Parenting stress in infancy was associated with neurodevelopment in 24-month-old children with congenital heart disease.

AIM: Having a child with congenital heart disease (CHD) is stressful for parents, but research on the impact this stress can have on child development has been lacking. We investigated the associations between parenting stress when children were infants and neurodevelopmental outcomes in toddlers with CHD. METHODS: This study was carried out at the Neurocardiac Clinic at the Sainte-Justine University Hospital in Montréal, Canada. Patients born from 2012 to 2019 and followed up to 24 months of age were recruited. Parenting stress levels were measured when the child was 4-6 months and 24 months and the child's neurodevelopment was assessed at 24 months. Multiple linear regressions analyses were carried out. RESULTS: We studied 100 children (56% boys) with CHD. Most of the parenting stress scores were below the clinical threshold. However, they accounted for a significant part of the variance in the children's cognitive (15%-16%), receptive language (14%-15%) and gross motor outcomes (15%-18%). They had no impact on the children's expressive language or fine motor outcomes. CONCLUSION: Higher parenting stress was associated with poorer neurodevelopmental outcomes in toddlers with CHD. Early screening of parenting stress in CHD clinics is necessary to provide individualised intervention for parents and optimise neurodevelopmental outcomes in children.

Pcgf5: An important regulatory factor in early embryonic neural induction.

Polycomb group RING finger (PCGF) proteins, a crucial subunits of the Polycomb complex, plays an important role in regulating gene expression, embryonic development, and cell fate determination. In our research, we investigated Pcgf5, one of the six PCGF homologs, and its impact on the differentiation of P19 cells into neural stem cells. Our findings revealed that knockdown of Pcgf5 resulted in a significant decrease in the expression levels of the neuronal markers Sox2, Zfp521, and Pax6, while the expression levels of the pluripotent markers Oct4 and Nanog increased. Conversely, Pcgf5 overexpression upregulated the expression of Sox2 and Pax6, while downregulating the expression of Oct4 and Nanog. Additionally, our analysis revealed that Pcgf5 suppresses Wnt3 expression via the activation of Notch1/Hes1, and ultimately governs the differentiation fate of neural stem cells. To further validate our findings, we conducted in vivo experiments in zebrafish. We found that knockdown of pcgf5a using morpholino resulted in the downregulated expression of neurodevelopmental genes such as sox2, sox3, and foxg1 in zebrafish embryos. Consequently, these changes led to neurodevelopmental defects. In conclusion, our study highlights the important role of Pcgf5 in neural induction and the determination of neural cell fate.

Translatome analysis of tuberous sclerosis complex 1 patient-derived neural progenitor cells reveals rapamycin-dependent and independent alterations.

BACKGROUND: Tuberous sclerosis complex (TSC) is an inherited neurocutaneous disorder caused by mutations in the TSC1 or TSC2 genes, with patients often exhibiting neurodevelopmental (ND) manifestations termed TSC-associated neuropsychiatric disorders (TAND) including autism spectrum disorder (ASD) and intellectual disability. Hamartin (TSC1) and tuberin (TSC2) proteins form a complex inhibiting mechanistic target of rapamycin complex 1 (mTORC1) signaling. Loss of TSC1 or TSC2 activates mTORC1 that, among several targets, controls protein synthesis by inhibiting translational repressor eIF4E-binding proteins. Using TSC1 patient-derived neural progenitor cells (NPCs), we recently reported early ND phenotypic changes, including increased cell proliferation and altered neurite outgrowth in TSC1-null NPCs, which were unaffected by the mTORC1 inhibitor rapamycin. METHODS: Here, we used polysome profiling, which quantifies changes in mRNA abundance and translational efficiencies at a transcriptome-wide level, to compare CRISPR-edited TSC1-null with CRISPR-corrected TSC1-WT NPCs generated from one TSC donor (one clone/genotype). To assess the relevance of identified gene expression alterations, we performed polysome profiling in postmortem brains from ASD donors and age-matched controls. We further compared effects on translation of a subset of transcripts and rescue of early ND phenotypes in NPCs following inhibition of mTORC1 using the allosteric inhibitor rapamycin versus a third-generation bi-steric, mTORC1-selective inhibitor RMC-6272. RESULTS: Polysome profiling of NPCs revealed numerous TSC1-associated alterations in mRNA translation that were largely recapitulated in human ASD brains. Moreover, although rapamycin treatment partially reversed the TSC1-associated alterations in mRNA translation, most genes related to neural activity/synaptic regulation or ASD were rapamycin-insensitive. In contrast, treatment with RMC-6272 inhibited rapamycin-insensitive translation and reversed TSC1-associated early ND phenotypes including proliferation and neurite outgrowth that were unaffected by rapamycin. CONCLUSIONS: Our work reveals ample mRNA translation alterations in TSC1 patient-derived NPCs that recapitulate mRNA translation in ASD brain samples. Further, suppression of TSC1-associated but rapamycin-insensitive translation and ND phenotypes by RMC-6272 unveils potential implications for more efficient targeting of mTORC1 as a superior treatment strategy for TAND.

