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PubMed2025

Impact of the maternal microbiome on neonatal immune development.

Historically, multigenerational health and disease transmission have primarily focused on genetic inheritance. However, the discovery that beneficial microorganisms known as commensal microbiota outnumber human genes tenfold has reshaped this perspective, highlighting their critical role in maintaining homeostasis and protecting against pathogens. Unlike the human genome, commensal microbiota is not genetically inherited but is acquired anew with each generation. with initial gut colonization playing a pivotal role in shaping an infant's immune system, neurodevelopment, and long-term health, all heavily influenced by maternal factors. In this review, we examine emerging research on maternal microbial influences on the fetus beginning in utero. We provide an updated overview of the current insights into the impact of the vaginal microbiome during parturition on offspring immunity and discuss the potential long-term health implications for infants born via cesarean section. We explore the advantages and limitations of techniques designed to mitigate these effects, such as vaginal seeding and emphasize that the development of the neonatal immune system is a dynamic process influenced by maternal factors beyond birth, including the transfer of microbiota through breast milk and skin contact. Finally, we present gaps in current research and propose future research directions to deepen our understanding of the impacts of the maternal microbiome on her child. Together, these insights demonstrate how maternal influence on offspring health and immunity extends beyond genetic factors, encompassing the transmission of microbiota, which, in turn, has profound long-term implications for health and disease resilience, offering a novel perspective on intergenerational health dynamics.

Humans↗

PubMed2006

Intermediate-term outcomes of the arterial switch operation for transposition of great arteries in neonates: alive but well?

OBJECTIVES: This interprovincial inception cohort study outlines the operative and intermediate outcomes of all neonates at a single institution with a broad referral area who underwent the arterial switch operation for transposition of great arteries, including complex types. Predictors of outcome are explored. METHODS: A total of 88 consecutive neonates underwent the arterial switch operation between 1996 and 2004 with full-flow (150 mg/kg/min) cardiopulmonary bypass with selective deep hypothermic circulatory arrest. Overall and event-free survivals were calculated. Health and neurodevelopment (Bayley Scales of Infant Development II) were assessed at 18 to 24 months of age. Univariate and multivariate analyses, sensitivity, and specificity were determined to identify preoperative, intraoperative, and postoperative factors associated with mental and/or motor delay. RESULTS: There was 1 operative mortality (1.1%). At the average 4-year follow-up, survival was 98.9% and freedom from reintervention was 93.2%. Eighty-five children were assessed. Three were excluded because of unrelated postoperative diagnoses. For the remaining 82, mean scores were 89 +/- 17 (49-118) for mental skills and 92 +/- 15 (49-125) for motor skills. Anatomic complexity, cardiopulmonary bypass, and deep hypothermic circulatory arrest times were not associated with developmental outcome. Preoperative variables of low gestational age and high preoperative lactate correctly classified 84.1% of mentally and/or motor-delayed children. CONCLUSION: Transposition of great arteries, including complex types, can be corrected with low surgical risk and good intermediate survival; however, neurodevelopmental outcome is a concern. These data suggest that although anatomic complexity may not affect late outcome, there may be potentially modifiable preoperative factors that can be optimized to improve developmental outcomes.

Cardiac Surgical Procedures↗

PubMed2006

Neuronal macroautophagy: from development to degeneration.

