Rare germline heterozygous missense variants in BRCA1-associated protein 1, BAP1, cause a syndromic neurodevelopmental disorder.

Nuclear deubiquitinase BAP1 (BRCA1-associated protein 1) is a core component of multiprotein complexes that promote transcription by reversing the ubiquitination of histone 2A (H2A). BAP1 is a tumor suppressor whose germline loss-of-function variants predispose to cancer. To our knowledge, there are very rare examples of different germline variants in the same gene causing either a neurodevelopmental disorder (NDD) or a tumor predisposition syndrome. Here, we report a series of 11 de novo germline heterozygous missense BAP1 variants associated with a rare syndromic NDD. Functional analysis showed that most of the variants cannot rescue the consequences of BAP1 inactivation, suggesting a loss-of-function mechanism. In T cells isolated from two affected children, H2A deubiquitination was impaired. In matching peripheral blood mononuclear cells, histone H3 K27 acetylation ChIP-seq indicated that these BAP1 variants induced genome-wide chromatin state alterations, with enrichment for regulatory regions surrounding genes of the ubiquitin-proteasome system (UPS). Altogether, these results define a clinical syndrome caused by rare germline missense BAP1 variants that alter chromatin remodeling through abnormal histone ubiquitination and lead to transcriptional dysregulation of developmental genes.

The role of T-cells in neurobehavioural development: Insights from the immunodeficient nude mice.

Mice homozygous for the nude mutation (Foxn1nu) are hairless and exhibit congenital dysgenesis of the thymic epithelium, resulting in a primary immunodeficiency of mature T-cells, and have been used for decades in research with tumour grafts. Early studies have already demonstrated social behaviour impairments and central nervous system (CNS) alterations in these animals, but did not address the complex interplay between CNS, immune system and behavioural alterations. Here we investigate the impact of T-cell immunodeficiency on behaviours relevant to the study of neurodevelopmental and neuropsychiatric disorders. Moreover, we aimed to characterise in a multidisciplinary manner the alterations related to those findings, through evaluation of the excitatory/inhibitory synaptic proteins, cytokines expression and biological spectrum signature of different biomolecules in nude mice CNS. We demonstrate that BALB/c nude mice display sociability impairments, a complex pattern of repetitive behaviours and higher sensitivity to thermal nociception. These animals also have a reduced IFN-γ gene expression in the prefrontal cortex and an absence of T-cells in meningeal tissue, both known modulators of social behaviour. Furthermore, excitatory synaptic protein PSD-95 immunoreactivity was also reduced in the prefrontal cortex, suggesting an intricate involvement of social behaviour related mechanisms. Lastly, employing biospectroscopy analysis, we have demonstrated that BALB/c nude mice have a different CNS spectrochemical signature compared to their heterozygous littermates. Altogether, our results show a comprehensive behavioural analysis of BALB/c nude mice and potential neuroimmunological influences involved with the observed alterations.

[Immunopsychiatry and SARS-CoV-2 pandemic: Links and possible consequences]. / Immuno-psychiatrie et pandémie de SARS-CoV-2 : liens et possibles conséquences.

OBJECTIVE: The SARS-CoV-2 (or COVID-19) pandemic has been propagating since December 2019, inducing a drastic increase in the prevalence of anxious and depressive disorders in the general population. Psychological trauma can partly explain these disorders. However, since psychiatric disorders also have an immuno-inflammatory component, the direct effects of the virus on the host's immune system, with a marked inflammatory response, but also the secondary inflammation to these psychosocial stressors, may cause the apparition or the worsening of psychiatric disorders. We describe here the probable immunopsychiatric consequences of the SARS-CoV-2 pandemic, to delineate possible screening actions and care that could be planned. METHOD: Data from previous pandemics, and existing data on the psychopathological consequences of the SARS-CoV-2 pandemic, allowed us to review the possible immunopsychiatric consequences of the SARS-CoV-2 pandemic, on the gestational environment, with the risk of consecutive neurodevelopmental disorders for the fetus on one hand, on the children and adults directly infected being at increased risks of psychiatric disorders on the other hand. RESULTS: As in previous pandemics, the activation of the immune system due to psychological stress and/or to infection during pregnancy, might lead to an increased risk of neurodevelopmental disorders for the fetus (schizophrenia and autism spectrum disorders). Furthermore, in individuals exposed to psychological trauma and/or infected by the virus, the risk of psychiatric disorders, especially mood disorders, is probably increased. CONCLUSION: In this context, preventive measures and specialized care are necessary. Thus, it is important to propose a close follow-up to the individuals who have been infected by the virus, in order to set up the earliest care possible. Likewise, in pregnant women, screening of mood disorders during the pregnancy or the postpartum period must be facilitated. The follow-up of the babies born during the pandemic must be strengthened to screen and care for possible neurodevelopmental disorders.