Gross anatomical variations of the insular cortex in first-episode schizophrenia.

BACKGROUND: Magnetic resonance imaging (MRI) studies have revealed gray matter reductions in the insular cortex of schizophrenia patients. Despite large inter-individual anatomical variations in the insular gyri of human brains, the gross anatomical features of the insular cortex and their relationships with clinical characteristics remain largely unknown in schizophrenia. METHODS: The present MRI study investigated variations in the insular gross anatomy (i.e., the development and split patterns of each gyrus and gyrus numbers) and their relationships with clinical variables and insular gray matter volumes in 66 patients with first-episode schizophrenia (FE-Sz) and 66 age- and sex-matched healthy controls. RESULTS: The FE-Sz group had a significantly larger number of insular gyri bilaterally with well-developed accessory, middle short, and posterior long insular gyri than the control group, and this was associated with a younger onset age and severe positive symptoms. The split patterns of major insular gyri did not significantly differ between the groups. The FE-Sz group was also characterized by a smaller gray matter volume in the insular cortex than the control group; however, this was not associated with the insular gross anatomy or clinical characteristics. CONCLUSION: As the insular gyral organization reflects brain development during mid to late gestation, the gross anatomical features of the insular cortex in schizophrenia, which were independent of gray matter volumes, may be used as early neurodevelopmental abnormality markers for the illness.

Prenatal anxiety during the pandemic context is related to neurodevelopment of 6-month-old babies.

Prenatal anxiety and depression in pandemic context could introduce changes in the fetal developmental trajectories that, ultimately, could alter the adaptive behaviors of the offspring, potentially affecting, for example, general neurodevelopment. The sample consisted of 105 mother-child dyads, recruited between March and May 2020. The dyads were evaluated longitudinally, prenatally and postnatally (6 months). The Pandemic Impact Questionnaire, the State-Trait Anxiety Inventory, and the Beck-II Depression Inventory were used to assess indicators of maternal anxiety and depression, respectively. Regarding the babies, their mothers responded to Age and Stages: 3, which assesses different dimensions of early neurodevelopment, in addition to a closed questionnaire to identify sociodemographic and maternal and child health variables. A series of mediation models were tested to examine the association between prenatal psychopathology/negative experiences of the pandemic and neurodevelopment. The results indicated that the negative experiences of the pandemic were indirectly associated with the socio-individual and fine motor neurodevelopment of the offspring, through maternal anxiety symptoms, during the third trimester, which functioned as a mediator.  Conclusions: This study provides evidence on the mediating effects of maternal anxiety on infant neurodevelopment in contexts of early adversity. It is important to point out the need to implement public health policies that allow a timely evaluation of neurodevelopmental variables during early childhood, which can implement early interventions to reduce the risks associated with these deficits. What is Known: • Effects of maternal mental health have been reported, effects on child neurodevelopment, in motor, cognitive, linguistic and socio-emotional dimensions. • Contexts of early adversity have been associated with maternal mental health and offspring development. What is New: • The context of pandemic adversity caused by COVID-19 is associated with motor and socio-individual neurodevelopment, mediated by maternal prenatal anxiety.

