The Role of Serotonin in Brain Development: From Molecular Pathways to Neurodevelopmental Risk.

From the Early Emergence of Psychiatry to Stem Cells and Neural Organoids.

Estrogens, the primary female sex hormones, were originally characterized through their important role in sexual maturation and reproduction. However, recent studies have shown that estrogens play critical roles in a number of brain functions, including cognition, learning and memory, neurodevelopment, and adult neuroplasticity. A number of studies from both clinical as well as preclinical research suggest a protective role of estrogen in neurodevelopmental disorders including autism spectrum disorder (ASD) and schizophrenia. Alterations in the levels of estrogen receptors have been found in subjects with ASD or schizophrenia, and adjunctive estrogen therapy has been shown to be effective in enhancing the treatment of schizophrenia. This review summarizes the findings on the role of estrogen in the pathophysiology of neurodevelopmental disorders with a focus on ASD and schizophrenia. We also discuss the potential of estrogen as a therapeutic target in the above disorders.

Maternal Immune Activation and Autism Spectrum Disorder: From Rodents to Nonhuman and Human Primates

“A developmental disability that hinders the normal functioning of the brain, affecting, in varying degrees, communication skills and social interaction. Repetitive behaviours, and different ways of learning, paying attention, or reacting to things are often distinctive signs”. This standard definition of autism fails to describe the complexity of a condition that ranges in its manifestations from severe intellectual impairment to superior cognitive skills, like in the Asperger syndrome. To comprise such diversity, autism disorders are now covered under the umbrella term “autism spectrum disorder” (ASD). In most cases, ASD manifests during the first 5 years of life, with boys significantly more likely to be diagnosed than girls. ASD usually goes together with several other problems that frequently include anxiety, sleep disorders, or epilepsy. No cure exists; treatment, such as speech therapy, just attempts to alleviate specific deficits of autistic patients. > Nothing is simple in autism. Even the real number of people affected is uncertain. Nothing is simple in autism. Even the real number of people affected is uncertain. The US CDC estimates that about 1 in 68 (or 1.5%) of children in the USA are living with ASD (http://www.cdc.gov/ncbddd/autism/data.html). The WHO has a more conservative estimate, last revised in January this year, of 1 in 160 children, based on a larger set of epidemiological surveys (http://www.who.int/mediacentre/factsheets/autism-spectrum-disorders/en/). Needless to say, most studies were conducted in developed countries, and the prevalence of ASD in many low‐ and middle‐income countries remains largely unknown. > Along the years, many potential causes have been indicated, including genetic and environmental factors, exposure to toxins during pregnancy, wide gaps between parent ages, and so on Although the general consensus is that prevalence rates are increasing globally, this point is debated too. Some analyses indicate that a large percentage of the increase in ASD owes to improved awareness and …

Over the past several decades there has been an increasing interest in the role of environmental factors in the etiology of neuropsychiatric and neurodevelopmental disorders. Epidemiologic studies have shifted from an exclusive focus on the identification of genetic risk alleles for such disorders to recognizing and understanding the contribution of xenobiotic exposures, infections, and the maternal immune system during the prenatal and early post-natal periods. In this review we discuss the growing literature regarding the effects of maternal brain-reactive antibodies on fetal brain development and their contribution to the development of neuropsychiatric and neurodevelopmental disorders. Autoimmune diseases primarily affect women and are more prevalent in mothers of children with neurodevelopmental disorders. For example, mothers of children with Autism Spectrum Disorder (ASD) are significantly more likely to have an autoimmune disease than women of neurotypically developing children. Moreover, they are four to five times more likely to harbor brain-reactive antibodies than unselected women of childbearing age. Many of these women exhibit no apparent clinical consequence of harboring these antibodies, presumably because the antibodies never access brain tissue. Nevertheless, these maternal brain-reactive antibodies can access the fetal brain, and some may be capable of altering brain development when present during pregnancy. Several animal models have provided evidence that in utero exposure to maternal brain-reactive antibodies can permanently alter brain anatomy and cause persistent behavioral or cognitive phenotypes. Although this evidence supports a contribution of maternal brain-reactive antibodies to neurodevelopmental disorders, an interplay between antibodies, genetics, and other environmental factors is likely to determine the specific neurodevelopmental phenotypes and their severity. Additional modulating factors likely also include the microbiome, sex chromosomes, and gonadal hormones. These interactions may help to explain the sex-bias observed in neurodevelopmental disorders. Studies on this topic provide a unique opportunity to learn how to identify and protect at risk pregnancies while also deciphering critical pathways in neurodevelopment.

