Characterisation of the consequences of maternal immune activation on distinct cell populations in the developing rat spinal cord.

Maternal immune activation (MIA) during gestation has been implicated in the development of neurological disorders such as schizophrenia and autism. Epidemiological studies have suggested that the effect of MIA may depend on the gestational timing of the immune challenge and the region of the central nervous system (CNS) in question. This study investigated the effects of MIA with 100 µg/kg lipopolysaccharide at either Embryonic days (E)12 or E16 on the oligodendrocytes, microglia and astrocytes of the offspring spinal cord. At E16, MIA decreased the number of olig2+ and Iba-1+ cells in multiple grey and white matter regions of the developing spinal cord 5 h after injection. These decreases were not observed at postnatal day 14. In contrast, MIA at E12 did not alter Olig2+ or Iba-1+ cell number in the developing spinal cord 5 h after injection, however, Olig2+ cell number was decreased in the ventral grey matter of the P14 spinal cord. No changes were observed in glial fibrillary acidic protein (GFAP) expression at P14 following MIA at either E12 or E16. These data suggest that E16 may be a window of immediate vulnerability to MIA during spinal cord development, however, the findings also suggest that the developmental process may be capable of compensation over time. Potential changes in P14 animals following the challenge at E12 are indicative of the complexity of the effects of MIA during the developmental process.

Peripheral administration of the Class-IIa HDAC inhibitor MC1568 partially protects against nigrostriatal neurodegeneration in the striatal 6-OHDA rat model of Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder characterised by nigrostriatal dopaminergic (DA) neurodegeneration. There is a critical need for neuroprotective therapies, particularly those that do not require direct intracranial administration. Small molecule inhibitors of histone deacetylases (HDIs) are neuroprotective in in vitro and in vivo models of PD, however it is unknown whether Class IIa-specific HDIs are neuroprotective when administered peripherally. Here we show that 6-hydroxydopamine (6-OHDA) treatment induces protein kinase C (PKC)-dependent nuclear accumulation of the Class IIa histone deacetylase (HDAC)5 in SH-SY5Y cells and cultured DA neurons in vitro. Treatment of these cultures with the Class IIa-specific HDI, MC1568, partially protected against 6-OHDA-induced cell death. In the intrastriatal 6-OHDA lesion in vivo rat model of PD, MC1568 treatment (0.5 mg/kg i.p.) for 7 days reduced forelimb akinesia and partially protected DA neurons in the substantia nigra and their striatal terminals from 6-OHDA-induced neurodegeneration. MC1568 treatment prevented 6-OHDA-induced increases in microglial activation in the striatum and substantia nigra. Furthermore, MC1568 treatment decreased 6-OHDA-induced increases in nuclear HDAC5 in nigral DA neurons. These data suggest that peripheral administration of Class IIa-specific HDIs may be a potential therapy for neuroprotective in PD.

The association between hypertensive disorders of pregnancy and childhood asthma.

BACKGROUND: Asthma is a chronic long-term inflammatory disease of the airways and is a major global health challenge. The primary aim of this study was to investigate the association between hypertensive disorders of pregnancy (HDP) and the risk of asthma at or before the age of seven years using the UK Millennium Cohort Study (MCS). METHODS: Overall, 18,552 families were recruited for wave one of the MCS when the child was 9 months old, and subsequently participated in waves two, three and four when they were three, five and seven years respectively. HDP were self-reported by mothers in wave one. The primary outcome was a parent-reported diagnosis of "ever asthma" at seven years, based on responses to a validated questionnaire. RESULTS: Following adjustment for a range of potential confounding factors, HDP was found to be associated with asthma in the offspring (adjusted odds ratio (AOR 1.35; 95% CI: 1.15-1.59)). A larger effect estimate was observed amongst children exposed to HDP and born preterm (AOR 1.81; 95% CI: 1.25-2.61) or small for gestational age (SGA) (AOR = 1.58; (95% CI: 1.15-2.18)). CONCLUSIONS: In conclusion, children exposed to HDP may be at increased odds of asthma diagnosis by age seven, particularly if they were born preterm or SGA. IMPACT: There is a paucity of data investigating the relationship between hypertensive disorders of pregnancy and childhood asthma, with recent studies showing conflicting results. Our study investigated this relationship using a large cohort with ample information on a wide range of confounding factors. Our study showed that individuals exposed to HDP may be at increased odds of asthma diagnosis by age seven years, particularly if they were also born SGA or preterm.