Macroautophagy, a lysosomal pathway responsible for the turnover of organelles and long-lived proteins, has been regarded mainly as an inducible process in neurons, which is mobilized in states of stress and injury. New studies show, however, that macroautophagy is also constitutively active in healthy neurons and is vital to cell survival. Neurons in the brain, unlike cells in the periphery, are protected from large-scale autophagy induction because they can use several different energy sources optimally, receive additional nutrients and neurotrophin support from glial cells, and benefit from hypothalamic regulation of peripheral nutrient supplies. Due to its exceptional efficiency, constitutive autophagy in healthy neurons proceeds in the absence of easily detectable autophagic vacuole intermediates. These intermediates can accumulate rapidly, however, when late steps in the autophagic process are blocked. Autophagic vacuoles also accumulate abnormally in affected neurons of several major neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease, where they have been linked to various aspects of disease pathogenesis including neuronal cell death. The build-up of autophagic vacuoles in these neurological disorders and others may reflect either heightened autophagy induction, impairment in later digestive steps in the autophagy pathway, or both. Determining the basis for AV accumulation is critical for understanding the pathogenic significance of autophagy in a given pathologic state and for designing possible therapies based on modulating autophagy. In this review, we discuss the special features of autophagy regulation in the brain, its suspected roles in neurodevelopment and plasticity, and recent progress toward understanding how dysfunctional autophagy contributes to neurodegenerative disease.

Animals↗

PubMed2006

Impact of intrauterine growth restriction and glucocorticoids on brain development: insights using advanced magnetic resonance imaging.

There are now a number of evidences showing that the developing organism adapts to the environment it finds itself. Short- and long-term adjustments, referred as "programming", take place and will initially induce intrauterine growth retardation but will also have consequences that will appear later in life. The use of magnetic resonance imaging (MRI) techniques in IUGR babies has delineated changes in the central nervous system (CNS) development that correlate with altered neurodevelopment and could be implicated in the development of neuropsychiatric disorders in adult life. Similarly, the use of corticosteroid treatment in preterm infants has also been implicated in abnormal CNS development. In this review, we will focus on the modifications of CNS development that occur after exposition to adverse environment such as undernutrition or corticosteroid treatment that can now be studied in vivo with advanced MRI technology.

Animals↗

PubMed2004

Chaotic solar cycles modulate the incidence and severity of mental illness.

This paper hypothesizes that the intensity of ultraviolet radiation (UVR) from the Sun predisposes humans to polygenic mutation fostering major mental illness (MMI) and other disorders of neurodevelopment. In addition, the variation in the intensity of this radiation acts to stress immune systems, possibly mediated by cytokines, resulting in variable clinical expressions of mental illness and autoimmune disorders. Organisms can adapt to chronic high-intensity UVR by producing melanin and by retaining various pigments. We found that 28% of 11-year solar cycles produce particularly severe solar flares during which UVR is 300% more intense and hence more damaging than normal. Out of a total of six severe cycles in the past 250 years, four have occurred in the past 55 years, possibly explaining the apparent increase in the incidence of MMI in recent decades. UVR is 10 times more mutagenic than ionizing radiation to nuclear DNA, and especially damaging to mitochondrial DNA. However, variable light as manifested by seasons stresses adaptability to UVR, possibly through an immune mechanism. We show that the region of the Earth having the most UVR, relative to the most variation in that light, is at 54 +/-10 degrees (N or S) latitude. Therefore, the most potential damage from sunlight occurs between the Equator and the Poles, not at the Equator itself. The human brain, our most important organ of adaptability, must be able to survive environmental variation, with successful matching to the environment resulting in adaptation. Unsuccessful adaptation to UVR (and possibly other types of radiation) results in mutation, which can produce neuro-chemical abnormalities manifested by MMI. We postulate that the combination of intensity and variation in UVR serves as a global modulator of MMI.

Causality↗

PubMed2005

Does god play dice with schizophrenia? A probabilistic model for the understanding of causation in mental illness.