A shifting view of neurodevelopmental disability

Managing insomnia in children with autism spectrum disorder

Neurodevelopmental disorders (NDDs) are a complex grouping of conditions arising in childhood relating to altered development and function of the brain. The primary conditions classified as NDDs include autism spectrum disorder (ASD), intellectual disability, attention deficit hyperactivity disorder, as well as motor, communication, and specific learning disorders. Many NDDs are known to have significant genetic risk, but the particular genes and molecular pathways controlling this genetic risk are still poorly understood. In addition to the genetic etiology of NDDs themselves, understanding the role of genetics in commonly associated comorbidities, such as sleep dysfunction or epilepsy in ASD, and how these insights might be leveraged to develop new therapeutics, remains a central goal of NDD genetic research. In ASD in particular, mutations in more than 100 genes have been significantly linked to increased risk for ASD. However, projections based on the frequency of mutations in these known risk genes has suggested that over 1000 genes may significantly increase risk for ASD when mutated. In response to this prediction, several machine learning approaches have been developed to use genome-wide data sources to predict which genes are the best candidates for ASD risk gene discovery. However, with different sources of data and training strategies used for each of these scores, there is not a clear consensus in the community on the most important predictors of genetic risk. My work develops a new ASD risk gene score that combines the benefits of all prior scores through a machine learning approach called ”ensemble learning”, unifying the previous scores while providing additional genome-wide data sources for model training. By comparing the previous scores with my work, I demonstrate the effectiveness of ensemble learning in this setting, and provide an ASD risk gene score that is enriched across a variety of ASD genetic data domains, such as common variant risk and gene expression data. While ASD as a whole has many known genetic associations, differences in medical issues experienced by those with ASD are highly variable, and the genetic factors underlying these comorbidities remain unclear. For instance, more than 70% of individuals with ASD have issues with sleep, but it is unknown whether genetic changes explain this difference seen between individuals with of ASD. Simply put, we know that genetics plays a large role in ASD, but we do not know the specifics of how genes map to subtypes of ASD. My work bridges this gap by studying the genetics of sleep dysfunction within individuals with ASD. To my knowledge, I am the first to be able to demonstrate and report that sleep dysfunction in ASD has a significant genetic component. Further, I find that genetic risk for ADHD, BMI, and several other conditions heightens an autistic individual’s risk for having issues with sleep. This work also uncovers associations between the type of sleep issue an individual has and the drugs that may be most effective for restoring normal sleep. Another major medical issue faced by individuals with ASD is epilepsy, with over 20% of individuals diagnosed with ASD having or going on to develop epilepsy later in life. Similar to sleep issues in ASD, treatment options in epilepsy are often effective but fall short in approximately 30% of cases. Finding treatments for these individuals who fail to find relief from the standard of care options is of critical importance. My work uses a bioinformatic technique called drug repositioning to computationally prioritize drugs that may be capable of reversing the transcriptional state induced by epilepsy. This approach yielded 184 potential therapeutic compounds, of which 4 were selected and tested in a zebrafish model of epilepsy. Three of the four compounds showed significant seizure suppression activity, including one with no previous literature surrounding its use in epilepsy (pyrantel tartrate). While a diverse set of work, the common thread is leveraging computational genetic techniques to better understand the causes, symptoms, and treatments of neurodevelopmental and associated disorders. By using ensemble learning, this work establishes a unified autism risk gene score that effectively summarizes a gene’s level of association with autism. Through studying sleep issues in ASD, I find a significant role for common variant risk and establish several genetic associations for poor sleep in ASD, such as ADHD and BMI genetic risk factors. Lastly, by using gene expression to model an effective therapeutic for epilepsy, this work reports on the first possible use of pyrantel tartrate in the treatment of epilepsy. Taken together, these findings demonstrate the power of leveraging big genetic datasets and innovative techniques in order to understand complex disease.