LMK235, a small molecule inhibitor of HDAC4/5, protects dopaminergic neurons against neurotoxin- and α-synuclein-induced degeneration in cellular models of Parkinson's disease.

Epigenetic modifications in neurodegenerative disease are under investigation for their roles in disease progression. Alterations in acetylation rates of certain Parkinson's disease (PD)-linked genes have been associated with the pathological progression of this disorder. In light of this, and given the lack of disease-modifying therapies for PD, HDAC inhibitors (HDIs) are under consideration as potential pharmacological agents. The neuroprotective effects of pan-HDACs and some class-specific inhibitors have been tested in in vivo and in vitro models of PD, with varying outcomes. Here we used gene co-expression analysis to identify HDACs that are associated with human dopaminergic (DA) neuron development. We identified HDAC3, HDAC5, HDAC6 and HDAC9 as being highly correlated with the DA markers, SLC6A3 and NR4A2. RT-qPCR revealed that mRNA expression of these HDACs exhibited similar temporal profiles during embryonic mouse midbrain DA (mDA) neuron development. We tested the neuroprotective potential of a number of class-specific small molecule HDIs on human SH-SY5Y cells, using neurite growth as a phenotypic readout of neurotrophic action. Neither the class I-specific HDIs, RGFP109 and RGFP966, nor the HDAC6 inhibitor ACY1215, had significant effects on neurite outgrowth. However, the class IIa HDI, LMK235 (a HDAC4/5 inhibitor), significantly increased histone acetylation and neurite outgrowth. We found that LMK235 increased BMP-Smad-dependent transcription in SH-SY5Y cells and that this was required for its neurite growth-promoting effects on SH-SY5Y cells and on DA neurons in primary cultures of embryonic day (E) 14 rat ventral mesencephalon (VM). These effects were also seen in SH-SY5Y cells transfected with HDAC5 siRNA. Furthermore, LMK235 treatment exerted neuroprotective effects against degeneration induced by the DA neurotoxin 1-methyl-4-phenylpyridinium (MPP+), in both SH-SY5Y cells and cultured DA neurons. Treatment with LMK235 was also neuroprotective against axonal degeneration induced by overexpression of wild-type (WT) or A53T mutant α-synuclein in both SH-SY5Y cells and primary cultures of DA neurons. In summary, these data show the neuroprotective potential of the class IIa HDI, LMK235, in cell models of relevance to PD.

The Growth Response to Beta-Hydroxybutyrate in SH-SY5Y Neuroblastoma Cells is Suppressed by Glucose and Pyruvate Supplementation.

Neuroblastoma (NB) is a childhood malignancy of the sympathetic nervous system and is commonly studied using the SH-SY5Y cell line. Its neoplastic and neurodevelopmental manifestations are characterised by a high glucose demand which maintains its high proliferative capacity. This metabolic phenotype may be utilised in dietary therapies such as the ketone diet which alter substrate availability and thus starve NB cells of their preferred biosynthetic requirements. However, the effects of ketone metabolism on cancer growth remain poorly understood due to the involvement of other metabolic substrates in experimental paradigms and complexities underlying the Warburg effect. We investigated how the primary ketone body beta-hydroxybutyrate (ßOHB) affects the growth of SH-SY5Y NB cells in the presence or absence of culture metabolic substrates. We demonstrated that while glucose deprivation reduced the growth and viability of SH-SY5Y cells, they proliferated and were initially unaffected by the addition of ßOHB. However, a growth response to ßOHB was subsequently revealed in media containing low levels of glucose, as well as in glucose and pyruvate deprived conditions. These data shed light on the roles of metabolic substrate availability as key determinants of the responses of SH-SY5Y NB cells to ketone supplementation.

Association between preeclampsia and autism spectrum disorder: a population-based study.