Systemic postnatal corticosteroid use for the prevention of bronchopulmonary dysplasia and its relationship to early neurodevelopment in extremely preterm infants.

BACKGROUND: Systemic postnatal corticosteroid use in extremely preterm infants poses a risk of adverse neurodevelopmental outcomes. This study explores their use beyond seven days of age with early neurodevelopmental assessments during the fidgety period (9-20 weeks postterm age). METHODS: This retrospective single-center cohort study included inborn extremely preterm infants from 1 January 2014 to 31 December 2018. Outborn infants, those with congenital or genetic abnormalities, and those who received postnatal corticosteroids for nonrespiratory reasons were excluded. The cohort was dichotomized based on the status of corticosteroid receipt. Early neurodevelopmental outcomes were reported using Prechtl's General Movements Assessment. RESULTS: Of the 282 infants, 67 (23.75%) received corticosteroids. Of these, 34 (50.75%) received them for dependency on invasive ventilation (intermittent positive-pressure ventilation), and the remainder received them for dependency on non-invasive ventilation continuous positive airway pressure (CPAP) or bi-level positive airway pressure (BiPAP). Abnormal or absent fidgety movements were observed in 13% of infants (7/54) who received corticosteroids compared to 2% of infants (3/146) who did not. An increased odds for an abnormal general movements assessment from corticosteroid use after adjusting for gestational age [adjusted odds ratio (aOR) = 5.5, 95% confidence interval (CI) = 1.14-26.56] was observed. The motor optimality scores differed between the two groups [corticosteroid group: 25.5 (23-26) versus no-corticosteroid group: 26 (24-28); z = - 2.02]. A motor optimality score < 20 was observed in 14.8% of infants (8/54) in the corticosteroid group compared to 2% of infants (3/146) in the noncorticosteroid group. This difference was significant after adjustment for gestational age (aOR 5.96, 95% CI 1.28-27.74). CONCLUSIONS: Abnormal early neurodevelopment was observed in infants who received systemic postnatal corticosteroids. The relationship between these findings and other factors influencing early neurodevelopment needs further exploration.

Gross anatomical features of the insular cortex in schizophrenia and schizotypal personality disorder: Potential relationships with vulnerability, illness stages, and clinical subtypes.

Introduction: Patients with schizophrenia have a higher number of insular gyri; however, it currently remains unclear whether the brain characteristics of patients with schizotypal personality disorder (SPD), a mild form of schizophrenia, are similar. It is also unknown whether insular gross anatomical features are associated with the illness stages and clinical subtypes of schizophrenia. Materials and methods: This magnetic resonance imaging study examined gross anatomical variations in the insular cortex of 133 patients with schizophrenia, 47 with SPD, and 88 healthy controls. The relationships between the insular gross anatomy and schizophrenia subgroups (71 first-episode and 58 chronic groups, 38 deficit and 37 non-deficit subtype groups) were also investigated. Results: The number of insular gyri was higher in the schizophrenia and SPD patients than in the controls, where the patients were characterized by well-developed accessory, middle short, and posterior long insular gyri. The insular gross anatomy did not significantly differ between the first-episode and chronic schizophrenia subgroups; however, the relationship between the developed accessory gyrus and more severe positive symptoms was specific to the first-episode group. The prevalence of a right middle short gyrus was higher in the deficit schizophrenia group than in the non-deficit group. Discussion: These findings suggest that schizophrenia and SPD patients may share an altered insular gross morphology as a vulnerability factor associated with early neurodevelopmental anomalies, which may also contribute to positive symptomatology in the early illness stages and clinical subtypes of schizophrenia.

Different Heschl's Gyrus Duplication Patterns in Deficit and Non-deficit Subtypes of Schizophrenia.