Neurodevelopmental Problems Not Linked to Antidepressant Exposure In Utero

Autism spectrum disorder (ASD), Attention-deficit/Hyperactivity disorder (ADHD), and other related neurodevelopmental disorders (NDDs) have, in some previous studies, been shown to increase the risk of being sexually victimized. However, no studies have examined whether the association is driven by a general NDD phenotype versus specific diagnoses, nor the etiology of the association. Using a genetically informative, prospective design, we examined the association between ASD and ADHD in childhood and coercive sexual victimization up to age 18. A total of 4,500 children participating in the Child and Adolescent Twin Study in Sweden (CATSS) were rated by their parents on NDDs at age 9 or 12years, and self-reported at age 18 on lifetime experiences of coercive sexual touching and/or coercive sex. First, we regressed sexual victimization on the NDDs. Second, we regressed sexual victimization on general and specific NDD symptoms identified via a bifactor model. Third, we decomposed the observed associations into genetic and environmental parts. In females, ASD was associated with an almost threefolded increased risk of coercive sexual victimization, and ADHD with a doubled risk. In males, the risk associated with ASD and ADHD was of the same magnitude but not significant. When controlling for overall NDD symptom load ASD or ADHD, no longer uniquely predicted coercive sexual victimization. The association between the NDD general factor and coercive sexual victimization was due to shared genetics. General NDD symptom load, rather than specific ASD or ADHD symptoms, seems to be a moderate vulnerability factor for coercive sexual victimization. We speculate that an evocative gene-environment correlation might account for this observation, such that sexual perpetrators actively target NDD individuals.

Introduction Neurodevelopmental disorders (NDDs) typically emerge in early childhood and have a profound impact on the development of the nervous system, leading to various neurological challenges in cognition, communication, social interaction, motor skills, and behavior. These disorders arise from disruptions in brain development mechanisms. NDDs include conditions such as cerebral palsy (CP), global developmental delay (GDD), intellectual disability (ID), attention-deficit/hyperactivity disorder (ADHD), and autism spectrum disorder (ASD), with ADHD and ASD being the most prevalent. However, there is a lack of comprehensive research on the causes of NDDs in children receiving care at tertiary hospitals in Saudi Arabia. Therefore, in this study, we aimto investigate the characteristics of patients with NDDs and explore the association between NDDs and seizures. It also focuses on identifying specific risk factors that may influence the relationship between NDDs and seizures. Methods We conducted a retrospective cross-sectional study at the pediatric neurology and developmental assessment clinic of King Abdulaziz University Hospital in Jeddah, Saudi Arabia. The study involved a review of electronic medical records from January 2021 to May 2023 for 200 pediatric patients who attended the clinic for NDD and seizures. Descriptive statistics summarized the data, using frequencies and percentages for categorical variables, and mean ± standard deviation for quantitative variables. The chi-square test identified differences between qualitative variables, with a significance threshold of p < 0.05. Results The study sample comprised 200 children ranging in age from one month to 14 years, with the majority of patients being from Jeddah city. Participants were categorized into four age groups: 17.0% (n=34) were aged between one month and three years, 18.5% (n=37) were aged between three and six years, 55.0% (n=110) were aged between six and 12 years old, and 9.5% (n=19) were aged between 12 and 14 years. The NDD subtypes identified were ASD 9.5%, ADHD 16.0%, CP 8.5%, GDD 30.5%, ID 5.5%, and 30% had multiple types of NDD. Generalized tonic-clonic seizures were the most common type observed. Conclusion Children with NDDs exhibit a high prevalence of seizures, with the age of the patient and consanguinity emerging as significant influencing factors in this correlation. Among the key findings is an emphasis on the importance of early detection and intervention for children with NDDs at higher risk of developing seizures. Overall, the study sheds light on the characteristics of NDD patients and their association with seizures, contributing to a better understanding of the complex relationship between NDDs and seizure occurrence. It also emphasizes the need for comprehensive assessment and management strategies that consider seizures in children with NDDs.

