Duchenne muscular dystrophy (DMD), an X-linked neuromuscular disorder, characterised by progressive immobility, chronic inflammation and premature death, is caused by the loss of the mechano-transducing signalling molecule, dystrophin. In non-contracting cells, such as neurons, dystrophin is likely to have a functional role in synaptic plasticity, anchoring post-synaptic receptors. Dystrophin-expressing hippocampal neurons are key to cognitive functions such as emotions, learning and the consolidation of memories. In the context of disease-induced chronic inflammation, we have explored the role of the pleiotropic cytokine, interleukin (IL)-6 in hippocampal dysfunction using immunofluorescence, electrophysiology and metabolic measurements in dystrophic mdx mice. Hippocampal long-term potentiation (LTP) of the Schaffer collateral-CA1 projections was suppressed in mdx slices. Given the importance of mitochondria-generated ATP in synaptic plasticity, reduced maximal respiration in the CA1 region may impact upon this process. Consistent with a role for IL-6 in this observation, early LTP was suppressed in dystrophin-expressing wildtype slices exposed to IL-6. In dystrophic mdx mice, exposure to IL-6 suppressed mitochondrial-mediated basal metabolism in CA1, CA3 and DG hippocampal regions. Furthermore, blocking IL-6-mediated signalling by administering neutralising monoclonal IL-6 receptor antibodies intrathecally, normalised LTP in mdx mice. The impact of dystrophin loss from the hippocampus was associated with modified cellular bioenergetics, which underpin energy-driven processes such as the induction of LTP. The additional challenge of pathophysiological levels of IL-6 resulted in altered cellular bioenergetics, which may be key to cognitive deficits associated with the loss of dystrophin.

Maternal immune activation (MIA) during pregnancy is implicated in offspring psychiatric disorders. However, it is unknown to what extent MIA affects neurodevelopment, particularly cerebrocortical anatomy, in the general population, and whether effects differ by sex. The current study used vertex-wise statistics to examine the association between maternal prenatal CRP, an archetypal systemic inflammatory marker, and offspring cortical thickness, surface area, and volume, in 2635 mother-child dyads (5.4-26.5 years) from three population-based cohorts, and one clinical cohort enriched for presence of inflammation markers. Maternal CRP within a normal physiological range (<10 mg/L) exhibited sex-specific quadratic associations with cortical morphological measures in 2 regions in males and 1 region in females at childhood. Elevated (>10 mg/L) CRP was associated with regional cortical morphology in females and in a pooled sample of sexes. Overall, MIA is associated with cortical development in a regional and sex-specific manner in studies spanning childhood to adulthood.

Early-onset pre-eclampsia is believed to arise from defective placentation in the first trimester, leading to placental ischaemia/reperfusion (I/R) and oxidative stress. However, our current understanding of the effects of I/R and oxidative stress on trophoblast function is ambiguous in part due to studies exposing trophoblasts to hypoxia instead of I/R, and which report conflicting results. Here, we present a model of simulated ischaemia/reperfusion (SI/R) to recapitulate the pathophysiological events of early-onset pre-eclampsia (PE), by exposing first trimester cytotrophoblast HTR-8/SVneo cells to a simulated ischaemia buffer followed by reperfusion. We examined different ischaemia and reperfusion times and observed that 1 h ischaemia and 24 h reperfusion induced an increase in reactive oxygen species (ROS) production (P<0.0001) and oxygen consumption rate (P<0.01). SI/R-exposed trophoblast cells exhibited deficits in migration, proliferation, and invasion (P<0.01). While the deficits in migration and proliferation were rescued by antioxidants, suggesting an ROS-dependent mechanism, the loss of invasion was not affected by antioxidants, which suggests a divergent ROS-independent pathway. In line with this, we observed a decrease in MMP-9, the key regulatory enzyme necessary for trophoblast invasion (P<0.01), which was similarly unaffected by antioxidants, and pharmacological inhibition of MMP-9 replicated the phenotype of deficient invasion (P<0.01). Collectively, these data demonstrate that I/R impairs trophoblast migration and proliferation via a ROS-dependent mechanism, and invasion via an ROS-independent loss of MMP-9, disambiguating the role of oxidative stress and providing insights into the response of trophoblasts to I/R in the context of early-onset PE.

