The maternal immune activation hypothesis has gained attention over the past 2 decades as a potential contributor to the etiology of autism. This hypothesis posits that maternal conditions associated with inflammation during pregnancy may increase the risk of autism in offspring. Autism is highly heritable, and causal environmental contributors to autism largely remain elusive. We review studies on maternal conditions during pregnancy, all associated with some degree of systemic inflammation, namely maternal infections, autoimmunity, and high body mass index. We also review studies of inflammatory markers in biological samples collected from mothers during pregnancy or from neonates and their relationship with autism assessed in children later in life. Recent reports indicate familial clustering of autism, autoimmunity, and infections, as well as genetic correlations between autism and aspects of immune function. Given this literature, there is an apparent risk of confounding of the reported associations between inflammatory exposures and autism by familial genetic factors in both clinical and epidemiological cohort studies. We highlight recent studies that have attempted to address potential confounding to assess evidence of causal effects of inflammation during early life in autism.

Early life exposure to immune activation and stress are critical factors involved in the development of mental and neurodevelopmental disorders in adulthood. This study explored the individual and combined effects of prenatal lipopolysaccharide-induced (LPS)-induced immune activation and postnatal maternal separation on cognitive performance and oxidative metabolism in male Wistar rats. Using a 2 × 2 factorial design, pregnant dams were exposed to LPS or saline on gestational day 15, and offspring underwent maternal separation from postnatal days 2-14. In adulthood, cognitive function was assessed using the Morris Water Maze, and regional brain energy metabolism was evaluated using quantitative histochemistry of cytochrome c oxidase (CCO) quantitative histochemistry in the prefrontal cortex, hippocampus, and retrosplenial cortex. Rats exposed to both stressors demonstrated significant impairments in spatial memory and cognitive flexibility, supporting the "two-hit" hypothesis of early adversity, which posits that early life exposure to an adverse environmental event (first hit) combined with subsequent exposure to stress during critical developmental periods (second hit) can significantly increase the risk of developing behavioral or neurodevelopmental disorders in adulthood. Accordingly, adult animals exposed to prenatal LPS and maternal separation showed prolonged escape latencies and decreased spatial memory retention during the behavioral tasks. Concurrently, CCO activity was markedly increased in all measured regions, reflecting heightened metabolic demands. These changes are consistent with impaired hippocampal-prefrontal-retrosplenial network integration and the underlying key processes involved in cognitive alterations such as memory or attention. This study underscores the synergistic effects of these environmental factors on cognitive and metabolic dysfunction, providing a translational model to better understand the etiology of neurodevelopmental disorders. The findings highlight the importance of addressing multiple interacting environmental factors in the context of early life adversity.

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficits in social communication, restricted interests, and repetitive behaviors. Emerging evidence suggests a link between immune dysregulation and ASD. This study investigates alterations in monocyte subpopulations and cytokine production in children with ASD and their potential associations with ASD risk and severity.

Initially, the immune status of peripheral blood mononuclear cells was assessed in cohort-I of 96 typically developing (TD) children and 92 children diagnosed with ASD using flow cytometry. Subsequently, the secretion of cytokines IL-6 and IL-10 by monocytes was evaluated following stimulation with a leukocyte activation mixture and intracellular protein staining technique in cohort-II.

Children with ASD exhibited significantly higher levels of total monocytes, classical monocytes (CD14hi/CD16-), and non-classical monocytes (CD14low/CD16+) compared to TD children (p < 0.001). Elevated levels of classical monocytes (β: 0.395; 95 %CI: 0.260-0.530; p < 0.001) and non-classical monocytes (β: 0.629; 95 %CI: 0.516-0.742; p < 0.001) were significantly associated with ASD after adjusting for age, sex and body mass index. Furthermore, increased production of IL-6 by monocytes was observed in children with ASD (p = 0.001). Logistic regression analysis revealed that classical monocytes (OR: 1.104; 95 %CI: 1.062-1.147; p < 0.001), non-classical monocytes (OR: 2.913; 95 %CI: 2.130-3.986; p < 0.001) and IL-6 production by monocytes (OR: 1.306; 95 %CI: 1.096-1.557; p = 0.003) are risk factors for ASD. Spearman correlation analysis revealed a negative correlation between classical monocyte levels and adaptive behavior developmental quotient (DQ) (r = - 0.377; p = 0.001), fine motor DQ (r = - 0.329; p = 0.003) and personal-social DQ (r = - 0.247; p = 0.029) in children with ASD.

Elevated classical and non-classical monocytes are potential risk factors for ASD and may influence neurodevelopmental outcomes. Further research is needed to elucidate the precise mechanisms and therapeutic implications.

Several studies have reported an association of autism spectrum disorder (ASD) with central nervous system (CNS) infections and intrauterine infections; however, the results remain unclear. This study aimed to examine this issue using an extensive national database. Utilizing JMDC medical claims database, we conducted a retrospective cohort study of children with at least three years of follow-up from birth, ensuring the mother's information was available. The focus was on the relationship between ASD incidence and exposures like viral meningitis/encephalitis, bacterial meningitis, and intrauterine infections. Cox proportional hazards was used to calculate hazard ratios (HRs) with covariates such as presence of maternal history of mental illness, preterm, low birth weight, respiratory and cardiac disorder, epilepsy, and cranial malformations. Sensitivity analysis was performed on sibling and multiple birth cohorts to adjust for genetic factors. Out of 276,195 mother-child pairs, bacterial meningitis was observed in 1326 (0.5%), viral meningitis/encephalitis in 6066 (2.2%), intrauterine infection in 3722 (1.3%), and ASD in 14,229 (5.2%) children. The adjusted HRs (95% confidence interval, p value) for ASD were 1.40 (1.25-1.57, p < 0.001), 1.14 (1.02-1.26, p = 0.013), and 1.06 (0.87-1.30, p = 0.539) for viral meningitis/encephalitis, intrauterine infection, and bacterial meningitis, respectively. After sensitivity analysis, the HRs for viral meningitis/encephalitis and ASD remained significantly high. Viral meningitis/encephalitis may be an independent risk factor for ASD. Awareness of this risk among healthcare professionals can lead to early intervention and potentially improved outcomes for affected children.

