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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 olig2sup+/supand Iba-1sup+/supcells 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 Olig2sup+/supor Iba-1sup+/supcell number in the developing spinal cord 5 h after injection, however, Olig2sup+/supcell 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.

There is an increasing interest in understanding the educational background of anatomy teachers arising from the reported shortage of such staff. This has led to the development of several anatomy graduate training programs, which provide courses on theoretical and practical teaching training as part of their curricula, to prepare graduates for a career in anatomy education. A recent study has reported the design of such a course as part of a Master’s program in Human Anatomy at University College Cork, Ireland. The aim of this study was to investigate the ability of students who were enrolled in this course, to apply conceptual knowledge of teaching and learning, to the practical design and delivery of anatomy teaching, and what challenges this posed. Consent was obtained from the students to analyze their reflective teaching portfolios. Analysis showed that students varied from those who demonstrated superficial understanding of core concepts in the teaching and learning, to those who were able to adapt and apply these concepts to their teaching. Moreover, they reported that a lack of experience in educational theory, and the brevity of their exposure to it, was a challenge. This highlights that it is important to equip future anatomy teachers with the necessary skills to build their identity as teachers, in parallel to developing their content knowledge. This highlights the need to develop their intrinsic motivational factors that will help them balance the dual identity both as teachers of, and researchers in, the discipline of anatomy.

Background and purpose Regulator of G-protein signal 4 (RGS4) is a signal transduction protein that accelerates intrinsic GTPase activity of Gαi/o and Gαq subunits, suppressing GPCR signaling. Here we investigate whether RGS4 modulates nociceptin/orphanin FQ (N/OFQ) opioid (NOP) receptor signaling and this modulation has relevance for L-Dopa-induced dyskinesia. Experimental approach HEK293T cells transfected with NOP, NOP/RGS4 or NOP/RGS19 were challenged with N/OFQ and the small molecule NOP agonist AT-403, using D1-stimulated cAMP levels as a readout. Primary rat striatal neurons and adult mouse striatal slices were challenged with N/OFQ or AT-403 in the presence of the experimental RGS4 chemical probe, CCG-203920, and D1-stimulated cAMP or phosphorylated extracellular signal regulated kinase 1/2 (pERK) responses were monitored. In vivo, CCG-203920 was co-administered with AT-403 and L-Dopa to 6-hydroxydopamine hemilesioned rats, and dyskinetic movements, striatal biochemical correlates of dyskinesia (pERK and pGluR1 levels) and striatal RGS4 levels were measured. Key results RGS4 expression reduced NOFQ and AT-403 potency and efficacy in HEK293T cells. CCG-203920 increased N/OFQ potency in primary rat striatal neurons, and potentiated AT-403 response in mouse striatal slices. CCG-203920 enhanced AT-403 mediated inhibition of dyskinesia and its biochemical correlates, without compromising its motor-improving effects. Unilateral dopamine depletion caused bilateral reduction of RGS4 levels, which was reversed by L-Dopa. L-Dopa acutely upregulated RGS4 in the lesioned striatum. Conclusions and implications RGS4 physiologically inhibits NOP receptor signaling. CCG-203920 enhanced NOP responses and improved the antidyskinetic potential of NOP receptor agonists, mitigating the effects of striatal RGS4 upregulation occurring during dyskinesia expression.