BACKGROUND: The environmental contribution of autism spectrum disorder (ASD) is approximately 17%-50%, highlighting the importance of investigating factors potentially contributing to the likelihood of its development, and of gaining a greater understanding of the pathogenesis surrounding ASD. The objective of this study was to examine the association between preeclampsia and ASD using a population-based cohort study. METHODS: All singleton live births in Sweden from 1982 to 2010 were included, using data from Swedish National Registers. Exposures of interest included: (a) preeclampsia (classified according to ICD-8, ICD-9 and ICD-10) and (b) preeclampsia and small for gestational age (SGA) combined, used as a proxy for preeclampsia with placental dysfunction. ASD status was based on ICD-9 and ICD-10. The cohort consisted of 2,842,230 children, with 54,071 cases of ASD. Follow-up began from the child's first birthday, and data were censored at first diagnosis of ASD, death, migration or end of study period (31st December 2016). We conducted multivariate Cox proportional hazards regression analysis, adjusting for several perinatal and sociodemographic factors, selected a priori. We further controlled for shared genetic and familial confounding using sibling-matched analysis. RESULTS: In the adjusted Cox proportional hazards regression analysis, preeclampsia was associated with a 25% increase in the likelihood of ASD (Hazard Ratio (HR): 1.25, 95% CI:1.19, 1.30) compared with those unexposed to preeclampsia, while in the sibling-matched analysis the HR was 1.17 (95% CI: 1.06, 1.28). The HR for preeclampsia and SGA combined was 1.66 (95% CI: 1.49, 1.85) in the adjusted Cox model and 1.95 (95% CI: 1.53, 2.48) in the sibling-matched analysis. CONCLUSIONS: Exposure to preeclampsia or preeclampsia/SGA (i.e. SGA baby exposed to preeclampsia) was associated with ASD. The stronger association with preeclampsia/SGA than preeclampsia alone suggests that placental pathology may be a mechanism for the increased likelihood of ASD.

The association between caesarean section and cognitive ability in childhood.

PURPOSE: Global rates of caesarean section (CS) rates have increased rapidly in recent years. This is a growing public health concern as it has been proposed that CS may impact cognitive outcomes in childhood. However, the evidence for this association is limited and inconsistent. Therefore, the aim of this study was to investigate the relationship between obstetric mode of delivery and longitudinal cognitive outcomes in childhood. METHODS: We examined this question using data from a longitudinal cohort study of 8845 participants from the Millennium Cohort Study, a nationally representative UK cohort, who completed a range of verbal and visual-spatial cognitive assessments at ages 3, 5, 7 and 11 years. RESULTS: We found a statistically significant association between planned CS and visual-spatial cognitive delay in the pattern construction assessment at age 5 (OR 1.31, 95% CI 0.99-1.72) and age 7 (OR 1.42, 95% CI 1.12-1.81). Additionally planned CS was also associated with increased odds of "early childhood delay" (OR 1.70, 95% CI 1.15-2.50) and borderline increased odds of "persistent delay" (OR 1.37, 95% CI 0.99-1.89) in visual-spatial cognitive tests. Mode of delivery was not associated with verbal ability or with patterns of delay at any age point in verbal cognitive tests. CONCLUSION: We have reported a small association between planned CS and visual-spatial cognitive delay in childhood. However, while this result should be interpreted with caution, it highlights the need to further explore this potential relationship and the causal basis of such an association.

The Association Between Preeclampsia and Childhood Development and Behavioural Outcomes.

OBJECTIVES: To examine the associations between preeclampsia and longitudinal child developmental and behavioural outcomes using data from a nationally representative study of children living in Ireland. METHODS: We used maternal-reported data from the Growing Up in Ireland longitudinal study of children. Data on preeclampsia and preeclampsia + small for gestational age (SGA) were collected when children were 9-months old. Data on child development and behavioural outcomes were collected at 9-months using the Ages and Stages Questionnaire (ASQ), and at 3 years, 5 years and 7-8 years using the Strengths and Difficulties Questionnaire (SDQ). Multivariate logistic regression analysis was used to examine the association between preeclampsia exposure and failure of ASQ domains, and abnormal SDQ domains. Linear spline multilevel models were used to examine the association between preeclampsia and preeclampsia + SGA and repeated measures of SDQ. All models controlled for several perinatal and sociodemographic factors. RESULTS: A total of 10,692 children were included in the study at baseline, representing a weighted total of 70,791. Multivariate logistic regression suggested that preeclampsia was not associated with failing any ASQ domain. Preeclampsia was associated with abnormal SDQ cut-off of emotional (≥ 5) and hyperactivity (≥ 7) domains at age 5 years only. In the linear spline model, mean SDQ score was higher at each time point in exposed groups. CONCLUSIONS FOR PRACTICE: While we did not find strong evidence of associations between preeclampsia and child developmental and behavioural outcomes overall, some associations between preeclampsia-exposure and subtle behavioural issues did persist. Further research is needed to replicate these findings, and determine the clinical significance of changes in SDQ scores.