Observational studies have suggested that shorter telomere length (TL) may be a risk factor for psychiatric disorders. However, whether this association underlie causal effects remains unknown. This study aims to investigate the potential association between TL and psychiatric disorders by conducting a bidirectional Mendelian randomization (MR) study. Summary statistics for TL were obtained from the UK Biobank (n = 472,174), while summary statistics for ten psychiatric disorders were acquired from the Psychiatric Genomics Consortium (PGC). The inverse-variance weighted (IVW) method was used as primary analysis, with the MR-Egger, weighted median, MR-PRESSO, simple mode, and weighted mode approaches were utilized as sensitivity analyses. Our findings indicated a potential association between genetic predisposition to attention deficit hyperactivity disorder (ADHD) and shortened TL (Beta = - 0.039, SE = 0.011, P = 4.00E-04). Additionally, posttraumatic stress disorder (PTSD) may be was potentially associated with TL (Beta = - 0.014, SE = 0.006, P = 0.019). Our findings suggest a potential correlation between ADHD and TL, yet no significant association exists between TL and other psychiatric disorders. Nevertheless, considering the small effect size and the fact that it might have limited practical clinical significance, TL may not function as a biomarker for psychiatric disorders.

Autism spectrum disorder (ASD) is a neurodevelopmental condition caused by both genetic and environmental factors. Since no single gene variant accounts for more than 1% of the cases, the converging actions of ASD-related genes and other factors, including microRNAs (miRNAs), may contribute to ASD pathogenesis. To date, few studies have simultaneously investigated the mRNA and miRNA profiles in an ASD-relevant model. The BTBR mouse strain displays a range of behaviors with ASD-like features but little is known about the protein-coding and noncoding gene expression landscape that may underlie the ASD-like phenotype. Here we performed parallel mRNA and miRNA profiling using the prefrontal cortex (PFC) of BTBR and C57BL/6 J (B6) mice. This identified 1063 differentially expressed genes and 48 differentially expressed miRNAs. Integration of mRNA and miRNA data identified a strong inverse relationship between upregulated (DEGs) and downregulated miRNAs, and vice versa. Pathway analysis, taking account of the inverse relationship between differentially expressed miRNAs and their target mRNAs highlighted significant shared enrichment in immune signaling, myelination, and neurodevelopmental processes. Notably, miRNA changes were predicted to affect synapse-related functions but we did not find enrichment of protein-coding genes linked to cellular components or biological processes related to synapses in the PFC of BTBR mice, indicating processes may evade miRNA control. In contrast, other miRNAs were predicted to have extensive relationships with DEGs suggesting their role as potential hub coordinators of gene expression. Profiling findings were confirmed via qRT-PCR for representative protein-coding transcripts and miRNAs. Our study underscores the complex interplay between gene expression and miRNA regulation within immune and inflammatory pathways in the BTBR model, offering insights into the neurodevelopmental mechanisms of ASD. These results support the value of the BTBR mouse model and identify strategies that could adjust molecular pathways for therapeutic applications in ASD research.

Accumulating evidence implicates immune dysregulation and chronic inflammation in neurodevelopmental disorders (NDDs), often manifesting as abnormal alterations in peripheral blood immune cell levels. The mononuclear phagocyte system, including monocytes and microglia, has been increasingly recognized for its involvement in the pathogenesis of NDDs. However, due to inconsistent findings in the literature, whether monocytes can serve as a reliable biomarker for NDDs remains controversial. To address this issue, we conducted a systematic review and meta-analysis of studies examining monocyte counts in NDD individuals. A comprehensive search was conducted across PubMed, Web of Science, and Scopus databases. Variables extracted for analysis encompassed the author's name, year of study, sample size, patient's age, type of disease, mean, standard deviation of monocytes and sex ratio. A total of 2503 articles were found by searching the three databases. After removed duplicates and screening titles, abstracts, and full texts, 17 articles met the inclusion criteria, and 20 independent studies were included in the meta-analysis. The results indicated significantly increased monocyte counts in 5 type NDDs compared to Typical Development (TD) groups (g = 0.36, 95%CI [0.23, 0.49]). Subgroup analyses revealed no significant differences in monocyte counts across different NDD types, gender, or age. These findings suggest that aberrant alterations in monocyte counts are common in NDD cases, indicating their potential as biomarkers for these conditions. Future research should further investigate the role of monocyte in understanding the mechanisms, early detection, and clinical diagnosis of NDDs.

Researchers are increasingly investigating the developmental origins of white matter alterations in autism spectrum disorder (ASD). A recent review by Canada, Evans, and Pelphrey highlights the roles of oligodendrocytes and microglia in ASD-related white matter abnormalities. Evidence suggests that ASD risk genes impact oligodendrocyte development and myelination, while microglia dysfunction due to immune challenges may further disrupt white matter formation. Emerging studies link neuroinflammation to altered white matter trajectories, supporting early intervention strategies. Future research integrating neuroimaging, genetics, and immune profiling may enhance our understanding and facilitate the development of targeted neuroimmune therapies for ASD.

Most current information about neurological disorders and diseases is derived from direct patient and animal studies. However, patient studies in many cases do not allow replication of the early stages of the disease and, therefore, offer limited opportunities to understand disease progression. On the other hand, although the use of animal models allows us to study the mechanisms of the disease, they present significant limitations in developing drugs for humans. Recently, 3D-cultured in vitro models derived from human pluripotent stem cells have surfaced as a promising system. They offer the potential to connect findings from patient studies with those from animal models. In this comprehensive review, we discuss their application in modeling neurodevelopmental conditions such as Down Syndrome or Autism, neurodegenerative diseases such as Alzheimer's or Parkinson's, and viral diseases like Zika virus or HIV. Furthermore, we will discuss the different models used to study prenatal exposure to drugs of abuse, as well as the limitations and challenges that must be met to transform the landscape of research on human brain disorders.

Elevated cytokine levels, including IL-6 and IL-1β, can contribute to persistent brain inflammation in children with autism and cytomegalovirus (CMV) infection, exacerbating autism-related behaviours and symptoms. This study evaluates the impact of CMV-induced cytokine increases on the eating behaviours and sensory profiles of children with autism.