Autism Spectrum disorder is one of the commonest and most important neurodevelopmental conditions affecting children today. With an increasing prevalence and an unclear aetiology, it is imperative we find early markers of autism, which may facilitate early identification and intervention. Alterations of gestational cytokine profiles have been reported in mothers of autistic children. Increasing evidence suggests that the intrauterine environment is an important determinant of autism risk. This study aims to examine the mid-gestational serum cytokine profiles of the mothers of autistic children from a well-characterised birth cohort. A nested sub-cohort within a large mother–child birth cohort were identified based on a confirmed multi-disciplinary diagnosis of autism before the age 10 years and neuro-typical matched controls in a 2:1 ratio. IFN-γ, IL-1β, IL-4, IL-6, IL-8, IL-17A, GMCSF and TNFα were measured in archived maternal 20-week serum using MesoScale Diagnostics multiplex technology and validation of our IL-17A measurements was performed using an ultrasensitive assay. From a cohort of 2137 children, 25 had confirmed autism before 10 years and stored maternal serum from mid-gestation. We examined the sera of these 25 cases and 50 matched controls. The sex ratio was 4:1 males to females in each group, and the mean age at diagnosis was 5.09 years (SD 2.13). We found that concentrations of IL-4 were significantly altered between groups. The other analytes did not differ significantly using either multiplex or ultra-sensitive assays. In our well-characterised prospective cohort of autistic children, we confirmed mid-gestational alterations in maternal IL-4 concentrations in autism affected pregnancies versus matched controls. These findings add to promising evidence from animal models and retrospective screening programmes and adds to the knowledge in this field.

Autism spectrum disorder (ASD) is a developmental disorder characterised by deficits in social interactions and communication, with stereotypical and repetitive behaviours. Recent evidence suggests that maternal immune dysregulation may predispose offspring to ASD. Independent samples t-tests revealed downregulation of IL-17A concentrations in cases, when compared to controls, at both 15 weeks (p = 0.02), and 20 weeks (p = 0.02), which persisted at 20 weeks following adjustment for confounding variables. This adds to the growing body of evidence that maternal immune regulation may play a role in foetal neurodevelopment.

Parkinson's disease (PD) is a neurodegenerative disorder characterised by motor and non-motor symptoms that impact quality of daily life, including diet and sleep. However, relatively little is known about dietary intake and quality in people with PD (PwP). Lifestyle factors, and how they relate to diet, are also insufficiently understood. The aims of this study were to investigate dietary intake and quality, sleep and quality of life in PwP, and to explore the relationships between these factors.Forty-five community-dwelling participants with PD (n = 45) were recruited to this cross-sectional study through the Cork Parkinson's Association, Ireland. Dietary intake was assessed using the EPIC food frequency questionnaire, and diet quality was assessed using the Healthy Diet Indicator. Dietary intakes were compared to Irish RDAs for adults 65 years. Sleep duration and quality were subjectively measured using the PD Sleep Scale and Pittsburgh sleep quality index and objectively measured by actigraphy in a subset of participants (n = 27). QOL was measured using the validated PDQ-39 questionnaire.Energy intake in PwP was significantly higher than that of the general population (2013 vs 1755 kcal/d, p = 0.01), despite their lower mean BMI (25.9 vs 27.7 kg/mCarbohydrates, protein, fruit and vegetable intakes were greater in PwP than population norms, but overall diet quality was low. Interventions to improve dietary and lifestyle factors may improve health and QOL in PwP.

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 (βOHB) 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 βOHB. However, a growth response to βOHB 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.

Hypoxic ischemic encephalopathy (HIE) is the most frequent cause of acquired infant brain injury. Early, clinically relevant biomarkers are required to allow timely application of therapeutic interventions. We previously reported early alterations in several microRNAs (miRNA) in umbilical cord blood at birth in infants with HIE. However, the exact timing of these alterations is unknown. Here, we report serial changes in six circulating, cross-species/bridging biomarkers in a clinically relevant porcine model of neonatal HIE with functional analysis. Six miRNAs—miR-374a, miR-181b, miR-181a, miR-151a, miR-148a and miR-128—were significantly and rapidly upregulated 1-h post-HI. Changes in miR-374a, miR-181b and miR-181a appeared specific to moderate-severe HI. Histopathological injury and five miRNAs displayed positive correlations and were predictive of MRS Lac/Cr ratios. Bioinformatic analysis identified that components of the bone morphogenic protein (BMP) family may be targets of miR-181a. Inhibition of miR-181a increased neurite length in both SH-SY5Y cells at 1 DIV (days in vitro) and in primary cultures of rat neuronal midbrain at 3 DIV. In agreement, inhibition of miR-181a increased expression of BMPR2 in differentiating SH-SY5Y cells. These miRNAs may therefore act as early biomarkers of HIE, thereby allowing for rapid diagnosis and timely therapeutic intervention and may regulate expression of signalling pathways vital to neuronal survival. Electronic supplementary material The online version of this article (10.1007/s12035-020-02018-w) contains supplementary material, which is available to authorized users.