While the pure sciences have moved over the XX century from the certainties of the Laplacian mechanistic models to probabilistic ones, such as quantum physics, the attempts to explain the causation in mental illness are still stuck to deterministic frameworks which are deceptively reassuring, but also too simplistic to approach problems of such a complexity. The deterministic approach has led to several false leads that have affected research in the aetiology in mental illness, especially schizophrenia, and only moving to probabilistic models will allow an understanding of the causal processes. In this paper is challenged the almost universally accepted assumption that, to explain the lack of complete concordance amongst identical twins in schizophrenia, there is the need to resort to environmental aetiological agents. It is described instead how, using a probabilistic framework, a polygenic model without threshold can satisfactorily explain the data available so far without having to resort to environmental factors. The genes predisposing to schizophrenia, probably through a derailment of the neurodevelopment, would have a normal distribution in the general population, while the liability for the illness will increase exponentially with the number of risk genes, with a small minority of the population being at high risk. The average genetic liability to develop schizophrenia in individuals who later are affected by the disorder is around 50%. The adoption of a probabilistic model for the understanding of the inheritance of schizophrenia has therefore far reaching consequences, revolutionizing the interpretation of the twin studies, allowing a consistent model which does not require environmental interventions in the aetiology of schizophrenia and offering a framework to make sense of findings from the epidemiological research which are not satisfactorily explained by the deterministic models adopted so far.

Genetic Predisposition to Disease↗

PubMed2005

Prion protein: a pattern recognition receptor for viral components and uric acid responsible for the induction of innate and adaptive immunity.

Prion protein, known as Prp(c), is a GPI-anchored membrane bound glycoprotein ubiquitously expressed in the body. To date, the precise nature of its physiological role remains a mystery. The prion protein's presence on neurons and immune effector cells suggests a dual neurological and immunological function. Some consensus exists regarding the proposed involvement of Prp(c) in neurodevelopment, where it would serve to mediate interactions between the extra-cellular matrix (ECM) and the neuron. There is also evidence that Prp plays a part in immunity, although the exact nature of the role remains unclear. Interestingly, a role in both immunity and development is a functional division seen in other types of receptors, most notably the Toll Receptor. In mammals, toll-like receptors (TLRs) are partly responsible for both innate and adaptive immune activity. However, recently several TLR independent pathways have been identified that initiate such responses. Unfortunately, receptors for such pathways remain unidentified. But based upon its functional homology to Toll Receptors, its known interactions with several viruses, and its possible downstream effector proteins, it is proposed that Prp(c) represents a new type of pattern recognition receptor responsible for TLR-independent induction of myeloid dendritic cell and macrophage maturation and later T-cell activation. From what is known of the ligands for the prion protein, it is proposed that this response would be initiated via the binding of uric acid, viral RNA, or viral structural proteins to Prp(c). It will further be proposed that Prp(c)'s ability to interact with viral components stems from its evolutionary origin as a horizontally transferred gene from an early RNA virus. Finally, Prp(c)'s functional role in immunity will be related to the pathophysiology of TSEs, with observations made concerning immune response to infection and agent composition.

Animals↗

PubMed2004

Expression patterns of the novel imprinted genes Nap1l5 and Peg13 and their non-imprinted host genes in the adult mouse brain.

Recent work has implicated imprinted gene functioning in neurodevelopment and behaviour and defining the expression patterns of these genes in brain tissue has become a key prerequisite to establishing function. In this work we report on the expression patterns of two novel imprinted loci, Nap1l5 and Peg13, in adult mouse brain using in situ hybridisation methods. Nap1l5 and Peg13 are located, respectively, within the introns of the non-imprinted genes Herc3 and the Tularik1 (T1)/KIAA1882 homologue in two separate microimprinted domains on mouse chromosomes 6 and 15. These 'host' genes are highly expressed in brain and consequently we were interested in assessing their expression patterns in parallel to the imprinted genes. The brain expression of all four genes appeared to be mainly neuronal. The detailed expression profiles of Nap1l5 and Peg13 were generally similar with widespread expression that was relatively high in the septal and hypothalamic regions, the hippocampus and the cerebral cortex. In contrast, there was some degree of dissociation between the imprinted genes and their non-imprinted hosts, in that, whilst there was again widespread expression of Herc3 and the T1/KIAA1882 homologue, these genes were also particularly highly expressed in Purkinje neurons and piriform cortex. We also examined expression of the novel imprinted genes in the adrenal glands. Nap1l5 expression was localised mainly to the adrenal medulla, whilst Peg13 expression was observed more generally throughout the adrenal medulla and the outer cortical layers.