A cross-sectional design was employed, involving children aged two to five years (CMV-reactive IgG), with ASD (n= 98) and TD (n = 96). Serological tests using ELISA were conducted to measure IgG CMV, IL-6, and IL-1β biomarkers. Eating behaviours were evaluated using the BAMBI (Brief Autism Mealtime Behaviour Inventory), and sensory profiles were assessed using the SSP (Short Sensory Profile). Statistical analyses were performed using Spearman's rank and chi-square tests.

The results show that autism significantly affects children's eating behaviours and sensory profiles (p < 0.001), with notable differences found between the groups. Correlation analysis revealed a significant association between IgG CMV and IL-6 (p = 0.026) and IL-1β (p = 0.014) in the ASD group. Additionally, eating behaviours (food refusal and limited variety) in ASD correlated with IL-6 and IL-1β. Sensory characteristics, such as tactile sensitivity, were found to correlate with IL-6 (p = 0.027) and IL-1β (p = 0.002) in the ASD group.

These findings suggest that CMV-infected children with autism are at increased risk of IL-6 and IL-1β dysregulation, contributing to sensory processing issues and eating behaviours. Further research is needed to enhance CMV testing protocols and better understand the virus's role in the development of sensory and behavioural issues in children with autism.

Cd99 molecule-like 2 (Cd99l2) is a type I transmembrane protein that plays a role in the transmigration of leukocytes across vascular endothelial cells. Despite its high expression in the brain, the role of Cd99l2 remains elusive. We find that Cd99l2 is expressed primarily in neurons and positively regulates neurite outgrowth and the development of excitatory synapses. We demonstrate that Cd99l2 inversely regulates the expression of immediate-early genes (IEGs), including Arc, Egr1, and c-Fos, by inhibiting the activity of the transcription factors CREB and SRF. Neuronal inactivation increases the transport of Cd99l2 to the cell surface from recycling endosomes, thereby enhancing Cd99l2-mediated inhibitory signaling. Additionally, Cd99l2 knockout mice exhibit impaired excitatory synaptic transmission and plasticity in the hippocampus, along with deficits in spatial memory and contextual fear conditioning. Based on these findings, we propose that neuronal Cd99l2 functions as a synaptic cell adhesion molecule that inversely controls neuronal activation.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition marked by diverse symptoms affecting social interaction, communication, and behavior. This research aims to explore bacterial lipopolysaccharide (LPS)- and immune-related (BLI) molecular subgroups in ASD to enhance understanding of the disorder.

We analyzed 89 control samples and 157 ASD samples from the GEO database, identifying BLI signatures using least absolute shrinkage and selection operator regression (LASSO) and logistic regression machine learning algorithms. A nomogram prediction model was developed based on these signatures, and we performed Gene Set Enrichment Analysis (GSEA), Gene Set Variation Analysis (GSVA), and immune cell infiltration analysis to assess the impact of BLI subtypes and their underlying mechanisms.

Our findings revealed 17 differentially expressed BLI genes in children with ASD, with BLNK, MAPK8, PRKCQ, and TNFSF12 identified as potential biomarkers. The nomogram demonstrated high diagnostic accuracy for ASD. We delineated two distinct molecular subtypes (Cluster 1 and Cluster 2), with GSVA indicating that Cluster 2 showed upregulation of immune- and inflammation-related pathways. This cluster exhibited increased levels of antimicrobial agents, chemokines, cytokines, and TNF family cytokines, alongside activation of bacterial lipoprotein-related pathways. A significant correlation was found between these pathways and distinct immune cell subtypes, suggesting a potential mechanism for neuroinflammation and immune cell infiltration in ASD.

Our research highlights the role of BLI-associated genes in the immune responses of individuals with ASD, indicating their contribution to the disorder's typification. The interplay between bacterial components, genetic predisposition, and immune dysregulation offers new insights for understanding ASD and developing personalized interventions.

Epilepsy is a complex neurological disorder characterized not only by seizures but also by significant neuropsychiatric comorbidities, affecting approximately one-third of those diagnosed. This review explores the intricate relationship between epilepsy and its associated psychiatric and cognitive disturbances, with a focus on the role of inflammation. Recent definitions of epilepsy emphasize its multifaceted nature, linking it to neurobiological, psychiatric, cognitive, and social deficits. Inflammation has emerged as a critical factor influencing both seizure activity and neuropsychiatric outcomes in epilepsy patients. This paper critically examines how dysregulated inflammatory pathways disrupt neurotransmitter transmission and contribute to depression, mood disorders, and anxiety prevalent among individuals with epilepsy. It also evaluates current therapeutic approaches and underscores the potential of anti-inflammatory therapies in managing epilepsy and related neuropsychiatric conditions. Additionally, the review highlights the importance of the anti-inflammatory effects of anti-seizure medications, antidepressants, and antipsychotics and their therapeutic implications for mood disorders. Also, the role of ketogenic diet in managing epilepsy and its psychiatric comorbidities is briefly presented. Furthermore, it briefly discusses the role of the gut-brain axis in maintaining neurological health and how its dysregulation is associated with epilepsy. The review concludes that inflammation plays a pivotal role in linking epilepsy with its neuropsychiatric comorbidities, suggesting that targeted anti-inflammatory interventions may offer promising therapeutic strategies. Future research should focus on longitudinal studies comparing outcomes between epileptic patients with and without neuropsychiatric comorbidities, the development of diagnostic tools, and the exploration of novel anti-inflammatory treatments to better manage these complex interactions.