Over the past decades, teaching and learning within the discipline of anatomy has undergone significant changes. Some of these changes are due to a reduction in the number of teaching hours, while others are related to advancements in technology. Faced with these many choices for change, it can be difficult for faculty to decide on which new developments in anatomical education need or indeed can be integrated into their course to enhance student learning. This article presents the universal design for learning (UDL) framework - an informed, evidence-based, and robust approach to underpin new course design and pedagogical reform in anatomy education. Universal design for learning is not a theory but a framework grounded in cognitive neuroscience that focuses on engaging multiple brain networks. The guidelines for UDL are organized into three core principles: (1) provide multiple means of representation, (2) provide multiple means of action and expression, and (3) provide multiple means of engagement. The learning space within the anatomy laboratory provides an excellent opportunity in which to apply this framework. This article also describes current trends employed in the teaching of anatomy. The principles of UDL are then outlined, followed by a description of how UDL approaches have been applied in the design and delivery of anatomy practical teaching to first year medical students at University College Cork. Future implications for this work are a consideration and investigation of how a course designed with the principles of UDL at its heart ultimately benefits student learning.

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.

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.

Parkinson’s disease is the most common movement disorder worldwide, affecting over 6 million people. It is an age-related disease, occurring in 1% of people over the age of 60, and 3% of the population over 80 years. The disease is characterized by the progressive loss of midbrain dopaminergic neurons from the substantia nigra, and their axons, which innervate the striatum, resulting in the characteristic motor and non-motor symptoms of Parkinson’s disease. This is paralleled by the intracellular accumulation of α-synuclein in several regions of the nervous system. Current therapies are solely symptomatic and do not stop or slow disease progression. One promising disease-modifying strategy to arrest the loss of dopaminergic neurons is the targeted delivery of neurotrophic factors to the substantia nigra or striatum, to protect the remaining dopaminergic neurons of the nigrostriatal pathway. However, clinical trials of two well-established neurotrophic factors, glial cell line-derived neurotrophic factor and neurturin, have failed to meet their primary end-points. This failure is thought to be at least partly due to the downregulation by α-synuclein of Ret, the common co-receptor of glial cell line-derived neurorophic factor and neurturin. Growth/differentiation factor 5 is a member of the bone morphogenetic protein family of neurotrophic factors, that signals through the Ret-independent canonical Smad signaling pathway. Here, we review the evidence for the neurotrophic potential of growth/differentiation factor 5 in in vitro and in vivo models of Parkinson’s disease. We discuss new work on growth/differentiation factor 5’s mechanisms of action, as well as data showing that viral delivery of growth/differentiation factor 5 to the substantia nigra is neuroprotective in the α-synuclein rat model of Parkinson’s disease. These data highlight the potential for growth/differentiation factor 5 as a disease-modifying therapy for Parkinson’s disease.

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).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.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)).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.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.