Dietary intake of glucoraphanin during pregnancy and lactation prevents the behavioral abnormalities in the offspring after maternal immune activation.

AIM: Epidemiological data suggest that maternal immune activation (MIA) plays a role in the etiology of neuropsychiatric disorders including autism spectrum disorder (ASD) and schizophrenia. However, there is no prophylactic nutrition that can prevent the onset of neurodevelopmental disorders in offspring after MIA. The aim of this study was undertaken to examine whether dietary intake of glucoraphanin (GF: the precursor of a natural anti-inflammatory compound sulforaphane) can prevent the onset of behavioral abnormalities in offspring after MIA. METHODS: One percent of GF food pellet or normal food pellet was given into female mice during pregnancy and lactation (from E5 to P21). Saline (5 mL/kg/d) or poly(I:C) (5 mg/kg/d) was injected into pregnant mice from E12 to E17. Behavioral tests and immunohistochemistry of parvalbumin (PV) were performed in male offspring. RESULTS: Dietary intake of GF during pregnancy and lactation prevented cognitive deficits and social interaction deficits in the juvenile offspring after MIA. Furthermore, dietary intake of GF during pregnancy and lactation prevented cognitive deficits in the adult offspring after MIA. Moreover, dietary intake of GF prevented the reduction of PV immunoreactivity in the medial prefrontal cortex of adult offspring after MIA. CONCLUSION: These data suggest that dietary intake of GF during pregnancy and lactation could prevent behavioral abnormalities in offspring after MIA.

Cytokine dysregulation persists in childhood post Neonatal Encephalopathy.

BACKGROUND: Cytokines are possible mediators of neuroinflammation and associated with adverse outcome in neonatal encephalopathy (NE). Our aim was to explore cytokine response in children with Neonatal Encephalopathy (NE) at school age compared to age-matched controls. METHOD: Follow up at school age, children who had NE and age-matched controls were assessed for their cytokine responses and neurodevelopment outcome. Pro- and anti-inflammatory cytokines in the serum, [Interleukin (IL)-1α, IL-1ß, IL-2, IL-6, IL-8, IL-18, Tumor necrosis factor (TNF)-α, TNF ß, Interferon (IFN)-γ, granulocyte-macrophage colony-stimulating factor (GM-CSF), vascular endothelial growth factor (VEGF), erythropoietin (EPO), IL-10 & IL-1RA] were measured at baseline and in response to in vitro stimulation with lipopolysaccharide (LPS: endotoxin). RESULTS: GM-CSF, TNF-ß, IL-2 IL-6 and IL-8 were significantly elevated at school age following NE (n = 40) compared to controls (n = 37). A rise in GM-CSF, IL-8, TNF-α, IL-1ß, & IL-6 were seen in NE group following LPS stimulation. Relative LPS hypo-responsiveness was also noted in children with severe NE with IL-10, VEGF, EPO and TNF-ß. Elevated TNF-ß was associated with low gross motor scores on assessment at school age. CONCLUSION: School-age children post-NE had significantly altered cytokine responses to endotoxin compared to controls. TNF-ß was associated with adverse developmental outcomes. This suggests the inflammatory process may persist into childhood and a longer therapeutic window may be available for neuroprotection therapies.

Molecular mechanisms underlying the models of neurodevelopmental disorders in maternal immune activation relevant to the placenta.

The rapid rise in the prevalence of autism spectrum disorders (ASD) and other psychiatric disorders displaying similar traits has increased the need to elucidate their molecular mechanisms. Epidemiological studies have shown that maternal infection during mid-pregnancy is associated with increased risk of neurodevelopmental disorders such as ASD in offspring. Using maternal infection models, researchers have gathered evidence relevant to such disorders. A comprehensive summary of the changes in the brain structure, function, and behavior in offspring induced by maternal immune activation (MIA) has been reported. However, the molecular mechanisms underlying the association between MIA and improper brain development, which ultimately lead to neurodevelopmental disorders, have not been fully reviewed. This paper summarizes the currently known molecular mechanisms associated with the MIA model, with a special focus on the role of the placenta in fetal brain development.

The Impact of Systemic Inflammation on Neurodevelopment.