Deficit syndrome schizophrenia is a characteristic subtype defined by persistent negative symptoms and poor functional outcomes; however, the biological mechanisms underlying this specific subtype have not yet been elucidated in detail. The present magnetic resonance imaging study examined the prevalence of duplicated Heschl's gyrus (HG), a potential neurodevelopmental marker, in schizophrenia patients with (N = 38) and without (N = 37) the deficit syndrome. The prevalence of the HG duplication pattern bilaterally was higher in the whole schizophrenia group than in 59 matched healthy controls. Furthermore, the prevalence of right HG duplication was significantly higher in the deficit schizophrenia group than in the non-deficit schizophrenia group. The HG pattern in schizophrenia was not associated with clinical variables, including illness duration, medication, and symptom severity, while right HG duplication correlated with higher scores for Proxy for the Deficit Syndrome. The present results suggest that the prominent neurodevelopmental pathology associated with gyral formation of HG may contribute to enduring negative symptomatology in schizophrenia.

A 4D infant brain volumetric atlas based on the UNC/UMN baby connectome project (BCP) cohort.

Spatiotemporal (four-dimensional) infant-dedicated brain atlases are essential for neuroimaging analysis of early dynamic brain development. However, due to the substantial technical challenges in the acquisition and processing of infant brain MR images, 4D atlases densely covering the dynamic brain development during infancy are still scarce. Few existing ones generally have fuzzy tissue contrast and low spatiotemporal resolution, leading to degraded accuracy of atlas-based normalization and subsequent analyses. To address this issue, in this paper, we construct a 4D structural MRI atlas for infant brains based on the UNC/UMN Baby Connectome Project (BCP) dataset, which features a high spatial resolution, extensive age-range coverage, and densely sampled time points. Specifically, 542 longitudinal T1w and T2w scans from 240 typically developing infants up to 26-month of age were utilized for our atlas construction. To improve the co-registration accuracy of the infant brain images, which typically exhibit dynamic appearance with low tissue contrast, we employed the state-of-the-art registration method and leveraged our generated reliable brain tissue probability maps in addition to the intensity images to improve the alignment of individual images. To achieve consistent region labeling on both infant and adult brain images for facilitating region-based analysis across ages, we mapped the widely used Desikan cortical parcellation onto our atlas by following an age-decreasing mapping manner. Meanwhile, the typical subcortical structures were manually delineated to facilitate the studies related to the subcortex. Compared with the existing infant brain atlases, our 4D atlas has much higher spatiotemporal resolution and preserves more structural details, and thus can boost accuracy in neurodevelopmental analysis during infancy.

Heschl's Gyrus Duplication Pattern in Individuals at Risk of Developing Psychosis and Patients With Schizophrenia.

An increased prevalence of duplicated Heschl's gyrus (HG), which may reflect an early neurodevelopmental pathology, has been reported in schizophrenia (Sz). However, it currently remains unclear whether individuals at risk of psychosis exhibit similar brain morphological characteristics. This magnetic resonance imaging study investigated the distribution of HG gyrification patterns [i.e., single HG, common stem duplication (CSD), and complete posterior duplication (CPD)] and their relationship with clinical characteristics in 57 individuals with an at-risk mental state (ARMS) [of whom 5 (8.8%) later developed Sz], 63 patients with Sz, and 61 healthy comparisons. The prevalence of duplicated HG patterns (i.e., CSD or CPD) bilaterally was significantly higher in the ARMS and Sz groups than in the controls, whereas no significant differences were observed in HG patterns between these groups. The left CSD pattern, particularly in the Sz group, was associated with a verbal fluency deficit. In the ARMS group, left CSD pattern was related to a more severe general psychopathology. The present results suggest that an altered gyrification pattern on the superior temporal plane reflects vulnerability factors associated with Sz, which may also contribute to the clinical features of high-risk individuals, even without the onset of psychosis.

Neonatal sleep development and early learning in infants with prenatal opioid exposure.