Pre-eclampsia (PE) is a hypertensive disorder of pregnancy which is associated with increased risk of neurodevelopmental disorders in exposed offspring. The pathophysiological mechanisms mediating this relationship are currently unknown, and one potential candidate is the anti-angiogenic factor soluble Fms-like tyrosine kinase 1 (sFlt-1), which is highly elevated in PE. While sFlt-1 can impair angiogenesis via inhibition of VEGFA signalling, it is unclear whether it can directly affect neuronal development independently of its effects on the vasculature. To test this hypothesis, the current study differentiated the human neural progenitor cell (NPC) line ReNcell® VM into a mixed culture of mature neurons and glia, and exposed them to sFlt-1 during development. Outcomes measured were neurite growth, cytotoxicity, mRNA expression of nestin, MBP, GFAP, and βIII-tubulin, and neurosphere differentiation. sFlt-1 induced a significant reduction in neurite growth and this effect was timing- and dose-dependent up to 100 ng/ml, with no effect on cytotoxicity. sFlt-1 (100 ng/ml) also reduced βIII-tubulin mRNA and neuronal differentiation of neurospheres. Undifferentiated NPCs and mature neurons/glia expressed VEGFA and VEGFR-2, required for endogenous autocrine and paracrine VEGFA signalling, while sFlt-1 treatment prevented the neurogenic effects of exogenous VEGFA. Overall, these data provide the first experimental evidence for a direct effect of sFlt-1 on neurite growth and neuronal differentiation in human neurons through inhibition of VEGFA signalling, clarifying our understanding of the potential role of sFlt-1 as a mechanism by which PE can affect neuronal development.

Hypertensive disorders of pregnancy, including pre-eclampsia, are a leading cause of serious and debilitating complications that affect both the mother and the fetus. Despite the occurrence and the health implications of these disorders there is still relatively limited evidence on the molecular underpinnings of the pathophysiology. An area that has come to the fore with regard to its influence on health and disease is the microbiome. While there are several microbiome niches on and within the body, the distal end of the gut harbors the largest of these impacting on many different systems of the body including the central nervous system, the immune system, and the reproductive system. While the role of the microbiome in hypertensive disorders, including pre-eclampsia, has not been fully elucidated some studies have indicated that several of the symptoms of these disorders are linked to an altered gut microbiome. In this review, we examine both pre-eclampsia and microbiome literature to summarize the current knowledge on whether the microbiome drives the symptoms of pre-eclampsia or if the aberrant microbiome is a consequence of this condition. Despite the paucity of studies, obvious gut microbiome changes have been noted in women with pre-eclampsia and the individual symptoms associated with the condition. Yet further research is required to fully elucidate the role of the microbiome and the significance it plays in the development of the symptoms. Regardless of this, the literature highlights the potential for a microbiome targeted intervention such as dietary changes or prebiotic and probiotics to reduce the impact of some aspects of these disorders.

Parkinson's disease (PD) is characterised by progressive loss of dopaminergic (DA) neurons from the substantia nigra (SN) and α-synuclein (αSyn) accumulation. Age is the biggest risk factor for PD and may create a vulnerable pre-parkinsonian state, but the drivers of this association are unclear. It is known that ageing increases αSyn expression in DA neurons and that this may alter molecular processes that are central to maintaining nigrostriatal integrity. To model this, adult female Sprague-Dawley rats received a unilateral intranigral injection of adeno-associated viral (AAV) vector carrying wild-type human αSyn (AAV-αSyn) or control vector (AAV-Null). AAV-αSyn induced no detrimental effects on motor behaviour, but there was expression of human wild-type αSyn throughout the midbrain and ipsilateral striatum at 20 weeks post-surgery. Microarray analysis revealed that the gene most-upregulated in the ipsilateral SN of the AAV-αSyn group was the SKI Family Transcriptional Corepressor 1 (SKOR1). Bioenergetic state analysis of mitochondrial function found that SKOR1 overexpression reduced the maximum rate of cellular respiration in SH-SY5Y cells. Furthermore, experiments in SH-SY5Y cells revealed that SKOR1 overexpression impaired neurite growth to the same extent as αSyn, and inhibited BMP-SMAD-dependent transcription, a pathway that promotes DA neuronal survival and growth. Given the normal influence of ageing on DA neuron loss in human SN, the extent of αSyn-induced SKOR1 expression may influence whether an individual undergoes normal nigrostriatal ageing or reaches a threshold for prodromal PD. This provides new insight into mechanisms through which ageing-related increases in αSyn may influence molecular mechanisms important for the maintenance of neuronal integrity.