Importance: Prenatal stress exposure has been linked to increased risk of autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD) in the offspring, although the evidence is inconsistent. Objective: This systematic review and meta-analysis was performed to systematically critically review the existing literature on the association between prenatal stress and the risk of ASD and ADHD. Data sources: Based on a registered protocol, we searched electronic databases PubMed, PsycINFO, Web of Science, Scopus and EMBASE for articles in accordance with a detailed search strategy. Study selection: Two investigators independently searched titles, abstracts and full-text articles. Cohort and case-control studies assessing prenatal exposure to stress and the risk of ASD or ADHD as an outcome measure were included. Study extraction and synthesis: Data extraction and quality assessment were performed independently by two investigators. We performed this study following the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA). Main Outcomes and Measures: Random-effects meta-analyses were performed to calculate adjusted and unadjusted pooled estimates for prenatal stress and risk of ASD and ADHD, using the generic inverse variance method. Results: Of 1456 studies emerged from the databases, 27 studies in total met the inclusion criteria of the systematic review (15 for ASD, 12 for ADHD). Prenatal stress was significantly associated with an increased risk of both ASD (pooled OR=1.64, [95% CI=1.15 – 2.34]; I2=90%) and ADHD (pooled OR=1.72, [95% CI= 1.27-2.34]; I2=85%). A significant association between prenatal and ASD was observed in the meta-analysis of the cohort but not case-control studies. Significant associations for between prenatal stress and ASD and ADHD were observed in low to moderate quality studies but in high quality studies. Conclusions and relevance: This study suggests that prenatal stress may be associated with an increased risk of ASD and ADHD in the offspring. However, several limitations in the included literature should be noted including significant heterogeneity, potential recall bias and lack of adjustment for key potential confounders. Future research exploring this association should address the limitations in the current literature in order to test whether this association is potentially causal or attributable to methodological limitations.

Reduced teaching resources, increasing student numbers and congested medical curricula have led to reports of inadequate anatomical knowledge among newly qualified doctors, placing scrutiny on pre-clinical education. We wished to gauge the opinions of practicing radiologists on undergraduate anatomy education. Members of the Irish Faculty of Radiologists were invited to complete a questionnaire based on anatomy teaching practices, its relevance and the standards of anatomical knowledge at graduation. Out of 67 respondents, 69% were of senior grade, with the majority working in diagnostic radiology. Respondents universally agreed that anatomy is central to radiology; however, decade of graduation significantly influenced radiologist's level of satisfaction with their anatomical knowledge at the start of their training. Fifty percent believed that the cadaver should remain the cornerstone of anatomy education. The vast majority of radiologists agreed that radiology and anatomy should be taught in tandem during pre-clinical training to better prepare students for clinical practice. Practicing radiologists believed they were best positioned to deliver radiology-based anatomy teaching. CT and MRI respectively were proposed as the preferred imaging modalities for teaching anatomy, although free comments showed varied opinion on how radiology and cadaveric anatomy should be integrated. Radiologists were also concerned with the anatomical knowledge of the junior doctor. This study may add to the debate concerning the vertical integration of anatomy in medical education and may help inform the delivery of radiology in the anatomy curriculum.

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.

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.

Letter to the Editor

Preeclampsia (PE) is a common and serious hypertensive disorder of pregnancy that occurs in approximately 3-5% of first-time pregnancies and is a well-known leading cause of maternal and neonatal mortality and morbidity. In recent years, there has been accumulating evidence that in utero exposure to PE acts as an environmental risk factor for various neurodevelopmental disorders, particularly autism spectrum disorder and ADHD. At present, the mechanism(s) mediating this relationship are uncertain. In this review, we outline the most recent evidence implicating a causal role for PE exposure in the aetiology of various neurodevelopmental disorders and provide a novel interpretation of neuroanatomical alterations in PE-exposed offspring and how these relate to their sub-optimal neurodevelopmental trajectory. We then postulate that inflammation and oxidative stress, two prominent features of the pathophysiology of PE, are likely to play a major role in mediating this association. The increased inflammation in the maternal circulation, placenta and fetal circulation in PE expose the offspring to both prenatal maternal immune activation-a risk factor for neurodevelopmental disorders, which has been well-characterised in animal models-and directly higher concentrations of pro-inflammatory cytokines, which adversely affect neuronal development. Similarly, the exaggerated oxidative stress in the mother, placenta and foetus induces the placenta to secrete factors deleterious to neurons, and exposes the fetal brain to directly elevated oxidative stress and thus adversely affects neurodevelopmental processes. Finally, we describe the interplay between inflammation and oxidative stress in PE, and how both systems interact to potentially alter neurodevelopmental trajectory in exposed offspring.