The aim of this chapter is to examine the role of sleep and cognition in the context of the cumulative risk model examining samples of at-risk infants and maternal-infant dyads. The cumulative risk model posits that non-optimal developmental outcomes are the result of multiple factors in a child's life including, but not limited to, prenatal teratogenic exposures, premature birth, family socioeconomic status, parenting style and cognitions as well as the focus of this volume, sleep. We highlight poor neonatal sleep as both an outcome of perinatal risk as well as a risk factor to developing attentional and cognitive capabilities during early childhood. Outcomes associated with and contributing to poor sleep and cognition during infancy are examined in relation to other known risks in our clinical population. Implications of this research and recommendations for interventions for this population are provided.

Dysregulation of Neurite Outgrowth and Cell Migration in Autism and Other Neurodevelopmental Disorders.

Despite decades of study, elucidation of the underlying etiology of complex developmental disorders such as autism spectrum disorder (ASD), schizophrenia (SCZ), intellectual disability (ID), and bipolar disorder (BPD) has been hampered by the inability to study human neurons, the heterogeneity of these disorders, and the relevance of animal model systems. Moreover, a majority of these developmental disorders have multifactorial or idiopathic (unknown) causes making them difficult to model using traditional methods of genetic alteration. Examination of the brains of individuals with ASD and other developmental disorders in both post-mortem and MRI studies shows defects that are suggestive of dysregulation of embryonic and early postnatal development. For ASD, more recent genetic studies have also suggested that risk genes largely converge upon the developing human cerebral cortex between weeks 8 and 24 in utero. Yet, an overwhelming majority of studies in autism rodent models have focused on postnatal development or adult synaptic transmission defects in autism related circuits. Thus, studies looking at early developmental processes such as proliferation, cell migration, and early differentiation, which are essential to build the brain, are largely lacking. Yet, interestingly, a few studies that did assess early neurodevelopment found that alterations in brain structure and function associated with neurodevelopmental disorders (NDDs) begin as early as the initial formation and patterning of the neural tube. By the early to mid-2000s, the derivation of human embryonic stem cells (hESCs) and later induced pluripotent stem cells (iPSCs) allowed us to study living human neural cells in culture for the first time. Specifically, iPSCs gave us the unprecedented ability to study cells derived from individuals with idiopathic disorders. Studies indicate that iPSC-derived neural cells, whether precursors or "matured" neurons, largely resemble cortical cells of embryonic humans from weeks 8 to 24. Thus, these cells are an excellent model to study early human neurodevelopment, particularly in the context of genetically complex diseases. Indeed, since 2011, numerous studies have assessed developmental phenotypes in neurons derived from individuals with both genetic and idiopathic forms of ASD and other NDDs. However, while iPSC-derived neurons are fetal in nature, they are post-mitotic and thus cannot be used to study developmental processes that occur before terminal differentiation. Moreover, it is important to note that during the 8-24-week window of human neurodevelopment, neural precursor cells are actively undergoing proliferation, migration, and early differentiation to form the basic cytoarchitecture of the brain. Thus, by studying NPCs specifically, we could gain insight into how early neurodevelopmental processes contribute to the pathogenesis of NDDs. Indeed, a few studies have explored NPC phenotypes in NDDs and have uncovered dysregulations in cell proliferation. Yet, few studies have explored migration and early differentiation phenotypes of NPCs in NDDs. In this chapter, we will discuss cell migration and neurite outgrowth and the role of these processes in neurodevelopment and NDDs. We will begin by reviewing the processes that are important in early neurodevelopment and early cortical development. We will then delve into the roles of neurite outgrowth and cell migration in the formation of the brain and how errors in these processes affect brain development. We also provide review of a few key molecules that are involved in the regulation of neurite outgrowth and migration while discussing how dysregulations in these molecules can lead to abnormalities in brain structure and function thereby highlighting their contribution to pathogenesis of NDDs. Then we will discuss whether neurite outgrowth, migration, and the molecules that regulate these processes are associated with ASD. Lastly, we will review the utility of iPSCs in modeling NDDs and discuss future goals for the study of NDDs using this technology.