Inflammatory mediators affect the brain during development. Neurodevelopmental disorders such as autism spectrum disorders, cognitive impairment, cerebral palsy, epilepsy, and schizophrenia have been linked to early life inflammation. Recent advances have shown the effects of systemic inflammation on children's neurodevelopment. We discuss the potential mechanisms by which inflammatory molecules can exert their effects on the developing brain and consider the roles of MHC class I molecules, the HPA axis, glial cells, and monoamine metabolism. Methods to prevent the effects of cytokine imbalance may lead to the development of new therapeutics for neuropsychiatric disorders. Future research should focus on identifying at-risk individuals and early effective interventions to prevent long-term neurodevelopmental disabilities.

The role of immune cells in brain development and neurodevelopmental diseases.

During brain development, the generation of neurons and glial cells is rigorously regulated by diverse mechanisms including the immune system. Dysfunction of the developing system results in the onset of neurodevelopmental disorders and psychological disorders. Recent studies have demonstrated that the immune system is implicated in brain development. As the central nervous system is physically separated from the circulatory system by the blood-brain barrier, circulating immune cells are unable to infiltrate into the brain parenchyma. However, several studies have demonstrated that immune cells, such as B cells, T cells and macrophages, are observed in the meningeal space, perivascular space and choroid plexus and have crucial roles in brain function. Moreover, genome-wide association studies have revealed that the immune system is implicated in neurodevelopmental disorders and psychological disorders. Here, we discuss the role of each of these immune cell types in brain development and the association with neurodevelopmental disorders.

Chronic inflammation and impaired development of the preterm brain.

The preterm newborn is at significant risk of neural injury and impaired neurodevelopment. Infants with mild or no evidence of injury may also be at risk of altered brain development, with evidence impaired cell maturation. The underlying causes are multifactorial and include exposure of both the fetus and newborn to hypoxia-ischemia, inflammation (chorioamnionitis) and infection, adverse maternal lifestyle choices (smoking, drug and alcohol use, diet) and obesity, as well as the significant demand that adaptation to post-natal life places on immature organs. Further, many fetuses and infants may have combinations of these events, and repeated (multi-hit) events that may induce tolerance to injury or sensitize to greater injury. Currently there are no treatments to prevent preterm injury or impaired neurodevelopment. However, inflammation is a common pathway for many of these insults, and clinical and experimental evidence demonstrates that acute and chronic inflammation is associated with impaired brain development. This review examines our current knowledge about the relationship between inflammation and preterm brain development, and the potential for stem cell therapy to provide neuroprotection and neurorepair through reducing inflammation and release of trophic factors, which promote cell maturation and repair.

Activation of neonatal microglia can be influenced by other neural cells.

During development, microglial progenitor cells migrate into the brain from the periphery, a process critical to the maturation of the developing brain. Although they perform functions similar to mature, adult microglia, immature microglia are distinct from mature microglia. Activation of immature microglia, via an early-life immune challenge, can lead to persistent changes in microglial function, resulting in long-term neuronal and cognitive dysfunction. Early-life immune activation is associated with multiple neurodevelopmental disorders, including autism, ADHD, schizophrenia, and cerebral palsy - disorders with known or suspected immune etiologies, and strong sex biases for males. Activation of immature microglia requires further examination to determine its potential role in these neurodevelopmental disorders. More work is also necessary to better understand the relationship between developing microglia and other developing neural cells during this critical period of development. Thus, we treated freshly isolated, sex-specific microglia from the rat hippocampus with lipopolysaccharide (LPS) on P4, in either the presence or absence of other neural cells. Mixed and microglial-specific cultures were analyzed for inflammatory gene expression to determine whether immature microglia exhibited a sex-specific response to immune activation, and if the presence of all other neural cells influenced that response. We found that the microglial response to an LPS-induced immune activation differed depending on the presence of other neural cells in the culture. We found very few sex differences in the cytokine response, except that the microglial expression of IL-6 following immune activation was more robust in male microglia that were in the presence of other neural cells than female microglia in the same condition.

The Pleiotropic MET Receptor Network: Circuit Development and the Neural-Medical Interface of Autism.

