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Article ; Online: The Impact of Maternal Inflammatory Conditions During Pregnancy on the Risk of Autism: Methodological Challenges.

Khashan, Ali S / O'Keeffe, Gerard W

Biological psychiatry global open science

2024 Volume 4, Issue 2, Page(s) 100287

Language	English
Publishing date	2024-03-15
Publishing country	United States
Document type	Journal Article
ISSN	2667-1743
ISSN (online)	2667-1743
DOI	10.1016/j.bpsgos.2023.100287
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Article ; Online: Characterisation of the consequences of maternal immune activation on distinct cell populations in the developing rat spinal cord.

Anderson, Rebecca C / O'Keeffe, Gerard W / McDermott, Kieran W

Journal of anatomy

2022 Volume 241, Issue 4, Page(s) 938–950

Abstract: 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 ...

Abstract	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<sup>+</sup> and Iba-1<sup>+</sup> 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<sup>+</sup> or Iba-1<sup>+</sup> cell number in the developing spinal cord 5 h after injection, however, Olig2<sup>+</sup> 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.
MeSH term(s)	Animals ; Astrocytes/physiology ; Glial Fibrillary Acidic Protein/metabolism ; Lipopolysaccharides/metabolism ; Microglia ; Rats ; Spinal Cord/metabolism
Chemical Substances	Glial Fibrillary Acidic Protein ; Lipopolysaccharides
Language	English
Publishing date	2022-07-09
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2955-5
ISSN	1469-7580 ; 0021-8782
ISSN (online)	1469-7580
ISSN	0021-8782
DOI	10.1111/joa.13726
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Article ; Online: sFlt-1 Impairs Neurite Growth and Neuronal Differentiation in SH-SY5Y Cells and Human Neurons.

Barron, Aaron / Barrett, Lauren / Tuulari, Jetro / Karlsson, Linnea / Karlsson, Hasse / McCarthy, Cathal M / O'Keeffe, Gerard W

Bioscience reports

2024

Abstract: 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 ... ...

Abstract	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.
Language	English
Publishing date	2024-05-03
Publishing country	England
Document type	Journal Article
ZDB-ID	764946-0
ISSN	1573-4935 ; 0144-8463
ISSN (online)	1573-4935
ISSN	0144-8463
DOI	10.1042/BSR20240562
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Article ; Online: Maternal hypertensive disorders of pregnancy and depression or anxiety in adolescence: Findings from the Millennium Cohort Study - a reply.

Keenan, Martin / Khashan, Ali S / O'Byrne, Laura J / O'Keeffe, Gerard W / Al Khalaf, Sukainah / Maher, Gillian M

Journal of affective disorders

2024 Volume 354, Page(s) 601–602

MeSH term(s)	Pregnancy ; Female ; Adolescent ; Humans ; Cohort Studies ; Depression/epidemiology ; Hypertension, Pregnancy-Induced ; Anxiety/epidemiology ; Anxiety Disorders/epidemiology ; Pregnancy Complications/epidemiology
Language	English
Publishing date	2024-03-19
Publishing country	Netherlands
Document type	Letter
ZDB-ID	135449-8
ISSN	1573-2517 ; 0165-0327
ISSN (online)	1573-2517
ISSN	0165-0327
DOI	10.1016/j.jad.2024.03.080
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Zs.A 1485: Show issues

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Article ; Online: A new role for placental IL-6 signalling in determining neurodevelopmental outcome.

O'Keeffe, Gerard W

Brain, behavior, and immunity

2017 Volume 62, Page(s) 9–10

MeSH term(s)	Brain ; Female ; Fetus ; Humans ; Interleukin-6 ; Placenta ; Pregnancy
Chemical Substances	Interleukin-6
Language	English
Publishing date	2017-02-17
Publishing country	Netherlands
Document type	Journal Article ; Comment
ZDB-ID	639219-2
ISSN	1090-2139 ; 0889-1591
ISSN (online)	1090-2139
ISSN	0889-1591
DOI	10.1016/j.bbi.2017.02.011
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Zs.A 2276: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 327: Show issues

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Article ; Online: The Universal Design for Learning Framework in Anatomical Sciences Education.

Balta, Joy Y / Supple, Briony / O'Keeffe, Gerard W

Anatomical sciences education

2020 Volume 14, Issue 1, Page(s) 71–78

Abstract: 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 ... ...

Abstract	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.
MeSH term(s)	Anatomy/education ; Curriculum ; Humans ; Learning ; Teaching ; Universal Design ; Universities
Language	English
Publishing date	2020-07-16
Publishing country	United States
Document type	Journal Article
ZDB-ID	2483491-9
ISSN	1935-9780 ; 1935-9772
ISSN (online)	1935-9780
ISSN	1935-9772
DOI	10.1002/ase.1992
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Zs.A 6787: Show issues

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Article ; Online: Preeclampsia and Neurodevelopmental Outcomes: Potential Pathogenic Roles for Inflammation and Oxidative Stress?

Barron, Aaron / McCarthy, Cathal M / O'Keeffe, Gerard W

Molecular neurobiology

2021 Volume 58, Issue 6, Page(s) 2734–2756

Abstract: 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 ... ...

Abstract	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.
MeSH term(s)	Animals ; Female ; Fetus/pathology ; Humans ; Inflammation/etiology ; Inflammation/pathology ; Nervous System/growth & development ; Nervous System/physiopathology ; Neurodevelopmental Disorders/etiology ; Neurodevelopmental Disorders/physiopathology ; Oxidative Stress ; Pre-Eclampsia/pathology ; Pregnancy
Language	English
Publishing date	2021-01-25
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	645020-9
ISSN	1559-1182 ; 0893-7648
ISSN (online)	1559-1182
ISSN	0893-7648
DOI	10.1007/s12035-021-02290-4
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Zs.A 2411: Show issues

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Article: Maternal Immune Activation and Interleukin 17A in the Pathogenesis of Autistic Spectrum Disorder and Why It Matters in the COVID-19 Era.