Oxytocin ameliorates maternal separation-induced ultrasonic vocalisation calls in mouse pups prenatally exposed to valproic acid.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder estimated by the World Health Organization to occur in one of 160 children worldwide. No pharmaceutical treatments are available to improve the deficits in social communication that are common symptoms of ASD. Recent clinical trials have focused on the nasal application of oxytocin, a neuronal peptide known to regulate a variety of social behaviours. However, the effect of oxytocin on this deficit is inconclusive. By contrast, evidence from ASD animal model studies indicates that when animals are treated with oxytocin during early development, improvements in social deficits are observed in adulthood. Thus, it is necessary to examine the effect of therapeutic target medication prescribed in early development. Mice prenatally exposed to valproic acid (VPA) are widely used as an animal model of ASD. However, many behavioural studies have been conducted during adulthood rather than early development. To establish a screening system to identify therapeutic drugs that are effective when delivered during the early postnatal period, it is important to examine the early developmental changes in their communicative behaviours. In the present study, we examined the ultrasonic vocalisation (USV) of VPA-exposed mice pups during their early postnatal developmental days. USV rates were comparable to those of the controls until the first week of their life but declined more on postnatal day 11. We checked the expression of oxytocin system in the hypothalamus and found the down-regulation of oxytocin and CD38, and up-regulation of oxytocin receptor in the VPA pups. Acute administration of oxytocin on postnatal day 11 increased the call rate of VPA pups. Taken together, we have demonstrated there was a deficiency in the oxytocinergic signalling in the VPA pups and also shown the existence of time periods that are effective with respect to screening the therapeutic drugs.

TSC patient-derived isogenic neural progenitor cells reveal altered early neurodevelopmental phenotypes and rapamycin-induced MNK-eIF4E signaling.

Background: Tuberous sclerosis complex (TSC) is a neurodevelopmental disorder with frequent occurrence of epilepsy, autism spectrum disorder (ASD), intellectual disability (ID), and tumors in multiple organs. The aberrant activation of mTORC1 in TSC has led to treatment with mTORC1 inhibitor rapamycin as a lifelong therapy for tumors, but TSC-associated neurocognitive manifestations remain unaffected by rapamycin. Methods: Here, we generated patient-specific, induced pluripotent stem cells (iPSCs) from a TSC patient with a heterozygous, germline, nonsense mutation in exon 15 of TSC1 and established an isogenic set of heterozygous (Het), null and corrected wildtype (Corr-WT) iPSCs using CRISPR/Cas9-mediated gene editing. We differentiated these iPSCs into neural progenitor cells (NPCs) and examined neurodevelopmental phenotypes, signaling and changes in gene expression by RNA-seq. Results: Differentiated NPCs revealed enlarged cell size in TSC1-Het and Null NPCs, consistent with mTORC1 activation. TSC1-Het and Null NPCs also revealed enhanced proliferation and altered neurite outgrowth in a genotype-dependent manner, which was not reversed by rapamycin. Transcriptome analyses of TSC1-NPCs revealed differentially expressed genes that display a genotype-dependent linear response, i.e., genes upregulated/downregulated in Het were further increased/decreased in Null. In particular, genes linked to ASD, epilepsy, and ID were significantly upregulated or downregulated warranting further investigation. In TSC1-Het and Null NPCs, we also observed basal activation of ERK1/2, which was further activated upon rapamycin treatment. Rapamycin also increased MNK1/2-eIF4E signaling in TSC1-deficient NPCs. Conclusion: MEK-ERK and MNK-eIF4E pathways regulate protein translation, and our results suggest that aberrant translation distinct in TSC1/2-deficient NPCs could play a role in neurodevelopmental defects. Our data showing upregulation of these signaling pathways by rapamycin support a strategy to combine a MEK or a MNK inhibitor with rapamycin that may be superior for TSC-associated CNS defects. Importantly, our generation of isogenic sets of NPCs from TSC patients provides a valuable platform for translatome and large-scale drug screening studies. Overall, our studies further support the notion that early developmental events such as NPC proliferation and initial process formation, such as neurite number and length that occur prior to neuronal differentiation, represent primary events in neurogenesis critical to disease pathogenesis of neurodevelopmental disorders such as ASD.

