Explore the vast range of titles available.

Exposure to maternal immune activation (MIA) in utero significantly elevates the risk of developing schizophrenia and other neurodevelopmental disorders. To understand the biological mechanisms underlying the link between MIA and increased risk, preclinical animal models have focussed on specific signalling pathways in the brain that mediate symptoms associated with neurodevelopmental disorders such as cognitive dysfunction. Reelin signalling in multiple brain regions is involved in neuronal migration, synaptic plasticity and long-term potentiation, and has been implicated in cognitive deficits. However, how regulation of Reelin expression is affected by MIA across cortical development and associated cognitive functions remains largely unclear. Using a MIA rat model, here we demonstrate cognitive deficits in adolescent object-location memory in MIA offspring and reductions in Reln expression prenatally and in the adult prefrontal cortex. Further, developmental disturbances in gene/protein expression and DNA methylation of downstream signalling components occurred subsequent to MIA-induced Reelin dysregulation and prior to cognitive deficits. We propose that MIA-induced dysregulation of Reelin signalling contributes to the emergence of prefrontal cortex-mediated cognitive deficits through altered NMDA receptor function, resulting in inefficient long-term potentiation. Our data suggest a developmental window during which attenuation of Reelin signalling may provide a possible therapeutic target.

Pulmonary arterial hypertension (PAH) is a rare but fatal disease. Current treatments increase life expectancy but have limited impact on the progressive pulmonary vascular remodelling that drives PAH. Osteoprotegerin (OPG) is increased within serum and lesions of patients with idiopathic PAH and is a mitogen and migratory stimulus for pulmonary artery smooth muscle cells (PASMCs). Here, we report that the pro-proliferative and migratory phenotype in PASMCs stimulated with OPG is mediated via the Fas receptor and that treatment with a human antibody targeting OPG can attenuate pulmonary vascular remodelling associated with PAH in multiple rodent models of early and late treatment. We also demonstrate that the therapeutic efficacy of the anti-OPG antibody approach in the presence of standard of care vasodilator therapy is mediated by a reduction in pulmonary vascular remodelling. Targeting OPG with a therapeutic antibody is a potential treatment strategy in PAH. Pulmonary arterial hypertension (PAH) is characterised by progressive pulmonary vascular remodelling. Here, Arnold et al. develop a therapeutic antibody targeting osteoprotegerin and find it attenuates pulmonary vascular remodelling in multiple rodent models of PAH, alone or in combination with standard of care vasodilator therapy.