Autism spectrum disorders (ASDs) are characterized by deficits in social functioning, stereotyped patterns of behaviors, narrowed interests, and elevated anxiety. Certain ASD symptoms can persist, whereas others may improve throughout the lifespan, but the specific patterns of changes have not been clearly delineated. Using a valproic acid (VPA) rat model of ASD, the present study took a developmental approach and examined how autistic-like behaviors, including anxiety-like behavior, object obsession, and social functioning deficits, manifested differently in three critical periods representing preadolescent (postnatal day [PND] 25), adolescent (PND 45), and adulthood life stage (PND 75) in a sex-dependent manner. Starting on PNDs 25, 45, and 75, VPA- or saline-exposed male and female offspring were tested in an elevated plus maze (EPM) and a newly validated composite social and object interaction and a triple recognition test (object, spatial, and social recognition). Across the three age groups, VPA-exposed offspring did not exhibit enhanced anxiety-like behavior in the EPM nor enhanced object interaction ("object obsession") in the triple recognition test. However, both male and female preadolescent (PND 25) VPA-exposed offspring showed a significantly increased latency to initiate social contact than the saline-exposed controls, although their latencies to contact novel objects were comparable to those of the controls. Male preadolescent and adolescent VPA-exposed offspring, to a lesser extent the female preadolescent offspring, exhibited significantly lower levels of social interaction. These social functioning deficits were absent in adult VPA offspring. Additionally, prenatal VPA exposure did not cause an impairment of object recognition, spatial recognition, or social recognition of a familiar conspecific. Unexpectedly, it enhanced social recognition of a novel conspecific, but only in adolescent female offspring. These findings suggest that this rat model based on prenatal VPA exposure is valid in capturing early social motivational and functioning deficits but is limited in its capacity to model increased object obsession and enhanced anxiety as seen in ASD, as well as the developmental trajectory of non-social ASD symptoms. Recognizing these limitations is important as it informs us how to properly use this model to investigate the neurobiology of ASD and incentivizes us to develop better rodent models.

Prenatal infections and activation of the maternal immune system have been proposed to contribute to causing neurodevelopmental disorders (NDDs), chronic conditions often linked to brain abnormalities. Microglia are the resident immune cells of the brain and play a key role in neurodevelopment. Disruption of microglial functions can lead to brain abnormalities and increase the risk of developing NDDs. How the maternal as well as the fetal immune system affect human neurodevelopment and contribute to NDDs remains unclear. An important reason for this knowledge gap is the fact that the impact of exposure to prenatal risk factors has been challenging to study in the human context. Here, we characterized a model of cerebral organoids (CO) with integrated microglia (COiMg). These organoids express typical microglial markers and respond to inflammatory stimuli. The presence of microglia influences cerebral organoid development, including cell density and neural differentiation, and regulates the expression of several ciliated and mesenchymal cell markers. Moreover, COiMg and organoids without microglia show similar but also distinct responses to inflammatory stimuli. Additionally, IFN-γ induced significant transcriptional and structural changes in the cerebral organoids, that appear to be regulated by the presence of microglia. Specifically, interferon-gamma (IFN-γ) was found to alter the expression of genes linked to autism. This model provides a valuable tool to study how inflammatory perturbations and microglial presence affect neurodevelopmental processes.

Although neurons release neurotransmitter before contact, the role for this release in synapse formation remains unclear. Cortical synapses do not require synaptic vesicle release for formation (Verhage et al., 2000; Sando et al., 2017; Sigler et al., 2017; Held et al., 2020), yet glutamate clearly regulates glutamate receptor trafficking (Roche et al., 2001; Nong et al., 2004) and induces spine formation (Engert and Bonhoeffer, 1999; Maletic-Savatic et al., 1999; Toni et al., 1999; Kwon and Sabatini, 2011; Oh et al., 2016). Using rat and murine culture systems to dissect molecular mechanisms, we found that glutamate rapidly decreases synapse density specifically in young cortical neurons in a local and calcium-dependent manner through decreasing N-methyl-d-aspartate receptor (NMDAR) transport and surface expression as well as cotransport with neuroligin (NL1). Adhesion between NL1 and neurexin 1 protects against this glutamate-induced synapse loss. Major histocompatibility I (MHCI) molecules are required for the effects of glutamate in causing synapse loss through negatively regulating NL1 levels in both sexes. Thus, like acetylcholine at the neuromuscular junction, glutamate acts as a dispersal signal for NMDARs and causes rapid synapse loss unless opposed by NL1-mediated trans-synaptic adhesion. Together, glutamate, MHCI, and NL1 mediate a novel form of homeostatic plasticity in young neurons that induces rapid changes in NMDARs to regulate when and where nascent glutamatergic synapses are formed.

Autism spectrum disorder (ASD) is a highly heterogeneous neurodevelopmental disorder with onset in childhood. The molecular mechanisms underlying ASD have not yet been elucidated completely. Evidence has emerged to support a link between microglial dysfunction and the etiology of ASD. This review summarizes current research on microglial dysfunction in neuroinflammation and synaptic pruning, which are associated with altered transcriptomes and autophagy in ASD. Dysbiosis of gut microbiota in ASD and its correlation with microglial dysfunction are also addressed.

Autism Spectrum Disorder (ASD) is a complex and heterogeneous neurodevelopmental condition characterized by a range of social, communicative, and behavioral challenges. This comprehensive review delves into key aspects of ASD. Clinical Overview and genetic features provide a foundational understanding of ASD, highlighting the clinical presentation and genetic underpinnings that contribute to its complexity. We explore the intricate neurobiological mechanisms at play in ASD, including structural and functional differences that may underlie the condition's hallmark traits. Emerging research has shed light on the role of the immune system and neuroinflammation in ASD. This section investigates the potential links between immunological factors and ASD, offering insights into the condition's pathophysiology. We examine how atypical functional connectivity and alterations in neurotransmitter systems may contribute to the unique cognitive and behavioral features of ASD. In the pursuit of effective interventions, this section reviews current therapeutic strategies, ranging from behavioral and educational interventions to pharmacological approaches, providing a glimpse into the diverse and evolving landscape of ASD treatment. This holistic exploration of mechanisms in ASD aims to contribute to our evolving understanding of the condition and to guide the development of more targeted and personalized interventions for individuals living with ASD.

The prevalence of many chronic noncommunicable diseases has been steadily rising over the past six decades. During this time, over 350,000 new chemical substances have been introduced to the lives of humans. In recent years, the epithelial barrier theory came to light explaining the growing prevalence and exacerbations of these diseases worldwide. It attributes their onset to a functionally impaired epithelial barrier triggered by the toxicity of the exposed substances, associated with microbial dysbiosis, immune system activation, and inflammation. Diseases encompassed by the epithelial barrier theory share common features such as an increased prevalence after the 1960s or 2000s that cannot (solely) be accounted for by the emergence of improved diagnostic methods. Other common traits include epithelial barrier defects, microbial dysbiosis with loss of commensals and colonization of opportunistic pathogens, and circulating inflammatory cells and cytokines. In addition, practically unrelated diseases that fulfill these criteria have started to emerge as multimorbidities during the last decades. Here, we provide a comprehensive overview of diseases encompassed by the epithelial barrier theory and discuss evidence and similarities for their epidemiology, genetic susceptibility, epithelial barrier dysfunction, microbial dysbiosis, and tissue inflammation.