Familial and genetic associations between autism spectrum disorder (ASD) and other neurodevelopmental and psychiatric disorders have been reported, sometimes with conflicting results. We estimated familial and genetic associations between ASD and nine disorder groups, and explored differences in these associations for ASD in the context of intellectual disability, epilepsy, chromosomal abnormalities, and congenital malformations. Individuals born between 1985 and 2009 living in Sweden on their seventh birthday were linked to their biological parents in order to identify different types of relatives. We retrieved information on all the disorders considered from the National Patient Register. Logistic regression was used to estimate the familial association between ASD and other neurodevelopmental and psychiatric disorders in the different groups of relatives. Structural equation modeling was used to estimate phenotypic (rp ) and genetic associations (rg ), as well as the contribution of genetic influences to rp . The study included 2,398,608 individuals. Among relatives of individuals diagnosed with ASD, there was an increased risk of the disorders considered, compared to relatives of individuals who were not diagnosed with ASD. Stronger associations were detected for ASD without any additional diagnosis of intellectual disability, epilepsy, chromosomal abnormalities, and congenital malformations. The strongest genetic correlation was estimated between ASD and other neurodevelopmental disorders (rg =0.73; 95% CI=0.66-0.79). Moderate genetic correlations were estimated for anxiety disorders (rg =0.47; 95% CI=0.33-0.61), depression (rg =0.52; 95% CI=0.37-0.66), and intentional self-harm (rg =0.54; 95% CI=0.36-0.71). ASD shows familial and genetic association not only with other neurodevelopmental disorders, but also with other psychiatric disorders, such as anxiety, depression, and intentional self-harm. Family history of ASD comorbid with intellectual disability, epilepsy, congenital malformations, or chromosomal abnormalities is less related to other psychiatric disorders, potentially suggesting a different etiology for this subgroup of patients.