Parkinson’s disease (PD) is a neurodegenerative disease characterised by the progressive degeneration of midbrain dopaminergic neurons, coupled with the intracellular accumulation of α-synuclein. Axonal degeneration is a central part of the pathology of PD. While the majority of PD cases are sporadic, some are genetic; the G2019S mutation in leucine-rich repeat kinase 2 (LRRK2) is the most common genetic form. The application of neurotrophic factors to protect dopaminergic neurons is a proposed experimental therapy. One such neurotrophic factor is growth differentiation factor (GDF)5. GDF5 is a dopaminergic neurotrophic factor that has been shown to upregulate the expression of a protein called nucleoside diphosphate kinase A (NME1). However, whether NME1 is neuroprotective in cell models of axonal degeneration of relevance to PD is unknown. Here we show that treatment with NME1 can promote neurite growth in SH-SY5Y cells, and in cultured dopaminergic neurons treated with the neurotoxin 6-hydroxydopamine (6-OHDA). Similar effects of NME1 were found in SH-SY5Y cells and dopaminergic neurons overexpressing human wild-type α-synuclein, and in stable SH-SY5Y cell lines carrying the G2019S LRRK2 mutation. We found that the effects of NME1 require the RORα/ROR2 receptors. Furthermore, increased NF-κB-dependent transcription was partially required for the neurite growth-promoting effects of NME1. Finally, a combined bioinformatics and biochemical analysis of the mitochondrial oxygen consumption rate revealed that NME1 enhanced mitochondrial function, which is known to be impaired in PD. These data show that recombinant NME1 is worthy of further study as a potential therapeutic agent for axonal protection in PD.

Parkinson's disease is a neurodegenerative disorder characterised by nigrostriatal dopaminergic degeneration, and intracellular a-synuclein aggregation. Current pharmacological treatments are solely symptomatic so there is a need to identify agents that can slow or stop dopaminergic degeneration. One proposed class of therapeutics are neurotrophic factors which promote the survival of nigrostriatal dopaminergic neurons. However, neurotrophic factors need to be delivered directly to the brain. An alternative approach may be to identify pharmacological agents which can reach the brain to stimulate neurotrophic factor expression and/or their signalling pathways in dopaminergic neurons. BMP2 is a neurotrophic factor that is expressed in the human substantia nigra; exogenous BMP2 administration protects against dopaminergic degeneration in in vitro models of PD. In this study, we investigated the neurotrophic potential of two FDA-approved drugs, quinacrine and niclosamide, that are modulators of BMP2 signalling. We report that quinacrine and niclosamide, like BMP2, significantly increased neurite length, as a readout of neurotrophic action, in SH-SY5Y cells and dopaminergic neurons in primary cultures of rat ventral mesencephalon. We also show that these effects of quinacrine and niclosamide require the activation of BMP-Smad signalling. Finally, we demonstrate that quinacrine and niclosamide are neuroprotective against degeneration induced by the neurotoxins, MPP+ and 6-OHDA, and by viral-mediated overexpression of a-synuclein in vitro. Collectively, this study identifies two drugs, that are safe for use in patients' to 'are approved for human use, that exert neurotrophic effects on dopaminergic neurons through modulation of BMP-Smad signalling. This rationalises the further study of drugs that target the BMP-Smad pathway as potential neuroprotective pharmacotherapy for Parkinson's disease.

