both nuclear and mitochondrial origin was higher in thioacetamide-treated animals. Administration of deoxyribonuclease resulted in a mild, nonsignificant decrease in total plasma DNA and plasma DNA of mitochondrial origin but not of nuclear origin. This was accompanied by a decrease in bilirubin, creatinine, and blood urea nitrogen as markers of renal function. In conclusion, the study confirmed the hepatotoxic and nephrotoxic effect of thioacetamide. The associated increase in cell-free DNA seems to be involved in hepatorenal pathogenesis because treatment with deoxyribonuclease resulted in a partial prevention of hepatorenal injury. Further experiments will focus on the effects of long-term treatment with deoxyribonuclease in other clinically more relevant models. Clinical studies should test endogenous deoxyribonuclease activity as a potential risk determinant for kidney or liver failure.NEW & NOTEWORTHY Thioacetamide-induced hepatorenal injury resulted in higher plasma cell-free DNA. Deoxyribonuclease decreased average cell-free DNA of mitochondrial origin but not nuclear origin. Deoxyribonuclease partially prevented hepatorenal injury in rats.

Long-Term Cola Intake Does Not Cause Evident Pathological Alterations in the Femoral Bone Microstructure: An Animal Study in Adult Mice.

Short-term animal experiments and association studies in humans have shown that cola intake may have a detrimental impact on bone mineral density (BMD); however, other bone parameters have not been investigated. This study examined the effects of long-term cola consumption on the femoral bone microstructure using adult mice (n = 32) as an animal model, which were divided into water and cola groups depending on whether they received water or cola along with a standard rodent diet for 6 months. Micro-computed tomography revealed that cola intake did not significantly affect all measured parameters characterizing trabecular bone mass and microarchitecture, as well as cortical microarchitecture and geometry in both sexes, although a slight deterioration of these parameters was noted. Cola consumption also resulted in a slightly, statistically insignificant worsening of bone mechanical properties. In contrast to female mice, males receiving cola had a lower area of primary osteons' vascular canals. Nevertheless, long-term cola intake did not cause evident pathological alterations in the femur of adult mice, possibly due to a balanced diet and no restriction of physical activity. Therefore, the adverse effects of cola consumption on BMD, the only bone parameter studied so far, may be caused by other risk and lifestyle factors.

Abnormal neuronal morphology and altered synaptic proteins are restored by oxytocin in autism-related SHANK3 deficient model.

Oxytocin has been suggested as a potential therapeutic agent in autism and other neuropsychiatric conditions. Although, the link between the deficit in "SH3 domain and ankyrin repeat containing protein 3" (SHANK3) and autism spectrum disorders is highly studied topic, developmental mechanisms are still poorly understood. In this study, we clearly confirm that SHANK3 deficiency is accompanied with abnormalities in neurite number and length, which are reversed by oxytocin treatment (1 µM, 48h) in primary hippocampal neurons. Transient silencing for the SHANK3 gene (siSHANK3) in neuron-like cell line (SH-SY5Y) revealed a significant decrease in the expression levels of Neurexins 1α, 1ß, 2α and 2ß. Oxytocin treatment compensated reduced levels of Synapsin I, PSD95 and Neuroligin 3 in siSHANK3 cells suggesting a marked potential of oxytocin to ameliorate defects present in conditions of SHANK3 deficiency. Further analysis of hippocampal tissue revealed that oxytocin application (0.1 µg/µl, s.c. at P2 and P3 day) affects levels of synaptic proteins and GTPases in both WT and SHANK3 deficient mice on day P5. Oxytocin stimulated the mRNA expression of RhoB and Rac1 in both WT and SHANK3 deficient mice. Our data suggest that autism relevant synaptic pathologies could be reversed by oxytocin treatment.

Beneficial effect of sugar-sweetened beverages on the risk of urinary tract infections.

Urinary tract infections (UTI) are among the most common bacterial infections. Drinking more liquids increases the frequency of urination and it is recommended as part of the prevention and/or management of UTI. The intake of sugar-sweetened beverages (SSB) is associated with obesity, diabetes and metabolic syndrome. However, cola and other SSB increase liquid intake and diuresis and could, thus, affect the risk of UTI and its complications. We hypothesize that intake of cola has a protective effect on UTI and pyelonephritis. Using an animal model of UTI, we have confirmed that dehydration with minimal urine output leads to higher bacterial counts in the kidneys in comparison to control mice (p = 0.01). The intake of SSB increased liquid intake and thus also diuresis and decreased renal bacterial counts as a marker of induced pyelonephritis (p = 0.036). The preliminary results show that dehydration is a risk factor for UTI and that higher diuresis induced by drinking SSB might be protective against pyelonephritis. The underlying mechanisms could include increased voiding frequency but potentially also active compounds in cola such as caffeine. These findings might have implications for the management of individuals at high risk of UTI. Further studies should verify the hypothesis and evaluate the practical relevance of this concept.

Exogenous deoxyribonuclease has a protective effect in a mouse model of sepsis.

Sepsis is associated with the activation of white blood cells (WBCs) that leads to the production of extracellular traps. This process increases extracellular DNA (ecDNA) that can be recognized by the innate immune system and leads to inflammation. Previous studies have shown that by cleaving ecDNA deoxyribonuclease (DNase) prevents the antibacterial effects of extracellular traps, but also has beneficial effects in sepsis. The aim of our study was to analyze the effects of DNase on WBCs in vitro and on ecDNA in a mouse model of sepsis. Our results confirmed that DNase decreases ecDNA by 70% and prevents the antibacterial effects of WBCs in vitro. Sepsis was induced in mice by intraperitoneal injection of E. coli. DNase was subsequently administered intravenously. In comparison to untreated septic mice DNase treatment improved the survival of septic mice by 60%, reduced their weight loss as well as inflammatory markers. Increased plasma DNase activity led to ecDNA concentrations in plasma comparable with the control group. In conclusion, the study showed that intravenous DNase improves survival of septic mice by cleavage of ecDNA, especially of nuclear origin. Further mechanistic studies are needed to prove the potential of DNase in the treatment or prevention of septic complications.