BDNF Induced Translation of Limk1 in Developing Neurons Regulates Dendrite Growth by Fine-Tuning Cofilin1 Activity.

Dendritic growth and branching are highly regulated processes and are essential for establishing proper neuronal connectivity. There is a critical phase of early dendrite development when these are heavily regulated by external cues such as trophic factors. Brain-derived neurotrophic factor (BDNF) is a major trophic factor known to enhance dendrite growth in cortical neurons, but the molecular underpinnings of this response are not completely understood. We have identified that BDNF induced translational regulation is an important mechanism governing dendrite development in cultured rat cortical neurons. We show that BDNF treatment for 1 h in young neurons leads to translational up-regulation of an important actin regulatory protein LIM domain kinase 1 (Limk1), increasing its level locally in the dendrites. Limk1 is a member of serine/threonine (Ser/Thr) family kinases downstream of the Rho-GTPase pathway. BDNF induced increase in Limk1 levels leads to increased phosphorylation of its target protein cofilin1. We observed that these changes are maintained for long durations of up to 48 h and are mediating increase in number of primary dendrites and total dendrite length. Thus, we show that BDNF induced protein synthesis leads to fine-tuning of the actin cytoskeletal reassembly and thereby mediate dendrite development.

Childhood-Onset Schizophrenia: Insights from Induced Pluripotent Stem Cells.

Childhood-onset schizophrenia (COS) is a rare psychiatric disorder characterized by earlier onset, more severe course, and poorer outcome relative to adult-onset schizophrenia (AOS). Even though, clinical, neuroimaging, and genetic studies support that COS is continuous to AOS. Early neurodevelopmental deviations in COS are thought to be significantly mediated through poorly understood genetic risk factors that may also predispose to long-term outcome. In this review, we discuss findings from induced pluripotent stem cells (iPSCs) that allow the generation of disease-relevant cell types from early brain development. Because iPSCs capture each donor's genotype, case/control studies can uncover molecular and cellular underpinnings of COS. Indeed, recent studies identified alterations in neural progenitor and neuronal cell function, comprising dendrites, synapses, electrical activity, glutamate signaling, and miRNA expression. Interestingly, transcriptional signatures of iPSC-derived cells from patients with COS showed concordance with postmortem brain samples from SCZ, indicating that changes in vitro may recapitulate changes from the diseased brain. Considering this progress, we discuss also current caveats from the field of iPSC-based disease modeling and how to proceed from basic studies to improved diagnosis and treatment of COS.

Tracing Early Neurodevelopment in Schizophrenia with Induced Pluripotent Stem Cells.

Schizophrenia (SCZ) is a devastating mental disorder that is characterized by distortions in thinking, perception, emotion, language, sense of self, and behavior. Epidemiological evidence suggests that subtle perturbations in early neurodevelopment increase later susceptibility for disease, which typically manifests in adolescence to early adulthood. Early perturbations are thought to be significantly mediated through incompletely understood genetic risk factors. The advent of induced pluripotent stem cell (iPSC) technology allows for the in vitro analysis of disease-relevant neuronal cell types from the early stages of human brain development. Since iPSCs capture each donor's genotype, comparison between neuronal cells derived from healthy and diseased individuals can provide important insights into the molecular and cellular basis of SCZ. In this review, we discuss results from an increasing number of iPSC-based SCZ/control studies that highlight alterations in neuronal differentiation, maturation, and neurotransmission in addition to perturbed mitochondrial function and micro-RNA expression. In light of this remarkable progress, we consider also ongoing challenges from the field of iPSC-based disease modeling that call for further improvements on the generation and design of patient-specific iPSC studies to ultimately progress from basic studies on SCZ to tailored treatments.

Maternal immune activation altered microglial immunoreactivity in the brain of postnatal day 2 rat offspring.