Introduction: Pre-eclampsia (PE) is a common and serious hypertensive disorder of pregnancy, which affects 3%–5% of first-time pregnancies and is a leading cause of maternal and neonatal morbidity and mortality. Prenatal exposure to PE is associated with an increased risk of neurodevelopmental disorders in affected offspring, although the cellular and molecular basis of this increased risk is largely unknown. Methods: Here, we examined the effects of exposure to maternal serum from women with PE or a healthy uncomplicated pregnancy on the survival, neurite growth and mitochondrial function of neuronally differentiated human SH-SY5Y neuroblastoma cells, which are commonly used to study neurite growth. Neurite growth and mitochondrial function are two strongly linked neurodevelopmental parameters in which alterations have been implicated in neurodevelopmental disorders. Following this, we investigated the pleiotropic cytokine interleukin-6 (IL-6) levels as a potential mechanism. Results: Cells exposed to 3% (v/v) PE serum for 72 h exhibited increased neurite growth (p < 0.05), which was validated in the human neural progenitor cell line, ReNcell® VM (p < 0.01), and mitochondrial respiration (elevated oxygen consumption rate (p < 0.05), basal mitochondrial respiration, proton leak, ATP synthesis, and non-mitochondrial respiration) compared to control serum-treated cells. ELISA analysis showed elevations in maternal IL-6 in PE sera (p < 0.05) and placental explants (p < 0.05). In support of this, SH-SY5Y cells exposed to 3% (v/v) PE serum for 24 h had increased phospho-STAT3 levels, which is a key intracellular mediator of IL-6 signalling (p < 0.05). Furthermore, treatment with anti-IL-6 neutralizing antibody blocked the effects of PE serum on neurite growth (p < 0.05), and exposure to IL-6 promoted neurite growth in SH-SY5Y cells (p < 0.01). Discussion: Collectively these data show elevated serum levels of maternal IL-6 in PE, which increases neurite growth and mitochondrial function in SH-SY5Y cells. This rationalizes the further study of IL-6 as a potential mediator between PE exposure and neurodevelopmental outcome in the offspring.

Parkinson's disease (PD) is neurodegenerative disorder with the pathological hallmarks of progressive degeneration of midbrain dopaminergic neurons from the substantia nigra (SN), and accumulation and spread of inclusions of aggregated α-synuclein (α-Syn). Since current PD therapies do not prevent neurodegeneration, there is a need to identify therapeutic targets that can prevent α-Syn-induced reductions in neuronal survival and neurite growth. We hypothesised that genes that are normally co-expressed with the α-Syn gene (SNCA), and whose co-expression pattern is lost in PD, may be important for protecting against α-Syn-induced dopaminergic degeneration, since broken correlations can be used as an index of functional misregulation. Gene co-expression analysis of the human SN showed that nuclear zinc finger HIT-type containing 1 (ZNHIT1) is co-expressed with SNCA and that this co-expression pattern is lost in PD. Overexpression of ZNHIT1 was found to increase deposition of the H2A.Z histone variant in SH-SY5Y cells, to promote neurite growth and to prevent α-Syn-induced reductions in neurite growth and cell viability. Analysis of ZNHIT1 co-expressed genes showed significant enrichment in genes associated with mitochondrial function. In agreement, bioenergetic state analysis of mitochondrial function revealed that ZNHIT1 increased cellular ATP synthesis. Furthermore, α-Syn-induced impairments in basal respiration, maximal respiration and spare respiratory capacity were not seen in ZNHIT1-overexpressing cells. These data show that ZNHIT1 can protect against α-Syn-induced degeneration and mitochondrial dysfunction, which rationalises further investigation of ZNHIT1 as a therapeutic target for PD.