Sleep disorders are common in youths with autism spectrum disorders. Inflammatory cytokines such as Il-1 beta and Il-6 in saliva have been associated with alterations in sleep quality in various conditions. We assessed whether there were associations between the salivary concentration of IL-1 beta and IL-6 and sleep quality in youths with ASD versus typically developing (TD) age- and gender-matched youths.

Forty children and adolescents with ASD or TD participated in this study (20% females). Their parents answered the items of a validated questionnaire on sleep quality (Pittsburgh Sleep Quality Index).

The mean Pittsburgh score was significantly higher (i.e., the quality of sleep was poorer) in the ASD group (8.68 ± 0.35 (SEM), ranging from 7 to 12 points), compared to the TD group (7.35 ± 0.54 (SEM), ranging from 2 to 12 points) (p = 0.02, Mann-Whitney U test). There were no significant differences in the salivary concentration of Il-1 beta and IL-6 receptor between the two groups, but salivary IL-1 beta concentration was inversely associated with poor sleep quality in the ASD group. No associations between the salivary Il-6 concentration and sleep quality were found in either group. Linear regression analysis by separate groups revealed significant associations between the sleep quality score and the concentration of IL-1 beta in the ASD group (p = 0.01, OR = -0.53, 95% CI -0.008-0.001). In contrast, no significant associations were observed in the TD group, or for IL-6 in either group. No significant effects of sex, age, or use of psychotropic medications were found.

Children and adolescents with ASD showed significantly poorer sleep quality based on their parents' reports compared to the TD group, and the salivary IL-1 beta concentration was inversely associated with sleep quality only in the ASD group. Further studies on the associations between inflammatory cytokines and sleep in ASD are needed.

Microglial abnormality and heterogeneity are observed in autism spectrum disorder (ASD) patients and animal models of ASD. Microglial depletion by colony stimulating factor 1-receptor (CSF1R) inhibition has been proved to improve autism-like behaviors in maternal immune activation mouse offspring. However, it is unclear whether CSF1R inhibition has extensive effectiveness and pharmacological heterogeneity in treating autism models caused by genetic and environmental risk factors. Here, we report pharmacological functions and cellular mechanisms of PLX5622, a small-molecule CSF1R inhibitor, in treating Cntnap2 knockout and valproic acid (VPA)-exposed autism model mice. For the Cntnap2 knockout mice, PLX5622 can improve their social ability and reciprocal social behavior, slow down their hyperactivity in open field and repetitive grooming behavior, and enhance their nesting ability. For the VPA model mice, PLX5622 can enhance their social ability and social novelty, and alleviate their anxiety behavior, repetitive and stereotyped autism-like behaviors such as grooming and marble burying. At the cellular level, PLX5622 restores the morphology and/or number of microglia in the somatosensory cortex, striatum, and hippocampal CA1 regions of the two models. Specially, PLX5622 corrects neurophysiological abnormalities in the striatum of the Cntnap2 knockout mice, and in the somatosensory cortex, striatum, and hippocampal CA1 regions of the VPA model mice. Incidentally, microglial dynamic changes in the VPA model mice are also reported. Our study demonstrates that microglial depletion and repopulation by transient CSF1R inhibition is effective, and however, has differential pharmacological functions and cellular mechanisms in rescuing behavioral deficits in the two autism models.

Environmental insults during early development heavily affect brain trajectories. Among these, maternal infections, high-fat diet regimens, and sleep disturbances pose a significant risk for neurodevelopmental derangements in the offspring. Notably, scattered evidence is starting to emerge that also paternal lifestyle habits may impact the offspring development. Given their key role in controlling neurogenesis, synaptogenesis and shaping neuronal circuits, microglia represent the most likely suspects of mediating the detrimental effects of prenatal insults. For some of these environmental triggers, like maternal infections, ample literature evidence demonstrates the central role of microglia, also delineating the specific transcriptomic and proteomic profiles induced by these insults. In other contexts, the analysis of microglia is still in its infancy. Fostering these studies is needed to define microglia as potential therapeutic target in the frame of disorders consequent to maternal immune activation.

Maternal immune activation (MIA) triggers neurobiological changes in offspring, potentially reshaping the molecular synaptic landscape, with the hippocampus being particularly vulnerable. However, critical details regarding developmental timing of these changes and whether they differ between males and females remain unclear.

We induced MIA in C57BL/6J mice on gestational day nine using the viral mimetic poly(I:C) and performed mass spectrometry-based proteomic analyses on hippocampal synaptoneurosomes of embryonic (E18) and adult (20 ± 1 weeks) MIA offspring.

In the embryonic synaptoneurosomes, MIA led to lipid, polysaccharide, and glycoprotein metabolism pathway disruptions. In the adult synaptic proteome, we observed a dynamic shift toward transmembrane trafficking, intracellular signalling cascades, including cell death and growth, and cytoskeletal organisation. In adults, many associated pathways overlapped between males and females. However, we found distinct sex-specific enrichment of dopaminergic and glutamatergic pathways. We identified 50 proteins altered by MIA in both embryonic and adult samples (28 with the same directionality), mainly involved in presynaptic structure and synaptic vesicle function. We probed human phenome-wide association study data in the cognitive and psychiatric domains, and 49 of the 50 genes encoding these proteins were significantly associated with the investigated phenotypes.