The distribution of the proteoglycan FORSE-1 in the developing mouse central nervous system.

Glycosylation is a major post-translational modification in which a carbohydrate known as a glycan is enzymatically attached to target proteins which regulate protein folding and stability. Glycans are strongly expressed in the developing nervous system where they play multiple roles during development. The importance of these glycan epitopes in neural development is highlighted by a group of conditions known as congenital disorders of glycosylation which lead to psychomotor difficulties, mental retardation, lissencephaly, microencephaly and epilepsy. One of these glycan epitopes, known as Lewis X, is recognised by the FORSE-1 antibody and is regionally expressed in the developing nervous system. In this study, we report the regional and temporal expression patterns of FORSE-1 immunolabelling during the periods of neurogenesis, gliogenesis and axonogenesis in developing mouse nervous system. We demonstrate the localisation of FORSE-1 on subsets of neuroepithelial cells and radial glial cells, and in compartments corresponding to axon tract formation. These spatial, temporal and regional expression patterns are suggestive of roles in the determination of different cell lineages and in the patterning of white matter during development, and help provide insights into the neuroanatomical regions affected by congenital disorders of glycosylation.

Prenatal maternal stress and risk of neurodevelopmental disorders in the offspring: a systematic review and meta-analysis.

PURPOSE: Exposure to prenatal stress has been reported to affect the risk of adverse neurodevelopmental outcomes in the offspring; however, there is currently no clear consensus. The aim of this systematic review and meta-analysis was to examine the existing literature on the association between prenatal stress and autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD) in the offspring. METHODS: Based on a registered protocol, we searched several electronic databases for articles in accordance with a detailed search strategy. We performed this study following the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA). RESULTS: Prenatal stress was significantly associated with an increased risk of both ASD (pooled OR 1.64 [95% CI 1.15-2.34]; I2 = 90%; 15 articles) and ADHD (pooled OR 1.72 [95% CI 1.27-2.34]; I2 = 85%; 12 articles). CONCLUSIONS: This study suggests that prenatal stress may be associated with ASD and ADHD; however, several limitations in the reviewed literature should be noted including significant heterogeneity and there is a need for carefully controlled future studies in this area.

Mild prenatal hypoxia-ischemia leads to social deficits and central and peripheral inflammation in exposed offspring.

Hypoxic-ischemic encephalopathy (HIE) resulting from intrauterine or perinatal hypoxic-ischemia (HI) is a leading cause of long-term neonatal neurodisability. While most studies of long-term outcome have focused on moderate and severe HIE in term infants, recent work has shown that those with mild HIE may have subtle neurological impairments. However, the impact of mild HI on pre-term infants is much less clear given that pre-term birth is itself a risk factor for neurodisability. Here we show that mild HI insult alters behaviour, inflammation and the corticosterone stress response in a rat model of pre-term HIE. Mild HI exposure led to social deficits in exposed offspring at postnatal day 30, without impairments in the novel object recognition test nor in the open field test. This was also accompanied by elevations in circulating adrenocorticotropic hormone and corticosterone indicating an exaggerated stress response. There were also elevations in il-1ß and il-6 but not tnf-α mRNA and protein in the brain and blood samples. In summary we find that a mild HI exposure leads to social deficits, central and peripheral inflammation, and an abnormal corticosterone response which are three core features of autism spectrum disorder. This shows that mild HI exposure may be a risk factor for an abnormal neurodevelopmental outcome in pre-term offspring.

Regulation of SPRY3 by X chromosome and PAR2-linked promoters in an autism susceptibility region.