Animals↗

PubMed2005

Expression pattern of the maternally imprinted gene Gtl2 in the forebrain during embryonic development and adulthood.

Recent work has uncovered a large number of imprinted genes, many of which are thought to play a role in neurodevelopment and behavior. In order to begin to understand the role of specific genes in these processes, their expression patterns will be key. In this study we used in situ hybridization to study the developmental expression of Gtl2 in the forebrain from E12.5 to adulthood, since preliminary data from a microarray study indicated differential expression between the ventral and dorsal telencephalon of the mouse at a critical time point in the generation and migration of cortical neuronal populations. Strong expression was observed in the diencephalon, ventral telencephalon, post mitotic cell layers of the neocortex and pyramidal cell layer of the hippocampus. Additionally, heavily labeled subpopulations of laminar restricted cells were seen in the latter two areas.

Animals↗

PubMed2004

Expression of the methyl-CpG-binding protein MeCP2 in rat brain. An ontogenetic study.

Rett syndrome (RS) is caused by mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2) and is characterized by arrested postnatal neurodevelopment. We followed the expression of MeCP2 protein in various brain structures of normal rat from birth to 2 years of age. By measuring the amount of protein using the Western blot technique, or by determining the percentage of immunoreactive cells, significant heterogeneity in MeCP2 distribution among various brain areas was observed. Highest expression was found in olfactory bulb and in frontal cortex. In contrast, little expression was detected in caudate-putamen, septum and hippocampus. Except in the olfactive nuclei, very few cells showed detectable MeCP2 protein at birth. The number increased during the first week of age, especially in cortex and nucleus accumbens. Rather than playing a global role in gene transcription, the heterogeneous distribution of MeCP2 transcription factor favors the idea that it has a specialized function in neurons.

Age Factors↗

PubMed2006

DYRK1A BAC transgenic mice show altered synaptic plasticity with learning and memory defects.

Among the various phenotypes seen in Down syndrome (DS), mental retardation is the most common and most debilitating condition suffered by individuals with DS. The DYRK1A gene on human chromosome 21q22.2 encodes a subfamily of protein kinases that displays dual substrate specificities and is known to play a critical role in neurodevelopment. To study DS mental retardation, we have generated transgenic mice that contain only one copy of the complete human DYRK1A gene in a bacterial artificial chromosome. The transgenic mice showed significant impairment in hippocampal-dependent memory tasks in a Morris water maze. Interestingly, we observed shifts in both long-term potentiation and long-term depression, which suggests a role for DYRK1A in bidirectional synaptic plasticity. These mice represent the most clinically relevant DYRK1A mouse model to date and provide us a valuable tool for the in vivo study of mechanisms that underlie the learning and memory deficit in DS.

Animals↗

PubMed2005

Maternal adversity, glucocorticoids and programming of neuroendocrine function and behaviour.

The fetus may be exposed to increased endogenous glucocorticoid or synthetic glucocorticoid in late gestation. Approximately 7% of pregnant women in Europe and North America are treated with synthetic glucocorticoid to promote lung maturation in fetuses at risk of preterm delivery. Very little is known about the mechanisms by which synthetic glucocorticoid or prenatal stress influence neurodevelopment in the human, or whether specific time windows of increased sensitivity exist. Glucocorticoids are essential for many aspects of normal brain development, but exposure of the fetal brain to excess glucocorticoid can have life-long effects on neuroendocrine function and behaviour. Both endogenous glucocorticoid and synthetic glucocorticoid exposure have a number of rapid effects in the fetal brain, including modification of neurotransmitter systems and transcriptional machinery. Such fetal exposure permanently alters hypothalamo-pituitary-adrenal (HPA) function in prepubertal, postpubertal and aging offspring, in a sex-dependent manner. Prenatal glucocorticoid manipulation also leads to modification of behaviour, brain and organ morphology, as well as altered regulation of other endocrine systems. Permanent changes in endocrine function will impact on health, since elevated cumulative exposure to endogenous glucocorticoid is linked to the premature onset of pathologies associated with aging.