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterised by specific motor impairments. The neuropathological hallmarks of PD include progressive degeneration of midbrain dopaminergic neurons, and loss of their axonal projections to the striatum. Additionally, there is progressive accumulation and spread of intracellular aggregates of α-synuclein. Although dopamine-replacement pharmacotherapy can treat PD symptoms in the short-term, there is a critical need for the development of disease-modifying therapies based on an understanding of the underlying disease mechanisms. One such mechanism is histone acetylation, which is a common epigenetic modification that alters gene transcription. A number of studies have described alterations in histone acetylation in the brains of PD patients. Moreover, α-synuclein accumulation has been linked to alterations in histone acetylation and pharmacological strategies aimed at modulating histone acetylation are under investigation as novel approaches to disease modification in PD. Currently, such strategies are focused predominantly on pan-inhibition of histone deacetylase (HDAC) enzymes. Inhibition of specific individual HDAC enzymes is a more targeted strategy that may allow for future clinical translation. However, the most appropriate class of HDACs that should be targeted for neuroprotection in PD is still unclear. Recent work has shed new light on the role of class-II HDACs in dopaminergic degeneration. For this reason, here we describe the regulation of histone acetylation, outline the evidence for alterations in histone acetylation in the PD brain, and focus on the roles of class II HDACs and the potential of class-II HDAC inhibition as a therapeutic approach for neuroprotection in PD.

Neuroblastoma (NB) is a paediatric cancer that arises in the sympathetic nervous system. Patients with stage 4 tumours have poor outcomes and 20% of high-risk cases have MYCN amplification. The bone morphogenetic proteins (BMPs) play roles in sympathetic neuritogenesis, by signalling through bone morphogenetic protein receptor (BMPR)2 and either BMPR1A or BMPR1B. Alterations in BMPR2 expression have been reported in NB; it is unknown if the expression of BMPR1A or BMPR1B is altered. We report lower BMPR2 and BMPR1B, and higher BMPR1A, expression in stage 4 and in MYCN-amplified NB. Kaplan–Meier plots showed that high BMPR2 or BMPR1B expression was linked to better survival, while high BMPR1A was linked to worse survival. Gene ontology enrichment and pathway analyses revealed that BMPR2 and BMPR1B co-expressed genes were enriched in those associated with NB differentiation. BMPR1A co-expressed genes were enriched in those associated with cell proliferation. Moreover, the correlation between BMPR2 and BMPR1A was strengthened, while the correlation between BMPR2 and BMPR1B was lost, in MYCN-amplified NB. This suggested that differentiation should decrease BMPR1A and increase BMPR1B expression. In agreement, nerve growth factor treatment of cultured sympathetic neurons decreased Bmpr1a expression and increased Bmpr1b expression. Overexpression of dominant negative BMPR1B, treatment with a BMPR1B inhibitor and treatment with GDF5, which signals via BMPR1B, showed that BMPR1B signalling is required for optimal neuritogenesis in NB cells, suggesting that loss of BMPR1B may alter neuritogenesis. The present study shows that expression of distinct BMPRs is associated with different survival outcomes in NB.

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.

Objective To examine the association between preeclampsia and attention-deficit hyperactivity disorder (ADHD), using a large Swedish-based registry cohort. Methods This study comprised 2 047 619 children, with 114 934 (5.6%) cases of ADHD. Preeclampsia was based on two alternate definitions: (i) preeclampsia (using ICD-9/ICD-10) and (ii) preeclampsia and small for gestational age (SGA) combined. ADHD was determined in one of two ways: (i) if a diagnosis of ADHD was present in the National Patient Register or (ii) if an individual was in receipt of ADHD medication in the Prescribed Drug Register. Multivariate Cox proportional hazards regression analysis allowed adjustment for several perinatal/sociodemographic factors. Sibling-matched analysis further controlled for shared genetic and familial confounding. Results In the adjusted Cox model, preeclampsia was associated with an increase in likelihood of ADHD (HR: 1.15, 95% CI: 1.12, 1.19). The HR for preeclampsia and those born SGA was 1.43 (95% CI: 1.31, 1.55) in the adjusted model, compared to those unexposed to preeclampsia/SGA. The sibling-matched analysis did not materially change these associations (HR: 1.13, 95% CI: 1.05, 1.22) and 1.55 (95% CI: 1.28, 1.88). Conclusions Exposure to preeclampsia or preeclampsia/SGA was associated with ADHD, independent of genetic/familial factors shared by siblings. However, it is important to note that sibling-matched analysis can only adjust for factors that are constant between pregnancies; therefore, residual confounding cannot be ruled out. Further research is needed to explore modifiable risk factors and identify those most-at-risk babies following delivery.