Microglia, the resident immune cells of the central nervous system, play critical roles in neurodevelopment, synaptic pruning, and neuronal wiring. Early in development, microglia migrate via the tangential and radial migration pathways to their final destinations and mature gradually, a process that includes morphological changes. Recent research has implicated microglial abnormality in the etiology of schizophrenia. Since prenatal exposure to viral or bacterial infections due to maternal immune activation (MIA) leads to increased risk of schizophrenia in the offspring during adulthood, the present study systematically investigated how MIA induced by polyinosinic:polycytidylic acid (a mimic of viral double-stranded RNA) affected microglial immunoreactivity along the migration and maturation trajectories in the brains of male and female rat offspring on postnatal day (PND) 2. The immunohistochemistry revealed significant changes in the density of IBA-1 immunoreactive cells in the corpus callosum, somatosensory cortex, striatum, and the subregions of the hippocampus of the MIA offspring. The male and female MIA offspring displayed markedly altered microglial immunoreactivity in both the tangential and radial migration, as well as maturation, pathways when compared to their sex- and age-matched controls as evidenced by morphology-based cell counting. Given the important roles of microglia in synaptic pruning and neuronal wiring and survival, these changes may lead to structural and functional neurodevelopmental abnormalities, and so contribute to the functional deficits observed in juvenile and adult MIA offspring. Future research is required to systematically determine how MIA affects microglial migration and maturation in rat offspring.

From the Psychiatrist's Couch to Induced Pluripotent Stem Cells: Bipolar Disease in a Dish.

Bipolar disease (BD) is one of the major public health burdens worldwide and more people are affected every year. Comprehensive genetic studies have associated thousands of single nucleotide polymorphisms (SNPs) with BD risk; yet, very little is known about their functional roles. Induced pluripotent stem cells (iPSCs) are powerful tools for investigating the relationship between genotype and phenotype in disease-relevant tissues and cell types. Neural cells generated from BD-specific iPSCs are thought to capture associated genetic risk factors, known and unknown, and to allow the analysis of their effects on cellular and molecular phenotypes. Interestingly, an increasing number of studies on BD-derived iPSCs report distinct alterations in neural patterning, postmitotic calcium signaling, and neuronal excitability. Importantly, these alterations are partly normalized by lithium, a first line treatment in BD. In light of these exciting findings, we discuss current challenges to the field of iPSC-based disease modelling and future steps to be taken in order to fully exploit the potential of this approach for the investigation of BD and the development of new therapies.

Neurobehavioral development prior to term-age of preterm infants and acute stressful events during neonatal hospitalization.

BACKGROUND: Neonatal Intensive Care Units (NICUs) protect preterm infants; otherwise, this is a stressful environment including painful stimuli. AIMS: To compare early neurobehavioral development prior to term-age in preterm infants at 34-36weeks of post-conceptional age in different gestational ages, and to examine the effects of prematurity level and acute stressful events during NICU hospitalization on neurobehavioral development. STUDY DESIGN: Cross-sectional design. SUBJECTS: Forth-five preterm infants, 34-36weeks of post-conceptional age, were distributed into groups: extreme preterm (EPT; 23-28weeks of gestational age; n=10), moderate preterm (MPT; 29-32weeks of gestational age; n=10), late preterm (LPT; 34-36weeks of gestational age; n=25). OUTCOME MEASURES: All of the neonates were evaluated using the Neurobehavioral Assessment of Preterm Infant (NAPI) prior to 37weeks of post-conceptional age. The Neonatal Infant Stressor Scale (NISS) was applied for EPT and MPT infants during NICU hospitalization, and medical charts were analyzed. RESULTS: The EPT group experienced significantly more acute stressful events during NICU hospitalization than the MPT group. The MPT group had lower scores in motor development and vigor than the EPT and LPT group, and they exhibited poorer quality crying than the LPT group. Motor development and vigor and alertness and orientation in preterm infants were predicted by prematurity level and acute stressful events. CONCLUSION: The extreme preterm was exposed to higher stressful experiences than moderate and late preterm infants. However, the moderate preterm infants presented more vulnerable than the other counterparts in motor and vigor outcomes.