People with autism spectrum disorder and other neurodevelopmental disorders (NDDs) are behaviorally and medically heterogeneous. The combination of polygenicity and gene pleiotropy-the influence of one gene on distinct phenotypes-raises questions of how specific genes and their protein products interact to contribute to NDDs. A preponderance of evidence supports developmental and pathophysiological roles for the MET receptor tyrosine kinase, a multifunctional receptor that mediates distinct biological responses depending upon cell context. MET influences neuron architecture and synapse maturation in the forebrain and regulates homeostasis in gastrointestinal and immune systems, both commonly disrupted in NDDs. Peak expression of synapse-enriched MET is conserved across rodent and primate forebrain, yet regional differences in primate neocortex are pronounced, with enrichment in circuits that participate in social information processing. A functional risk allele in the MET promoter, enriched in subgroups of children with autism spectrum disorder, reduces transcription and disrupts socially relevant neural circuits structurally and functionally. In mice, circuit-specific deletion of Met causes distinct atypical behaviors. MET activation increases dendritic complexity and nascent synapse number, but synapse maturation requires reductions in MET. MET mediates its specific biological effects through different intracellular signaling pathways and has a complex protein interactome that is enriched in autism spectrum disorder and other NDD candidates. The interactome is coregulated in developing human neocortex. We suggest that a gene as pleiotropic and highly regulated as MET, together with its interactome, is biologically relevant in normal and pathophysiological contexts, affecting central and peripheral phenotypes that contribute to NDD risk and clinical symptoms.

Prenatal immune programming of the sex-dependent risk for major depression.

Maternal immune functioning during pregnancy contributes to sex-dependent deficits in neurodevelopment and to behaviors associated with affective traits in preclinical studies, and has been indirectly associated with offspring depression in epidemiologic studies. We therefore investigated the association between immune activity during pregnancy and the risk of depression among male and female offspring. We conducted a case-control study of depression (n=484 cases and n=774 controls) using data from the New England Family Study, a pregnancy cohort enrolled between 1959 and 1966 that assessed psychiatric outcomes in adult offspring (mean age=39.7 years). We assayed concentrations of three pro-inflammatory cytokines, interleukin (IL)-1ß, IL-6 and tumor necrosis factor (TNF)-α, and the anti-inflammatory cytokine, IL-10, in maternal serum collected at the end of the second and beginning of the third trimesters. High maternal TNF-α was associated with reduced odds of depression among both male and female offspring (odds ratio (OR)=0.68; confidence interval (CI)=0.48, 0.98). However, when considering the TNF-α to IL-10 ratio, a measure of the ratio of pro- to anti-inflammatory loading, maternal immune effects on offspring depression differed significantly by sex (χ(2)=13.9, degrees of freedom=4, P=0.008). Among females, higher maternal TNF-α:IL-10 was associated with reduced odds of depression (OR=0.51; CI=0.32, 0.81), whereas, among males, high maternal TNF-α:IL-10 was associated with elevated odds of depression (OR=1.86; CI=1.02, 3.39). Thus, the balance between TNF-α and IL-10 in maternal prenatal serum was associated with depression in a sex-dependent manner. These findings are consistent with the role of TNF-α in the maturation of the sexually dimorphic fetal brain circuitry that regulates stress and affective responses, and support a prenatal stress-immune model of depression pathogenesis.

Maternal stress, nutrition and physical activity: Impact on immune function, CNS development and psychopathology.

Evidence suggests that maternal and fetal immune dysfunction may impact fetal brain development and could play a role in neurodevelopmental disorders, although the definitive pathophysiological mechanisms are still not completely understood. Stress, malnutrition and physical inactivity are three maternal behavioral lifestyle factors that can influence immune and central nervous system (CNS) functions in both the mother and fetus, and may therefore, increase risk for neurodevelopmental/psychiatric disorders. First, we will briefly review some aspects of maternal-fetal immune system interactions and development of immune tolerance. Second, we will discuss the bidirectional communication between the immune system and CNS and the pathways by which immune dysfunction could contribute to neurodevelopmental disorders. Third, we will discuss the effects of prenatal stress and malnutrition (over and undernutrition) on perinatal programming of the CNS and immune system, and how this might influence neurodevelopment. Finally, we will discuss the beneficial impact of physical fitness during pregnancy on the maternal-fetal unit and infant and how regular physical activity and exercise can be an effective buffer against stress- and inflammatory-related disorders. Although regular physical activity has been shown to promote neuroplasticity and an anti-inflammatory state in the adult, there is a paucity of studies evaluating its impact on CNS and immune function during pregnancy. Implementing stress reduction, proper nutrition and ample physical activity during pregnancy and the childbearing period may be an efficient strategy to counteract the impact of maternal stress and malnutrition/obesity on the developing fetus. Such behavioral interventions could have an impact on early development of the CNS and immune system and contribute to the prevention of neurodevelopmental and psychiatric disorders. Further research is needed to elucidate this relationship and the underlying mechanisms of protection. This article is part of a Special Issue entitled SI: Neuroimmunology in Health And Disease.