Parkinson’s disease is the second most common neurodegenerative disorder; it affects 1% of the population over the age of 65. The number of people with Parkinson’s disease is set to rapidly increase due to changing demographics and there is an unmet clinical need for disease-modifying therapies. The pathological hallmarks of Parkinson’s disease are the progressive degeneration of dopaminergic neurons in the substantia nigra and their axons which project to the striatum, and the aggregation of α-synuclein; these result in a range of debilitating motor and non-motor symptoms. The application of neurotrophic factors to protect and potentially regenerate the remaining dopaminergic neurons is a major area of research interest. However, this strategy has had limited success to date. Clinical trials of two well-known neurotrophic factors, glial cell line-derived neurotrophic factor and neurturin, have reported limited efficacy in Parkinson’s disease patients, despite these factors showing potent neurotrophic actions in animal studies. There is therefore a need to identify other neurotrophic factors that can protect against α-synuclein-induced degeneration of dopaminergic neurons. The bone morphogenetic protein (BMP) family is the largest subgroup of the transforming growth factor-β superfamily of proteins. BMPs are naturally secreted proteins that play crucial roles throughout the developing nervous system. Importantly, many BMPs have been shown to be potent neurotrophic factors for dopaminergic neurons. Here we discuss recent work showing that transcripts for the BMP receptors and BMP2 are co-expressed with several key markers of dopaminergic neurons in the human substantia nigra, and evidence for downregulation of BMP2 expression at distinct stages of Parkinson’s disease. We also discuss studies that explored the effects of BMP2 treatment, in in vitro and in vivo models of Parkinson’s disease. These studies found potent effects of BMP2 on dopaminergic neurites, which is important given that axon degeneration is increasingly recognized as a key early event in Parkinson’s disease. Thus, the aim of this mini-review is to give an overview of the BMP family and the BMP-Smad signalling pathway, in addition to reviewing the available evidence demonstrating the potential of BMP2 for Parkinson’s disease therapy.

The loss of midbrain dopaminergic (mDA) neurons and their axons is central to Parkinson’s disease (PD). Growth differentiation factor (GDF)5 has been proposed as a neurotrophic factor for PD therapy. However the molecular mediators of its neurotrophic action are unknown. To address this, we performed proteomics analysis and identified that GDF5 increases the expression of two proteins, serine threonine receptor associated protein kinase (STRAP) and nucleoside diphosphate kinase (NME)1, in the SH-SY5Y neuronal cell line. We show that mRNAs encoding these proteins are expressed in the developing and adult midbrain in vivo. We also report that the expression of both STRAP and NME1 is necessary and sufficient for the promotion of neurite growth by GDF5 on SH-SY5Y cells. In summary, we identify NME1 and STRAP as key mediators of the neurotrophic effects of GDF5, which rationalises their further study as therapeutic targets for the protection of dopaminergic neurons in PD.

Accumulation of α-synuclein is a pathological hallmark of Parkinson’s disease (PD) and has been linked to reductions in neurite length and axonal degeneration of midbrain dopaminergic neurons. Mutations in SNCA, which encodes α-synuclein, and loss of function mutations in PTEN-induced putative kinase-1 (PINK1) cause familial PD. There is a need to identify the mechanisms by which α-synuclein overexpression and the loss of PINK1 induce neurodegeneration in PD. To do this, we employed rat ventral midbrain cultures to investigate the effects of overexpression of wildtype or mutant (A53T) α-synuclein, and of siRNA knockdown of PINK1, on neurite length and on mitochondrial and Golgi integrity. We found reduced neurite length and increased levels of both Golgi fragmentation and mitochondrial fission in response to overexpression of wildtype or mutant α-synuclein, and to PINK1 knockdown. Reductions in neurite length induced by these two PD risk genes were significantly correlated with increases in Golgi fragmentation and mitochondrial fission. Combined α-synuclein overexpression and PINK1 knockdown induced a greater reduction in neurite length and increase in Golgi fragmentation, than either alone. This study provides novel evidence that α-synuclein overexpression and PINK1 deletion converge to induce significant increases in Golgi fragmentation and mitochondrial fission in midbrain neurons, that are correlated with decreases in neurite length. This highlights the need for further studies on these converging mechanisms in dopaminergic neurodegeneration in PD.