Carter, Michael / Casey, Sophie / O'Keeffe, Gerard W / Gibson, Louise / Gallagher, Louise / Murray, Deirdre M

Frontiers in psychiatry

2022 Volume 13, Page(s) 823096

Abstract: Autism spectrum disorder (ASD) is the commonest neurodevelopmental disability. It is a highly complex disorder with an increasing prevalence and an unclear etiology. Consensus indicates that ASD arises as a genetically modulated, and environmentally ... ...

Abstract	Autism spectrum disorder (ASD) is the commonest neurodevelopmental disability. It is a highly complex disorder with an increasing prevalence and an unclear etiology. Consensus indicates that ASD arises as a genetically modulated, and environmentally influenced condition. Although pathogenic rare genetic variants are detected in around 20% of cases of ASD, no single factor is responsible for the vast majority of ASD cases or that explains their characteristic clinical heterogeneity. However, a growing body of evidence suggests that ASD susceptibility involves an interplay between genetic factors and environmental exposures. One such environmental exposure which has received significant attention in this regard is maternal immune activation (MIA) resulting from bacterial or viral infection during pregnancy. Reproducible rodent models of ASD are well-established whereby induction of MIA in pregnant dams, leads to offspring displaying neuroanatomical, functional, and behavioral changes analogous to those seen in ASD. Blockade of specific inflammatory cytokines such as interleukin-17A during gestation remediates many of these observed behavioral effects, suggesting a causative or contributory role. Here, we review the growing body of animal and human-based evidence indicating that interleukin-17A may mediate the observed effects of MIA on neurodevelopmental outcomes in the offspring. This is particularly important given the current corona virus disease-2019 (COVID-19) pandemic as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during pregnancy is a potent stimulator of the maternal immune response, however the long-term effects of maternal SARS-CoV-2 infection on neurodevelopmental outcomes is unclear. This underscores the importance of monitoring neurodevelopmental outcomes in children exposed to SARS-CoV-2-induced MIA during gestation.
Language	English
Publishing date	2022-02-17
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2564218-2
ISSN	1664-0640
ISSN	1664-0640
DOI	10.3389/fpsyt.2022.823096
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Article: Maternal pre-eclampsia serum increases neurite growth and mitochondrial function through a potential IL-6-dependent mechanism in differentiated SH-SY5Y cells.

Barron, Aaron / Manna, Samprikta / McElwain, Colm J / Musumeci, Andrea / McCarthy, Fergus P / O'Keeffe, Gerard W / McCarthy, Cathal M

Frontiers in physiology

2023 Volume 13, Page(s) 1043481

Abstract: Introduction: ...

Abstract	Introduction:
Language	English
Publishing date	2023-01-12
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2564217-0
ISSN	1664-042X
ISSN	1664-042X
DOI	10.3389/fphys.2022.1043481
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Article ; Online: Maternal hypertensive disorders of pregnancy and depression or anxiety in adolescence: Findings from the Millennium Cohort Study.

Keenan, Martin / Khashan, Ali S / O'Byrne, Laura J / O'Keeffe, Gerard W / Al Khalaf, Sukainah / Maher, Gillian M

Journal of affective disorders

2023 Volume 347, Page(s) 23–28

Abstract: Background: The short-term effects of hypertensive disorders of pregnancy (HDP) on the health of the fetus are well known; however, their impacts on the risk of mental health in the exposed offspring are not fully understood. Our aim was to examine the ... ...

Abstract	Background: The short-term effects of hypertensive disorders of pregnancy (HDP) on the health of the fetus are well known; however, their impacts on the risk of mental health in the exposed offspring are not fully understood. Our aim was to examine the association between HDP and depression/anxiety at age 17 years. Methods: We used data from The Millennium Cohort Study, a nationally representative longitudinal study of children born in the United Kingdom. Data on HDP and potential confounders were collected when children were 9-months. Data on depression and anxiety were collected as one variable when children were aged 17 years using self-reported doctor diagnosis, and reclassified as depression/anxiety (overall), depression/anxiety with treatment, and depression/anxiety without treatment. Crude and adjusted logistic regression models were performed to examine the association between HDP and depression/anxiety, adjusting for several maternal and socio-economic factors. Results: There were 9517 singleton mother-child pairs included in the analyses. Adjusted logistic regression suggested an association between HDP and depression/anxiety (adjusted odds ratio, (aOR):1.30 [95 % CI, 1.02-1.66]) at age 17 years. A similar association was observed for HDP and depression/anxiety with treatment (aOR:1.33 [95 % CI, 1.01-1.73]) and HDP and depression/anxiety without treatment (aOR: 1.30 [95 % CI, 0.80-2.12]), although the latter did not reach statistical significance. Limitations: Data on severity and classifications of HDP were not available. Conclusion: Exposure to HDP may be associated with an increased likelihood of depression or anxiety at age 17 years. Future research should consider severity and different classifications of HDP.
MeSH term(s)	Pregnancy ; Female ; Adolescent ; Humans ; Cohort Studies ; Hypertension, Pregnancy-Induced/diagnosis ; Longitudinal Studies ; Depression/epidemiology ; Anxiety/epidemiology ; Risk Factors
Language	English
Publishing date	2023-11-18
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	135449-8
ISSN	1573-2517 ; 0165-0327
ISSN (online)	1573-2517
ISSN	0165-0327
DOI	10.1016/j.jad.2023.11.042
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