Pre-eclampsia is a very common and potentially fatal pregnancy complication faced by millions of pregnant mothers worldwide every year. As well as affecting the mother, though, the disorder has been shown to have a harmful effect on the infant, including a negative influece on foetal brain development. Children born to a pregnancy affected by pre-eclampsia have a higher risk of neurodevelopmental disorders such as autism spectrum disorder, but, truthfully, we don't know why. This article describes the link between pre-eclampsia and foetal neurodevelopment - what we know and what we don't, and how our research is trying to uncover the mechanisms of the relationship between the two. Essentially, we are taking three approaches to this research question: growing neuron-like cells in the lab and modelling pre-eclampsia's effects on them; growing placental cells and stressing them in a way that mimics the placental pathology of pre-eclampsia; and analysing a large dataset from Finland which includes data on neurodevelopment from brain scans. Overall, these three strategies, little by little, are increasing our understanding of the elusive relationship between these two important disorders.

Pre-eclampsia (PE) is a common and serious hypertensive disorder of pregnancy, which affects 3-5% of first-time pregnancies and is a leading cause of maternal and neonatal morbidity and mortality. Prenatal exposure to PE is associated with an increased risk of neurodevelopmental disorders in affected offspring, although the cellular and molecular basis of this are largely unknown. In this study we examined the effects of exposure to maternal serum from women with PE or a healthy uncomplicated pregnancy on the survival, neurite growth and mitochondrial function of SH-SY5Y cells. We report that cells exposed to PE serum exhibited increased neurite growth and mitochondrial respiration, two important neurodevelopmental parameters, compared to those treated with control serum. Levels of the pleiotropic cytokine IL-6 were significantly elevated in the PE sera, and cells exposed to PE serum displayed increased phospho-STAT3 levels which is a key intracellular mediator of IL-6 signalling. Finally, we show that treating these cells with IL-6 alone is sufficient to induce a similar neurite growth and respiratory phenotype to PE serum-exposed cells. This suggests that elevated IL-6 seen in maternal serum in PE may be responsible at least in part for its inducing increased neurite growth and mitochondrial respiration in SH-SY5Y cells. Overall, this study demonstrates that there are circulating factors in the serum of women with pre-eclampsia that affect neuronal development and oxygen consumption differently to that of a healthy uncomplicated pregnancy, and that immune dysregulation via elevated IL-6 may be important in mediating these effects.

Stress, particularly during childhood, is a major risk factor for the development of depression. Depression is twice as prevalent in women compared to men, which suggests that biological sex also contributes to depression susceptibility. However, the neurobiology underpinning sex differences in the long-term consequences of childhood stress remains unknown. Thus, the aim of this study was to determine whether stress applied during the prepubertal juvenile period (postnatal day 27–29) in rats induces sex-specific changes in anxiety-like behaviour, anhedonia, and antidepressant-like behaviour in adulthood in males and females. The impact of juvenile stress on two systems in the brain associated with these behaviours and that develop during the juvenile period, the mesocorticolimbic dopaminergic system and hippocampal neurogenesis, were also investigated. Juvenile stress altered escape-oriented behaviours in the forced swim test in both sexes, decreased latency to drink a palatable substance in a novel environment in the novelty-induced hypophagia test in both sexes, and decreased open field supported rearing behavior in females. These behavioural changes were accompanied by stress-induced increases in tyrosine hydroxylase immunoreactivity in the prefrontal cortex of both sexes, but not other regions of the mesocorticolimbic dopaminergic system. Juvenile stress did not impact anhedonia in adulthood as measured by the saccharin preference test and had no effect hippocampal neurogenesis across the longitudinal axis of the hippocampus. These results suggest that juvenile stress has long-lasting impacts on antidepressant-like and reward-seeking behaviour in adulthood and these changes may be due to alterations to catecholaminergic innervation of the medial prefrontal cortex.