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-1β 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.

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.

Objective: Evidence suggests that perinatal factors may contribute to the development of ADHD. Our objective was to examine the association between hypertensive disorders of pregnancy (HDP) and ADHD, and behavioral difficulties among 7-year-old children. Method: The study cohort consisted of 13,192 children (weighted = 13,500) who participated in the Millennium Cohort Study (MCS) at age 7. HDP (raised blood pressure, preeclampsia, eclampsia, and toxemia) were reported by mothers 9 months postdelivery. ADHD was reported by parents at age 7 years. Weighted logistic regression models were used to assess the association. Results: In all, 1,069 (7.9%) women reported HDP and 166 (1.2%) children had an ADHD diagnosis. There was a significant association between HDP and ADHD (adjusted odds ratio [OR] = 1.78, 95% confidence interval [CI] = [1.03, 3.07]). Conclusion: These findings suggest that HDP is associated with an increased risk of ADHD. It is important to confirm this in larger cohorts and to understand the biological basis of this association.

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.

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.

Background Hypertensive disorders of pregnancy (HDP) have been linked to adverse neurodevelopmental outcomes, including attention deficit hyperactivity disorder (ADHD). However, limitations of the literature such as residual confounding, and confounding due to shared genetics need to be addressed before more definitive conclusions can be reached. Therefore, the objective of this study was to examine the association between HDP and ADHD, using large Swedish-based registry data, allowing us to control for a wide range of confounding factors including confounding due to shared genetics. Methods All singleton live births in Sweden from 1990 to 2010 were included in the study. Data on HDP were obtained from the Medical Birth Register, and included three exposures of interest: 1. Preeclampsia 2. Chronic hypertension (both of which were classified according to ICD-9 and ICD-10 coding) 3. Preeclampsia and small for gestational age (SGA) combined, used as a proxy for the recent inclusion of uteroplacental dysfunction in the definition of preeclampsia. Data on ADHD was obtained from the National Patient Register and Prescribed Drug Register. A diagnosis of ADHD was determined in one of two ways: 1. If a diagnosis of ADHD was present in the National Patient Register, using ICD-10 coding. 2. If an individual was in receipt of ADHD medication, classified according to Anatomical Therapeutic Chemical classification system. Multivariate Cox proportional hazards regression analysis was conducted, adjusting for several perinatal and sociodemographic factors, selected a priori from previous literature. Sibling-matched analysis further controlled for shared genetic and familial confounding when an association was present in the adjusted Cox model. Results The cohort consisted of 2,047,619 children, with 114,934 (5.6%) cases of ADHD. In the adjusted Cox model, preeclampsia was associated with a 15% increase in the likelihood of ADHD (Hazard Ratio (HR): 1.15, 95% CI: 1.12, 1.19) compared to those unexposed to preeclampsia. Result of the sibling-matched analysis did not change materially (HR: 1.13, 95% CI: 1.05, 1.22). The HR for preeclampsia and those born SGA was 1.43 (95% CI: 1.31, 1.55) in the adjusted model, and 1.55 (95% CI: 1.28, 1.88) in the sibling-matched analysis. The HR for chronic hypertension-ADHD was 1.07 (95% CI: 0.97, 1.18) in the adjusted Cox model. Conclusion Exposure to preeclampsia or preeclampsia/SGA (i.e. SGA baby exposed to preeclampsia) was associated with ADHD, while chronic hypertension was not associated with ADHD. Placental pathology may be a common factor increasing the likelihood of ADHD given the stronger association with preeclampsia/SGA than preeclampsia alone.