Animals↗

PubMed2005

Imprinted gene expression in the brain.

In normal mammals, autosomal genes are present in duplicate (i.e. two alleles), one inherited from the father, and one from the mother. For the majority of genes both alleles are transcribed (or expressed) equally. However, for a small subset of genes, known as imprinted genes, only one allele is expressed in a parent-of-origin dependent manner (note that the 'imprint' here refers to the epigenetic mechanism through which one allele is silenced, and is completely unrelated to classical 'filial imprinting' manifest at the behavioural level). Thus, for some imprinted genes expression is only (or predominantly) seen from the paternally inherited allele, whilst for the remainder, expression is only observed from the maternally inherited allele. Early work on this class of genes highlighted their importance in gross developmental and growth phenotypes. Recent studies in mouse models and humans have emphasised their contribution to brain function and behaviour. In this article, we review the literature concerning the expression of imprinted genes in the brain. In particular, we attempt to define emerging organisation themes, especially in terms of the direction of imprinting (i.e. maternal or paternal expression). We also emphasise the likely role of imprinted genes in neurodevelopment. We end by pointing out that, so far as discerning the precise functions of imprinted genes in the brain is concerned, there are currently more questions than answers; ranging from the extent to which imprinted genes might contribute to common mental disorders, to wider issues related to how easily the new data on brain may be accommodated within the dominant theory regarding the origins and maintenance of imprinting, which pits the maternal and paternal genomes against each other in an evolutionary battle of the sexes.

Animals↗

PubMed2026

Epigenome-wide placental methylation landscapes in relation to antenatal depressive symptoms.

Antenatal depressive symptoms (ADS) are common during pregnancy and are linked to adverse maternal and offspring neurodevelopmental outcomes. The placenta plays a central role in maternal-fetal communication and may function as an epigenetic sensor of maternal psychological stress. However, placental epigenetic signatures associated with ADS remain poorly understood. This study investigated epigenome-wide placental DNA methylation patterns associated with ADS in an Indian cohort. Placental samples were collected at delivery from women recruited in early pregnancy into the STRiDE cohort. Depressive symptoms were assessed at 24-28 weeks' gestation using the Patient Health Questionnaire-9 (PHQ-9). Participants were classified as controls (PHQ-9 ≤ 4; n = 53) or ADS (PHQ-9 > 4; n = 54). Genome-wide DNA methylation profiling was performed using the Illumina Infinium MethylationEPIC array. Epigenome-wide association analysis identified no CpG sites that remained statistically significant after Benjamini-Hochberg FDR correction. Top nominal CpGs showed medium-to-large effect sizes for ADS. Exploratory analyses of the top nominally associated CpGs annotated to genes including TAP2, LRCH1, SLITRK2, RASSF1 and IL3 implicated in immune regulation, cellular signalling and neurodevelopment. Gene enrichment analysis suggested the involvement of biological processes and pathways related to synaptic organization, ion transport, Hippo signalling, and thyroid hormone regulation. In conclusion, the study findings provide preliminary evidence of DNA methylation signatures linked to potential candidate genes and biological pathways that may be relevant to ADS, supporting the need for validation in larger independent cohorts and functional experimental studies.

Asian Indians↗

PubMed2003

The human frizzled-3 (FZD3) gene on chromosome 8p21, a receptor gene for Wnt ligands, is associated with the susceptibility to schizophrenia.