Sprouty proteins are regulators of cell growth and branching morphogenesis. Unlike mouse Spry3, which is X-linked, human SPRY3 maps to the pseudoautosomal region 2; however, the human Y-linked allele is not expressed due to epigenetic silencing by an unknown mechanism. SPRY3 maps adjacent to X-linked Trimethyllysine hydroxylase epsilon (TMLHE), recently identified as an autism susceptibility gene. We report that Spry3 is highly expressed in central and peripheral nervous system ganglion cells in mouse and human, including cerebellar Purkinje cells and retinal ganglion cells. Transient over-expression or knockdown of Spry3 in cultured mouse superior cervical ganglion cells inhibits and promotes, respectively, neurite growth and branching. A 0.7 kb gene fragment spanning the human SPRY3 transcriptional start site recapitulates the endogenous Spry3-expression pattern in LacZ reporter mice. In the human and mouse the SPRY3 promoter contains an AG-rich repeat and we found co-expression, and promoter binding and/or regulation of SPRY3 expression by transcription factors MAZ, EGR1, ZNF263 and PAX6. We identified eight alleles of the human SPRY3 promoter repeat in Caucasians, and similar allele frequencies in autism families. We characterized multiple SPRY3 transcripts originating at two CpG islands in the X-linked F8A3-TMLHE region, suggesting X chromosome regulation of SPRY3. These findings provide an explanation for differential regulation of X and Y-linked SPRY3 alleles. In addition, the presence of a SPRY3 transcript exon in a previously described X chromosome deletion associated with autism, and the cerebellar interlobular variation in Spry3 expression coincident with the reported pattern of Purkinje cell loss in autism, suggest SPRY3 as a candidate susceptibility locus for autism.

Distinct alterations in motor & reward seeking behavior are dependent on the gestational age of exposure to LPS-induced maternal immune activation.

The dopaminergic system is involved in motivation, reward and the associated motor activities. Mesodiencephalic dopaminergic neurons in the ventral tegmental area (VTA) regulate motivation and reward, whereas those in the substantia nigra (SN) are essential for motor control. Defective VTA dopaminergic transmission has been implicated in schizophrenia, drug addiction and depression whereas dopaminergic neurons in the SN are lost in Parkinson's disease. Maternal immune activation (MIA) leading to in utero inflammation has been proposed to be a risk factor for these disorders, yet it is unclear how this stimulus can lead to the diverse disturbances in dopaminergic-driven behaviors that emerge at different stages of life in affected offspring. Here we report that gestational age is a critical determinant of the subsequent alterations in dopaminergic-driven behavior in rat offspring exposed to lipopolysaccharide (LPS)-induced MIA. Behavioral analysis revealed that MIA on gestational day 16 but not gestational day 12 resulted in biphasic impairments in motor behavior. Specifically, motor impairments were evident in early life, which were resolved by adolescence, but subsequently re-emerged in adulthood. In contrast, reward seeking behaviors were altered in offspring exposed MIA on gestational day 12. These changes were not due to a loss of dopaminergic neurons per se in the postnatal period, suggesting that they reflect functional changes in dopaminergic systems. This highlights that gestational age may be a key determinant of how MIA leads to distinct alterations in dopaminergic-driven behavior across the lifespan of affected offspring.

A Case Study in the Use of Primary Literature in the Context of Authentic Learning Pedagogy in the Undergraduate Neuroscience Classroom.

Providing opportunities for undergraduate science students to develop causal reasoning skills and the ability to think like research scientists is a crucial part of their preparation for professional practice as a scientist and/or a clinician. This has led many to question whether the traditional academic in-class lecture still has a functional role in today's undergraduate science education. Here, we performed a case study to attempt to maximize the use of in-class time to create a more authentic learning opportunity for undergraduate neuroscience students in our institution, the majority of whom go on to be research active scientists. We hypothesised that using seminal research papers as a teaching tool in a flipped classroom setting would model for neuroscience students what it means to think like a research scientist, would provide an opportunity for them to develop their causal reasoning skills and allow them to become more comfortable with the nature of professional practice (i.e., research) in the context of the discipline. We describe the design and implementation of this teaching approach to undergraduate final year neuroscience students, and evaluate their perception of it. We provide evidence that this approach models for the students what it means to reason like a research scientist, and discuss the implications of these findings for future practice. We propose that these findings will help add to the educational experience of all Neuroscience students whether they are on pre-med or on a research track.

An Attitudinal Survey of Undergraduate Neuroscience Students Regarding Their Views on the Relevance of Lectures to their Education.