Prenatal maternal immune activation (mIA) is associated with increased susceptibility to neurodevelopmental disorders (NDDs) in later life as evidenced by epidemiological studies that have associated prenatal infection with increased risk of NDDs such as schizophrenia (SZ). Prenatal induction of mIA in rodents produces behavioural and neuropathological phenotypes in the offspring, characteristic of NDD cognitive deficits. Previous studies in rodent models of mIA have characterised elicited maternal cytokine responses and altered cytokine balance in the placenta but are lacking with regards to how mIA affects functionality of placental and yolk sac nutrient transport systems. In this study it was hypothesised that mIA and the associated maternal proinflammatory cytokine response, induced by the viral mimetic poly(I:C), impairs placental amino acid transporter capacity, leading to altered fetal brain development and predisposition to NDDs later in life.This study administered poly(I:C) on gestational day (GD) 15 to pregnant Wistar dams to investigate the effects of mIA induction on maternal proinflammatory cytokine release and gestational growth trajectory, as well as characterising inflammatory changes and elicited effects in the fetoplacental unit, as compared to vehicle-treated controls. The molecular properties of poly(I:C) from two major commercial suppliers were found to differ with respect to molecular weight and endotoxin contamination, and this impacted on fetal phenotypic outcomes. Various techniques were employed to investigate the impact of poly(I:C)-mediated mIA induction on placental and yolk sac transport function, with a focus on system L amino acid transporters (LATs), including gene and protein expression analyses of LAT subunits in the placenta and yolk sac at 3 h (GD15), 24 h (GD16) and 6 days (GD21) following poly(I:C) administration and assessment of system L activity by measurement of in vivo maternofetal transfer of 14C-leucine at GD16 and GD21. The effect of poly(I:C) on fetal, placental and yolk sac growth and the concentration of branched amino acids (BCAAs) in these tissues, as well as placental morphology were investigated, and effects were examined according to fetal sex, to determine sexual dimorphic phenomena.At GD16, poly(I:C) induced sex-specific and gestational-dependent inflammatory responses in the placenta and yolk sac as well as on LAT expression and system L activity (reduced accumulation of 14C-leucine in the fetus), accompanied by reduced placental weight (in males) and disrupted labyrinth zone organisation. In contrast, at GD21, placental system L expression (but not yolk sac) and activity was increased in poly(I:C)-treated group, accompanied by an increased fetal plasma BCAA concentration (in males). Fetal bodyweight was unaffected by poly(I:C) treatment at all gestational timepoints, indicative of sustained fetal growth. However, fetal brain: bodyweight ratio was increased post-mIA at all timepoints. A biphasic response in the placenta to mIA characterised by an early impairment of system L transport (GD15, 16) followed by a compensatory upregulation of activity to maintain fetal growth (GD21) was observed. It is proposed that the earlier impairment of amino acid transport alters BCAA provision to the fetus, altering developmental trajectories of fetal organs and potentially influencing neurodevelopmental processes, further supported by decreased expression of SZ-susceptibility gene reelin in fetal brain 3 h post-poly(I:C) administration. This may predispose the fetus to NDD risk in postnatal life, despite the compensatory placental adaptation near term (upregulated system L transport) and maintained fetal growth. The pattern of LAT subtype expression differed between placenta and yolk sac, but supported the capacity for system L–mediated amino acid transport by both tissues. The ability of the rodent yolk sac to respond to mIA is presented for the first time and whilst responding similarly in the acute phase, it displayed divergent responses to the placenta at GD21. This may impact consequentially on a subset of vulnerable fetuses, reducing survival rates and detrimentally impacting on amino acid provision. In summary, poly(I:C)-mediated mIA evoked changes in placental and yolk sac system L amino acid transport function which could influence fetal amino acid provision, impacting on fetal brain developmental processes with enduring consequences, that could lead to NDDs in the offspring.

Maternal oxycodone (oxy) exposure can disrupt placental function and fetal neurodevelopment, but the molecular mechanisms remain unclear. We investigated whether prenatal oxy exposure activates inflammation and stress response pathways in the placenta and fetal brain, and if maternal melatonin supplementation attenuates these effects. Female Sprague-Dawley rats received either saline or oxy via oral gavage for 15 days before mating (10-15mg/kg/day dose escalation) and throughout pregnancy (15mg/kg/day). From gestational day (GD) 12.5, half of the dams received melatonin (10mg/kg/day). On GD 19.5, placental and fetal brain tissues were collected. Changes in expression of markers of oxidative stress, antioxidant defense signaling, inflammation, ER stress, and apoptosis were assessed by western blotting. Data were analyzed by two-way ANOVA with Tukey's post hoc test. Neither oxy exposure nor melatonin treatment increased markers of oxidative stress or antioxidant defenses in the placenta and fetal brain. Oxy exposure increased placental IL-1β expression but did not alter expression of the other inflammatory markers examined. Oxy increased phosphorylation of eIF2α and increased the phospho-eIF2α:eIF2α ratio in the placentas of male fetuses, and fetal brains of both sexes. CHOP expression was increased in the placentas and brains of female, but not male fetuses after oxy exposure. Oxy exposure increased levels of cleaved caspase-3 and cleaved caspase-9 in the fetal brain, but not the placenta; melatonin treatment attenuated the oxy-induced increase in cleaved caspase-9, but not cleaved caspase-3. Prenatal oxy exposure induced a modest inflammatory response in the placenta and activated the integrated stress response and intrinsic apoptotic signaling in the fetal brain. Maternal melatonin supplementation partially mitigated the oxy-induced upregulation of caspase-9 but did not prevent stress signaling in either tissue. These findings demonstrate the presence of sex-specific placental and fetal brain responses to prenatal oxy exposure but suggest that melatonin may not provide complete protection against oxy-induced neurodevelopmental impairment.