Neurodevelopmental abnormalities have been reported in studies on the pathogenesis of schizophrenia. The Wnt-signaling pathway has been implicated in a variety of processes in neurodevelopment, and the frizzled proteins have been identified as receptors for Wnt ligands. Of the frizzled proteins, frizzled-3 (FZD3) is required for formation of the neural crest and for development of major fiber tracts in the CNS. The human FZD3 gene is located on chromosome 8p21, a positive linkage locus for schizophrenia. We analyzed polymorphisms of the FZD3 gene in patients with schizophrenia and control subjects in the Japanese population. We found a significant association between schizophrenia and the FZD3 gene in single nucleotide polymorphisms and haplotype analyses. Our data suggest that dysregulation of the Wnt-signaling pathway may be involved in the susceptibility to schizophrenia.

Adult↗

PubMed2004

Perinatal flunitrazepam exposure causes persistent alteration of parvalbumin-immunoreactive interneuron localization in rat prefrontal cortex.

GABA regulates proliferation via GABAA receptors during development of the neocortex. We recently demonstrated that the endogenous GABAA receptor modulator allopregnanolone plays a role in regulating normal neurodevelopment in prefrontal cortex. Benzodiazepine exposure during early development produces marked behavioral changes in adult rats. To determine if exposure to benzodiazepines during development alters GABAergic interneurons in prefrontal cortex (PFC), rat pups were exposed to flunitrazepam (2.5 mg/kg) on postnatal day (P) 2 and assayed for parvalbumin- and calbindin-immunoreactivity on P80. The ratio of parvalbumin labeled cells in deep vs. superficial layers increased five-fold; calbindin-immunoreactivity and total cell number were not altered. These data are consistent with altered distribution of a subset of interneurons after benzodiazepine exposure and suggest a role for GABAA receptor modulation in normal development of GABAergic systems in PFC.

Animals↗

PubMed2004

Psychotic symptoms in Alzheimer's disease are not influenced by polymorphic variation at the dopamine receptor DRD3 gene.

It has been suggested that genetic influences unmasked during neurodevelopment to produce schizophrenia may appear throughout neurodegeneration to produce AD plus psychosis. Risk of schizophrenia and psychosis in Alzheimer's disease (AD) has been linked to polymorphic variation at the dopamine receptor DRD3 gene implying similar causative mechanisms. We tested this association in a large cohort of Alzheimer's disease patients with a diagnosis of probable AD of 3 years or more duration from the relatively genetically homogenous Northern Irish population. We assessed relationships between genotypes/alleles of the DRD3 BalI polymorphism and the presence or absence of psychotic symptoms (delusions, hallucinations) in AD patients during the month prior to interview and at any stage during the dementia. No significant associations were found when delusions and hallucinations were cross-tabulated against S and G alleles and SS, SG and GG genotypes. Logistic regression failed to detect any influence of APOE, gender, family history or prior psychiatric history. In conclusion, we were unable to confirm previously reported associations between the DRD3 BalI polymorphism and psychotic symptoms in AD.

Aged↗

PubMed2004

Tumor suppressor gene TP53 is genetically associated with schizophrenia in the Chinese population.

Schizophrenia is a debilitating mental disorder. The TP53 tumor suppressor gene, encoding a phosphoprotein, is a key element in maintaining genomic stability and cell apoptosis. Recently, reduced risk of cancer in patients of schizophrenia has been reported. Some evidence also suggests the possible implication of TP53 in neurodevelopment. In order to examine the role of the TP53 gene in the pathogenesis of schizophrenic disorders, we investigated the genetic association between a functional polymorphism rs1042522 and schizophrenia by sequencing the fragment covering 72Pro> Arg in 701 cases and 695 controls in this work. In addition, we studied two other SNPs rs2078486 and rs8064946 by allele-specific PCR in the same samples. Though rs1042522 and rs8064946 did not show positive association with schizophrenia, we did observe statistically significant differences on SNP rs2078486 (P-value = 0.029; OR = 1.21; 95% CI 1.02-1.42) and on haplotype CAC (P-value = 0.0068; OR = 1.36; 95% CI 1.09-1.70). These results demonstrated that TP53 might play a role in susceptibility to schizophrenia.

Adult↗