In the study by Khalifa et al. in this issue of Acta Paediatrica 1, levels of the excitatory neurotransmitter glutamate were analysed in a clinical sample of young children aged 3–10 years with autism spectrum disorders (ASD). The 30 children were randomly selected from the ASD Outpatient Clinic at the Abou El-Reesh Hospitals, Cairo University and compared to 30 randomly selected controls, without any mental disorders or major medical illnesses, whose siblings were attending another outpatient clinic at the hospital. The prevalence of ASD has been the subject of many studies, and, as the authors report, many of which have reported a dramatic increase during the last decade. A Swedish study 2 reported that considerably fewer ASD symptoms now seemed to be required for a clinical diagnosis of ASD, particularly after the preschool years. These findings suggest that increases in ASD diagnoses could be partly due to how ASD is diagnosed. The increased level of serum glutamate that was found by Khalifa et al. 1 is interesting and in line with other studies of serum glutamate in children with autism that they refer to and has clinical and further research implications. As the authors point out, glutamate is one of the major excitatory neurotransmitters in the human brain and plays a significant role in brain development, cell migration, synapse induction and cell differentiation. It is also involved in a wide range of neural and cognitive functions, such as learning and memory. Although glutamate does not cross the blood–brain barrier readily, levels of glutamate in blood and cerebrospinal fluid have been positively correlated in humans, suggesting that peripheral glutamate levels can reflect the glutamate level in the brain 3. In an early study (1992) 4, the concentration of glutamate, but of no other amino acid, was markedly elevated in the cerebrospinal fluid of patients with Rett syndrome, a genetic disorder characterised by the loss of functions and in many cases a period with autistic features. Attempts to understand the pathobiology of the glutamatergic system have led to new investigational treatments for ASD. The potential implications of modulating the glutamatergic system while treating ASD, by using specific drugs that affect glutamatergic receptors, have been explored in preclinical and clinical studies. These have specifically targeted the NMDA receptors (agonists and antagonists), the AMPA/kainate receptors (antagonists) and metabotropic glutamate receptor 5 (mGluR5) (antagonists) and other mechanisms in the glutamatergic system 5. However, despite the potentially encouraging preliminary findings of clinical trials using glutamate, there are several limitations. These are mainly associated with the fact that ASD is a very heterogeneous disorder with many potential aetiologies, including those where a glutamatergic dysfunction might not play a key role in the pathophysiology 5. There is a growing interest in this area, and studies have indicated an imbalance in excitatory (glutamatergic) and inhibitory γ-aminobutyric acid (GABAergic) neurotransmission in ASD 1. Although GABA is best known as an inhibitory neurotransmitter, it can be either inhibitory or excitatory, depending on intraneuronal (Cl−), which is modulated by two isoforms of the cation-Cl− cotransporter family. These are NKCC1, an isoform of the Na+-K+-2Cl− cotransporter, and KCC2, an isoform of the K+-Cl− cotransporter. NKCC1 transports Cl−, along with Na+ and K+, into the neuron, which increases (Cl−) leading to depolarisation (excitatory state) on the opening of Cl− channels, such as GABA-A receptors. KCC2 transports Cl−, along with K+, out of the neuron, which decreases (Cl−) leading to hyperpolarisation (inhibitory state) with Cl− channel opening 6. NKCC1 is widely distributed throughout the body and is also found in neurons 6. Normally, adult neurons have low intracellular chloride levels underlying the GABAergic inhibitory drive. In contrast, there are high chloride levels and concomitant excitatory GABA actions in a wide range of pathological conditions. Reducing GABAergic inhibition produces neuronal hyperexcitability, and can lead to deleterious neurological and psychiatric sequelae, including ASD 7. These observations have raised considerable interest in the development of pharmacological treatments that restore physiological (Cl−) levels and GABAergic inhibition in pathological conditions 7, 8. Based on animal studies of autism, revealing that the NKCC1 chloride-importer inhibitor bumetanide restores physiological chloride levels and enhances GABAergic inhibition, clinical treatment studies have been performed and published by a French group from 2010 onwards 7, 8. In 2017, this group published a double-blind, randomised, placebo-controlled, multisite study that assessed the efficacy, safety, pharmacokinetics and the optimal dose of bumetanide in children and adolescents with ASD, including Asperger's syndrome 7. The study group consisted of 88 children and adolescents aged 2–18 years, and the treatment period was 3 months. The findings showed that bumetanide improved core symptoms of ASD and presented a favourable benefit/risk ratio, particularly when 1.0 mg of bumetanide was administered twice daily. The frequency and incidence of adverse events were directly correlated with the bumetanide dose 7. Another study was carried out by the French group based on findings that constraining eye contact leads to an exaggerated increase in amygdala activation in ASD. Functional magnetic resonance imaging and eye tracking were performed on adolescents and young adults with high-functioning ASD before and after bumetanide. This revealed that bumetanide normalised the amygdala activation levels during constrained eye contact with dynamic emotional face stimuli. In addition, eye-tracking data revealed that bumetanide increased the time spent in spontaneous eye gaze during a free-viewing mode of the same face stimuli. The data support the excitatory/inhibitory dysfunction hypothesis for ASD and indicate that bumetanide may improve specific aspects of social processing in ASD 9. The results from the bumetanide studies are interesting and promising and should be followed up by further, large double-blind placebo-controlled trials in patients with ASD. It would be preferable if these included different aetiologically and clinically defined subgroups, for example ASD with coexisting intellectual disability, attention-deficit hyperactivity disorder, epilepsy and those with other coexisting developmental disorders. If possible, these should include approaches to monitor the molecular mechanisms of medication responses. Along with data from a meta-analysis, Khalifa et al. 1 discussed the potential role of glutamate as a biomarker of ASD but underscored that larger sample studies are needed to verify whether it can be used for early detection of autism. However, since the findings of higher glutamate levels seem to be prevalent in many central nervous system disorders, it would be necessary to base any diagnosis of ASD on a full clinical neurodevelopmental assessment, including evaluation of the ASD symptom criteria. Autism spectrum disorder is a highly heterogeneous neurodevelopmental disorder, with regard to its aetiology and clinical presentation 10, and most patients with ASD have at least one coexisting neurodevelopmental or neuropsychiatric disorder. These include intellectual disability, attention-deficit hyperactivity disorder, developmental language disorder, anxiety disorders, tic disorders, obsessive-compulsive disorder, feeding, sleeping and eating disorder, motor coordination disorder, epilepsy and, or, other types of specific problems, including mood dysregulation, sensory abnormalities and self-harm behaviour. An important challenge for future research is to explore the extent to which glutamatergic and GABAergic imbalance underlies specific subsets of patients with ASD. The studies to date are encouraging and support possible and promising pharmacological treatment options to improve functioning in individuals with ASD by targeting the glutamatergic and GABAergic systems. The author has no conflict of interests to report.

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.

Copy number variation is now recognized as an important class of risk factor for several child psychiatric disorders. In this article, we first explain what copy number variants (CNVs) are. We then consider key findings and what these have told us about the etiology of these conditions. Finally, we discuss whether these findings can yet translate into clinical practice.