Advances in technology have seen a significant growth in the integration of e-learning into university education. Coupled with this trend are the learning approaches used by "Generation Connected" or GenC students, whose prolific use of digital technology is a defining characteristic. This has resulted in questions being asked as to whether in-class university lecture time is still relevant to university education. Here we conducted a case study with a group of undergraduate neuroscience students to assess their views on the relevance of attending lectures, why they attend or the reasons for non-attendance, and on what makes a good lecture. This is with a view to informing the design of new teaching approaches that may be more beneficial in maximising student engagement, and facilitating learning. The survey instrument was a ten-item questionnaire that collected both qualitative and quantitative data. Over 90% of students were of the view that lectures were beneficial to their learning, while only 4% thought they were an outdated mode of education. Three main themes emerged when students were asked what makes a good lecture: 1. Engagement, 2. Time, and 3. Varied format. We discuss the implications of these findings and suggest how these student views could be woven into the design of teaching approaches to increase the relevance of in-class lecture time in undergraduate neuroscience education.

Viral vector delivery of neurotrophic factors for Parkinson's disease therapy.

Parkinson's disease (PD) is a neurodegenerative disorder characterised by the progressive loss of midbrain dopaminergic neurons, which causes motor impairments. Current treatments involve dopamine replacement to address the disease symptoms rather than its cause. Factors that promote the survival of dopaminergic neurons have been proposed as novel therapies for PD. Several dopaminergic neurotrophic factors (NTFs) have been examined for their ability to protect and/or restore degenerating dopaminergic neurons, both in animal models and in clinical trials. These include glial cell line-derived neurotrophic factor, neurturin, cerebral dopamine neurotrophic factor and growth/differentiation factor 5. Delivery of these NTFs via injection or infusion to the brain raises several practical problems. A new delivery approach for NTFs involves the use of recombinant viral vectors to enable long-term expression of these factors in brain cells. Vectors used include those based on adenoviruses, adeno-associated viruses and lentiviruses. Here we review progress to date on the potential of each of these four NTFs as novel therapeutic strategies for PD, as well as the challenges that have arisen, from pre-clinical analysis to clinical trials. We conclude by discussing recently-developed approaches to optimise the delivery of NTF-carrying viral vectors to the brain.

Downregulation of Umbilical Cord Blood Levels of miR-374a in Neonatal Hypoxic Ischemic Encephalopathy.

OBJECTIVE: To investigate the expression profile of microRNA (miRNA) in umbilical cord blood from infants with hypoxic ischemic encephalopathy (HIE). STUDY DESIGN: Full-term infants with perinatal asphyxia were identified under strict enrollment criteria. Degree of encephalopathy was defined using both continuous multichannel electroencephalogram in the first 24 hours of life and modified Sarnat score. Seventy infants (18 controls, 33 with perinatal asphyxia without HIE, and 19 infants with HIE [further graded as 13 mild, 2 moderate, and 4 severe]) were included in the study. MiRNA expression profiles were determined using a microarray assay and confirmed using quantitative real-time polymerase chain reaction. RESULTS: Seventy miRNAs were differentially expressed between case and control groups. Of these hsa-miR-374a was the most significantly downregulated in infants with HIE vs controls. Validation of hsa-miR-374a expression using quantitative real-time polymerase chain reaction confirmed a significant reduction in expression among infants with HIE compared with those with perinatal asphyxia and healthy controls (mean relative quantification [SD] = 0.52 [0.37] vs 1.10 [1.52] vs 1.76 [1.69], P < .02). CONCLUSIONS: We have shown a significant step-wise downregulation of hsa-miR-374a expression in cord blood of infants with perinatal asphyxia and subsequent HIE.

Activin signalling and pre-eclampsia: from genetic risk to pre-symptomatic biomarker.

Pre-eclampsia is a multi-system condition in pregnancy that is characterised by the onset of hypertension and proteinuria in women after the 20th week and it remains a leading cause of maternal and fetal mortality. Despite this the causative molecular basis of pre-eclampsia remains poorly understood. As a result, an intensive research effort has focused on understanding the molecular mechanisms involved in pre-eclampsia and using this information to identify new pre-symptomatic bio-markers of the condition. Activin A and its receptor, ACVR2A, have been extensively studied in this regard. Activin A is a member of the transforming growth factor (TGF)-ß superfamily that has a wide range of biological functions depending on the cellular context. Recent work has shown that polymorphisms in ACVR2A may be a genetic risk factor for pre-eclampsia. Furthermore, both placenta and serum levels of Activin A are significantly increased in pre-eclampsia suggesting that Activin A may be a possible biomarker for the condition. Here we review the latest advances in this field and link these with new molecular data that suggest that the oxidative stress and pro-inflammatory cytokine production seen in pre-eclampsia may result in increased placental Activin A secretion in an attempt to maintain placental function.