Our data emphasise the dynamic effects of viral-like MIA on developing and mature hippocampi and provide novel targets for study following prenatal immune challenges. The 22 proteins that changed directionality from the embryonic to adult hippocampus, suggestive of compensatory over-adaptions, are particularly attractive for future investigations.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social interaction and communication, as well as the occurrence of stereotyped and repetitive behaviors. Previous studies have provided solid evidence of dysregulated immune system in ASD; however, limited studies have investigated autoantibody profiles in individuals with ASD. This study aims to screen plasma autoantibodies in a well-defined cohort of young children with ASD (n = 100) and their matched controls (n = 60) utilizing a high-throughput KoRectly Expressed (KREX) i-Ome protein-array technology. We identified differential protein expression of 16 autoantibodies in ASD, which were correlated with differential gene expression of these markers in independent ASD cohorts. Meanwhile, we identified a distinct list of 33 autoantibodies associated with ASD severity; several of which were correlated with maternal age and birth weight in ASD. In addition, we found dysregulated numbers of circulating B cells and activated HLADR+ B cells in ASD, which were correlated with altered levels of several autoantibodies. Further in-depth analysis of B cell subpopulations revealed an increased frequency of activated naïve B cells in ASD, as well as an association of resting naïve B cells and transitional B cells with ASD severity. Pathway enrichment analysis revealed disrupted MAPK signaling in ASD, suggesting a potential relevance of this pathway to altered autoantibodies and B cell dysfunction in ASD. Finally, we found that a combination of eight autoantibodies associated with ASD severity showed an area under the curve (ROC-AUC) of 0.937 (95% CI = 0.890, 0.983; p < 0.001), which demonstrated the diagnostic accuracy of the eight-marker signature in the severity classification of ASD cases. Overall, this study determined dysregulated autoantibody profiles and B cell dysfunction in children with ASD and identified an eight-autoantibody panel for ASD severity classification.

Converging data show that exposure to maternal immune activation (MIA) in utero alters brain development in animals and increases the risk of neurodevelopmental disorders in humans. A recently developed non-human primate MIA model affords opportunities for studies with uniquely strong translational relevance to human neurodevelopment. The current longitudinal study used 1H-MRS to investigate the developmental trajectory of prefrontal cortex metabolites in male rhesus monkey offspring of dams (n = 14) exposed to a modified form of the inflammatory viral mimic, polyinosinic:polycytidylic acid (Poly IC), in the late first trimester. Brain metabolites in these animals were compared to offspring of dams that received saline (n = 10) or no injection (n = 4). N-acetylaspartate (NAA), glutamate, creatine, choline, myo-inositol, taurine, and glutathione were estimated from PRESS and MEGA-PRESS acquisitions obtained at 6, 12, 24, 36, and 45 months of age. Prior investigations of this cohort reported reduced frontal cortical gray and white matter and subtle cognitive impairments in MIA offspring. We hypothesized that the MIA-induced neurodevelopmental changes would extend to abnormal brain metabolite levels, which would be associated with the observed cognitive impairments. Prefrontal NAA was significantly higher in the MIA offspring across all ages (p < 0.001) and was associated with better performance on the two cognitive measures most sensitive to impairment in the MIA animals (both p < 0.05). Myo-inositol was significantly lower across all ages in MIA offspring but was not associated with cognitive performance. Taurine was elevated in MIA offspring at 36 and 45 months. Glutathione did not differ between groups. MIA exposure in male non-human primates is associated with altered prefrontal cortex metabolites during childhood and adolescence. A positive association between elevated NAA and cognitive performance suggests the hypothesis that elevated NAA throughout these developmental stages reflects a protective or resilience-related process in MIA-exposed offspring. The potential relevance of these findings to human neurodevelopmental disorders is discussed.

Autism spectrum disorder (ASD) is a neurodevelopmental condition marked by social interaction difficulties, repetitive behaviors, and immune dysregulation with elevated pro-inflammatory markers. Autophagic deficiency also contributes to social behavior deficits in ASD. Histamine H3 receptor (H3R) antagonism is a potential treatment strategy for brain disorders with features overlapping ASD, such as schizophrenia and Alzheimer's disease.

This study investigated the effects of sub-chronic systemic treatment with the H3R antagonist E159 on social deficits, repetitive behaviors, neuroinflammation, and autophagic disruption in male BTBR mice.

E159 (2.5, 5, and 10 mg/kg, i.p.) improved stereotypic repetitive behavior by reducing self-grooming time and enhancing spontaneous alternation in addition to attenuating social deficits. It also decreased pro-inflammatory cytokines in the cerebellum and hippocampus of treated BTBR mice. In BTBR mice, reduced expression of autophagy-related proteins LC3A/B and Beclin 1 was observed, which was elevated following treatment with E159, attenuating the disruption in autophagy. The co-administration with the H3R agonist MHA (10 mg/kg, i.p.) reversed these effects, highlighting the role of histaminergic neurotransmission in observed behavioral improvements.

These preliminary findings suggest the therapeutic potential of H3R antagonists in targeting neuroinflammation and autophagic disruption to improve ASD-like behaviors.

Fast-spiking parvalbumin (PV)-positive cells are key players in orchestrating pyramidal neuron activity, and their dysfunction is consistently observed in myriad brain diseases. To understand how immune complement pathway dysregulation in PV cells drives disease pathogenesis, we have developed a transgenic line that permits cell-type specific overexpression of the schizophrenia-associated C4 gene. We found that overexpression of mouse C4 (mC4) in PV cells causes sex-specific alterations in anxiety-like behavior and deficits in synaptic connectivity and excitability of PFC PV cells. Using a computational model, we demonstrated that these microcircuit deficits led to hyperactivity and disrupted neural communication. Finally, pan-neuronal overexpression of mC4 failed to evoke the same deficits in behavior as PV-specific mC4 overexpression, suggesting that perturbations of this neuroimmune gene in fast-spiking neurons are especially detrimental to circuits associated with anxiety-like behavior. Together, these results provide a causative link between C4 and the vulnerability of PV cells in brain disease.

How early in life stress-immune related environmental factors increase risk predisposition to schizophrenia remains unknown. We examined if pro-inflammatory changes perturb the brain epidermal growth factor (EGF) system, a system critical for neurodevelopment and mature CNS functions including synaptic plasticity. We quantified genes from key EGF and immune system pathways for mRNA levels and eight immune proteins in post-mortem dorsolateral prefrontal (DLPFC; Brodmann's Area (BA) 46) and orbitofrontal (OFC; BA11) cortices from people with schizophrenia, mood disorders and neurotypical controls. In BA46, 64 genes were differentially expressed, predominantly in schizophrenia, where attenuated expression of the MAPK-ERK, NRG1-PI3K-AKT and mTOR cascades indicated reduced EGF system signalling, and similarly diminished immune molecular expression, notably in TLR, TNF and complement pathways, along with low NF-κB1 and elevated IL12RB2 protein levels were noted. There was nominal evidence for altered convergence between ErbB-PI3K-AKT-mTOR and TLR pathways in BA46 in schizophrenia. Comparatively minimal changes were noted in BA11. Overall, distinct pathway gene expression changes may reflect variant pathological processes involving immune and EGF system signalling between schizophrenia and mood disorder, particularly in DLPFC. Further, the abnormal convergence between innate immune signalling and candidate EGF signalling pathways may indicate a pathologically important interaction in the developing brain in response to environmental stressors.

Autism spectrum disorder (ASD) is a multifactorial neurodevelopmental condition with several identified risk factors, both genetic and non-genetic. Among these, prenatal exposure to valproic acid (VPA) has been extensively associated with the development of the disorder. The zebrafish, a cost- and time-effective model, is useful for studying ASD features. Using validated VPA-induced ASD zebrafish models, we aimed to provide new insights into VPA exposure effects during embryonic development and to identify new potential biomarkers associated with ASD-like features. Dose-response analyses were performed in vivo to study larval phenotypes and mechanisms underlying neuroinflammation, mitochondrial dysfunction, oxidative stress, microglial cell status, and motor behaviour. Wild-type and transgenic Tg(mpeg1:EGFP) zebrafish were water-exposed to VPA doses (5 to 500 µM) from 6 to 120 h post-fertilisation (hpf). Embryos and larvae were monitored daily to assess survival and hatching rates, and numerous analyses and tests were conducted from 24 to 120 hpf. VPA doses higher than 50 µM worsened survival and hatching rates, while doses of 25 µM or more altered morphology, microglial status, and larval behaviours. VPA 50 µM also affected mRNA expression of inflammatory cytokines and neurogenesis-related genes, mitochondrial respiration, and reactive oxygen species accumulation. The study confirmed that VPA alters brain homeostasis, synaptic interconnections, and neurogenesis-related signalling pathways, contributing to ASD aetiopathogenesis. Further studies are essential to identify novel ASD biomarkers for developing new drug targets and tailored therapeutic interventions for ASD.

Autism spectrum disorder (ASD) is a major neurodevelopmental disorder affecting 1 in 36 children in the United States. While neurons have been the focus of understanding ASD, an altered neuro-immune response in the brain may be closely associated with ASD, and a neuro-immune interaction could play a role in the disease progression. As the resident immune cells of the brain, microglia regulate brain development and homeostasis via core functions including phagocytosis of synapses. While ASD has been traditionally considered a polygenic disorder, recent large-scale human genetic studies have identified SCN2A deficiency as a leading monogenic cause of ASD and intellectual disability. We generated a Scn2a-deficient mouse model, which displays major behavioral and neuronal phenotypes. However, the role of microglia in this disease model is unknown. Here, we reported that Scn2a-deficient mice have impaired learning and memory, accompanied by reduced synaptic transmission and lower spine density in neurons of the hippocampus. Microglia in Scn2a-deficient mice are partially activated, exerting excessive phagocytic pruning of post-synapses related to the complement C3 cascades during selective developmental stages. The ablation of microglia using PLX3397 partially restores synaptic transmission and spine density. To extend our findings from rodents to human cells, we established a microglia-incorporated human cerebral organoid model carrying an SCN2A protein-truncating mutation identified in children with ASD. We found that human microglia display increased elimination of post-synapse in cerebral organoids carrying the SCN2A mutation. Our study establishes a key role of microglia in multi-species autism-associated models of SCN2A deficiency from mouse to human cells.

Maternal inflammatory response (MIR) during early gestation in mice induces a cascade of physiological and behavioral changes that have been associated with autism spectrum disorder (ASD). In a prior study and the current one, we find that mild MIR results in chronic systemic and neuro-inflammation, mTOR pathway activation, mild brain overgrowth followed by regionally specific volumetric changes, sensory processing dysregulation, and social and repetitive behavior abnormalities. Prior studies of rapamycin treatment in autism models have focused on chronic treatments that might be expected to alter or prevent physical brain changes. Here, we have focused on the acute effects of rapamycin to uncover novel mechanisms of dysfunction and related to mTOR pathway signaling. We find that within 2 hours, rapamycin treatment could rapidly rescue neuronal hyper-excitability, seizure susceptibility, functional network connectivity and brain community structure, and repetitive behaviors and sensory over-responsivity in adult offspring with persistent brain overgrowth. These CNS-mediated effects are also associated with alteration of the expression of several ASD-,ion channel-, and epilepsy-associated genes, in the same time frame. Our findings suggest that mTOR dysregulation in MIR offspring is a key contributor to various levels of brain dysfunction, including neuronal excitability, altered gene expression in multiple cell types, sensory functional network connectivity, and modulation of information flow. However, we demonstrate that the adult MIR brain is also amenable to rapid normalization of these functional changes which results in the rescue of both core and comorbid ASD behaviors in adult animals without requiring long-term physical alterations to the brain. Thus, restoring excitatory/inhibitory imbalance and sensory functional network modularity may be important targets for therapeutically addressing both primary sensory and social behavior phenotypes, and compensatory repetitive behavior phenotypes.

Maternal exposure to inflammation is one of the causes of autism spectrum disorder (ASD). Electrical stimulation of the vagus nerve exerts a neuroprotective effect via its anti-inflammatory action. We thus investigated whether transcutaneous auricular vagus nerve stimulation (taVNS) can enhance social abilities in a mouse model of ASD induced by maternal immune activation (MIA).

ASD mouse model were constructed by intraperitoneal injection of polyinosinic:polycytidylic acid (poly (I:C)). TaVNS with different parameters were tested in ASD mouse model and in C57BL/6 mice, then various behavioral tests and biochemical analyses related to autism were conducted. ASD model mice were injected with an interleukin (IL)-17a antibody into the brain, followed by behavioral testing and biochemical analyses.

TaVNS reduced anxiety, improved social function, decreased the number of microglia, and inhibited M1 polarization of microglia. Additionally, taVNS attenuated the expression of the IL-17a protein in the prefrontal cortex and blood of ASD model mice. To examine the possible involvement of IL-17a in taVNS-induced neuroprotection, we injected an IL-17a antibody into the prefrontal cortex of ASD model mice and found that neutralizing IL-17a decreased the number of microglia and inhibited M1 polarization. Furthermore, neutralizing IL-17a improved social function in autism model mice.

Our study revealed that reduced neuroinflammation is an important mechanism of taVNS-mediated social improvement and neuroprotection against autism. This effect of taVNS could be attributed to the inhibition of the IL-17a pathway.

Histamine performs dual roles as an immune regulator and a neurotransmitter in the mammalian brain. The histaminergic system plays a vital role in the regulation of wakefulness, cognition, neuroinflammation, and neurogenesis that are substantially disrupted in various neurodegenerative and neurodevelopmental disorders. Histamine H3 receptor (H3R) antagonists and inverse agonists potentiate the endogenous release of brain histamine and have been shown to enhance cognitive abilities in animal models of several brain disorders. Microglial activation and subsequent neuroinflammation are implicated in impacting embryonic and adult neurogenesis, contributing to the development of Alzheimer's disease (AD), Parkinson's disease (PD), and autism spectrum disorder (ASD). Acknowledging the importance of microglia in both neuroinflammation and neurodevelopment, as well as their regulation by histamine, offers an intriguing therapeutic target for these disorders. The inhibition of brain H3Rs has been found to facilitate a shift from a proinflammatory M1 state to an anti-inflammatory M2 state, leading to a reduction in the activity of microglial cells. Also, pharmacological studies have demonstrated that H3R antagonists showed positive effects by reducing the proinflammatory biomarkers, suggesting their potential role in simultaneously modulating crucial brain neurotransmissions and signaling cascades such as the PI3K/AKT/GSK-3β pathway. In this review, we highlight the potential therapeutic role of the H3R antagonists in addressing the pathology and cognitive decline in brain disorders, e.g., AD, PD, and ASD, with an inflammatory component.

Autism spectrum disorder (ASD) is a heterogenous neurodevelopmental disorder marked by functional abnormalities in brain that causes social and linguistic difficulties. The incidence of ASD is more prevalent in males compared to females, but the underlying mechanism, as well as molecular indications for identifying sex-specific differences in ASD symptoms remain unknown. Thus, impacting the development of personalized strategy towards pharmacotherapy of ASD. The current study employs an integrated bioinformatic approach to investigate the genes and pathways uniquely associated with sex specific differences in autistic individuals. Based on microarray dataset (GSE6575) extracted from the gene expression omnibus, the dysregulated genes between the autistic and the neurotypical individuals for both sexes were identified. Gene set enrichment analysis was performed to ascertain biological activities linked to the dysregulated genes. Protein-protein interaction network analysis was carried out to identify hub genes. The identified hub genes were examined to determine their functions and involvement in the associated pathways using Enrichr. Additionally, hub genes were validated from autism-associated databases and the potential small molecules targeting the hub genes were identified. The present study utilized whole blood transcriptomic gene expression analysis data and identified 2211 and 958 differentially expressed unique genes in males and females respectively. The functional enrichment analysis revealed that male hub genes were functionally associated with RNA polymerase II mediated transcriptional regulation whereas female hub genes were involved in intracellular signal transduction and cell migration. The top male hub genes exhibited functional enrichment in tyrosine kinase signalling pathway. The pathway enrichment analysis of male hub genes indicates the enrichment of papillomavirus infection. Female hub genes were enriched in androgen receptor signalling pathway and functionally enriched in focal adhesion specific excision repair. Identified drug like candidates targeting these genes may serve as a potential sex specific therapeutics. Wortmannin for males, 5-Fluorouracil for females had the highest scores. Targeted and sex-specific pharmacotherapies may be created for the management of ASD. The current investigation identifies sex-specific molecular signatures derived from whole blood which may serve as a potential peripheral sex-specific biomarkers for ASD. The study also uncovers the possible pharmacological interventions against the selected genes/pathway, providing support in development of therapeutic strategies to mitigate ASD. However, experimental proofs on biological systems are warranted.

Prenatal infections and activation of the maternal immune system have been proposed to contribute to causing neurodevelopmental disorders (NDDs), chronic conditions often linked to brain abnormalities. Microglia are the resident immune cells of the brain and play a key role in neurodevelopment. Disruption of microglial functions can lead to brain abnormalities and increase the risk of developing NDDs. How the maternal as well as the fetal immune system affect human neurodevelopment and contribute to NDDs remains unclear. An important reason for this knowledge gap is the fact that the impact of exposure to prenatal risk factors has been challenging to study in the human context. Here, we characterized a model of cerebral organoids (CO) with integrated microglia (COiMg). These organoids express typical microglial markers and respond to inflammatory stimuli. The presence of microglia influences cerebral organoid development, including cell density and neural differentiation, and regulates the expression of several ciliated mesenchymal cell markers. Moreover, COiMg and organoids without microglia show similar but also distinct responses to inflammatory stimuli. Additionally, IFN-γ induced significant transcriptional and structural changes in the cerebral organoids, that appear to be regulated by the presence of microglia. Specifically, interferon-gamma (IFN-γ) was found to alter the expression of genes linked to autism. This model provides a valuable tool to study how inflammatory perturbations and microglial presence affect neurodevelopmental processes.

Exosomes are 30-150 nm small extracellular vesicles (sEVs) which are highly stable and encapsulated by a phospholipid bilayer. Exosomes contain proteins, lipids, RNAs (mRNAs, microRNAs/miRNAs, long non-coding RNAs/lncRNAs), and DNA of their parent cell. In pathological conditions, the composition of exosomes is altered, making exosomes a potential source of biomarkers for disease diagnosis. Exosomes can cross the blood-brain barrier (BBB), which is an advantage for using exosomes in the diagnosis of central nervous system (CNS) diseases. Neuropsychiatric diseases belong to the CNS diseases, and many potential diagnostic markers have been identified for neuropsychiatric diseases. Here, we review the potential diagnostic markers of exosomes in neuropsychiatric diseases and discuss the potential application of exosomal biomarkers in the early and accurate diagnosis of these diseases. Additionally, we outline the limitations and future directions of exosomes in the diagnosis of neuropsychiatric diseases.