Autistic-like Behaviors Research Articles

Transient CSF1R inhibition ameliorates behavioral deficits in Cntnap2 knockout and valproic acid-exposed mouse models of autism

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.

Abnormal increased mTOR signaling regulates seizure threshold in Dravet syndrome

Excessive activation of mTOR has been observed in the brains of mouse models for Dravet syndrome. We aim to confirm whether that the overactivation of mTOR contributes to the neuropathological changes leading to epileptogenesis and neurobehavior deficits to support a novel pharmacological therapeutic approach for Dravet syndrome. The mTOR inhibitor everolimus, as a clinical antiseizure medication, was utilized to investigate whether mTOR is involved in hyperthermia-induced seizures, anxiety-like, and autism-like behaviors, as well as to explore potential pathogenic mechanisms in Scn1aE1099X/+ mice, a model of Dravet syndrome. First, we found that mTOR signaling was upregulated in hippocampus tissues and neural cultures derived from Scn1aE1099X/+ mice prior to seizure onset. Behaviorally, everolimus increased the seizure threshold and improved anxiety-like and autism-like behaviors in Scn1aE1099X/+ mice. Electrophysiologically, everolimus reduced the frequency of spontaneous excitatory postsynaptic currents in dentate granule neurons from Scn1aE1099X/+ mice. Biochemically, everolimus prevented hyperthermia-induced phosphorylation of hippocampal S6 ribosome in hippocampus, and it delayed hyperthermia-induced increase of cytosolic Ca2+ level in primary neuronal cultures derived from Scn1aE1099X/+ mice. Our results provide the evidence that overactivated mTOR as an important neuropathological change which regulates seizure threshold, impairments of neurobehavior, neuronal glutamatergic transmission and intracellular Ca2+ levels in Scn1aE1099X/+ mice. Inhibition of mTOR is a potential pharmacological therapeutic approach.

Advanced paternal age exacerbates neuroinflammation in offspring via m6A modification-mediated intergenerational inheritance

BackgroundThe trend of postponing childbearing age is prevalent worldwide. Advanced paternal age (APA) is associated with adverse pregnancy outcomes and offspring health. However, the underlying mechanism by which paternal aging affects the risk of offspring neuropsychiatric disorders is unclear. Our study aims to explore the behavioral phenotypes and the pathologic epigenetic alterations of APA offspring inherited from aging sperm.MethodsBehavioral tests, ELISA assay, immunofluorescence and western blotting were performed on offspring mice. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA immunoprecipitation sequencing (RIP-seq) were used to investigate the modified N6-methyladenosine (m6A) profiles of paternal sperm and offspring hippocampus. Intervention of gene expression by lentivirus and adeno-associated virus in both vivo and vitro examined the potential therapeutic targets of intergenerational inherited neuroinflammation.ResultsIn our study, APA offspring exhibit cognitive impairment and autism-like behavior. An increase in neuroinflammation in APA offspring is associated with microglial overactivation, which manifests as abnormal morphology and augmented engulfment. MeRIP-seq of F0 sperm and F1 hippocampus reveal that Nr4a2 is hypermethylated with decreased expression in APA offspring involving in synaptic plasticity and microglial function. In addition, Ythdc1, an m6A reader protein, is markedly elevated in aging sperm and remains elevated in adult hippocampus of APA group. Enhanced Ythdc1 recognizes and suppresses the hypermethylated Nr4a2, thereby contributing to the abnormal phenotype in offspring. The overexpression of Ythdc1 triggers microglial activation in vitro and its suppression in the hippocampus of APA progeny alleviates behavioral aberrations and attenuates neuroinflammation.ConclusionOur study provides additional evidence of the abnormal behavioral phenotypes of APA offspring and reveals potential epigenetic inheritance signatures and targeted genes for future research.

Deciphering autism heterogeneity: a molecular stratification approach in four mouse models

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by impairments in social interaction and communication, as well as restrained or stereotyped behaviors. The inherent heterogeneity within the autism spectrum poses challenges for developing effective pharmacological treatments targeting core features. Successful clinical trials require the identification of robust markers to enable patient stratification. In this study, we identified molecular markers within the oxytocin and immediate early gene families across five interconnected brain structures of the social circuit. We used wild-type and four heterogeneous mouse models, each exhibiting unique autism-like behaviors modeling the autism spectrum. While dysregulations in the oxytocin family were model-specific, immediate early genes displayed widespread alterations, reflecting global changes across the four models. Through integrative analysis, we identified Egr1, Foxp1, Homer1a, Oxt, and Oxtr as five robust and discriminant molecular markers that allowed the successful stratification of the four models. Importantly, our stratification demonstrated predictive values when challenged with a fifth mouse model or identifying subgroups of mice potentially responsive to oxytocin treatment. Beyond providing insights into oxytocin and immediate early gene mRNA dynamics, this proof-of-concept study represents a significant step toward the potential stratification of individuals with ASD. This work has implications for the success of clinical trials and the development of personalized medicine in autism.

Combined Exposure to Folate and Lead during Pregnancy and Autistic-Like Behaviors among Canadian Children from the MIREC Pregnancy and Birth Cohort.

Folic acid (FA) supplementation may attenuate the associations between gestational exposure to certain chemicals and autism or autistic-like behaviors, but to our knowledge, this has not been assessed for lead. We examined whether the relationship between gestational blood-lead levels (BLLs) and autistic-like behaviors was modified by gestational plasma total folate concentrations, FA supplementation, and maternal methylenetetrahydrofolate reductase (MTHFR) 677C>T genotype. We used data from the Maternal-Infant Research on Environmental Chemicals study (2008-2011), a Canadian pregnancy and birth cohort study. Childhood autistic-like behaviors were documented in 601 children 3-4 y of age with the Social Responsiveness Scale-2 (SRS-2), where higher scores denote more autistic-like behaviors. We measured BLLs and plasma total folate concentrations during the first and third trimesters of pregnancy. We also estimated gestational FA supplementation via surveys and genotyped the maternal MTHFR 677C>T single nucleotide polymorphism (SNP). We estimated the confounder-adjusted associations between -transformed BLLs and SRS-2 scores by two indicators of folate exposure and maternal MTHFR 677C>T genotype using linear regression. Third-trimester BLLs were associated with increased SRS-2 scores [; 95% confidence interval (CI): 1.1, 5.5] among participants with low ( percentile), third-trimester, plasma total folate concentrations, but BLL-SRS-2 associations were null (; 95% CI: , 0.5) among those in the middle category ( and percentiles) (p-interaction ). FA supplementation also attenuated these associations. Both folate indicators modified first-trimester BLL-SRS-2 associations, but to a lesser extent. Third-trimester BLL-SRS-2 associations were slightly stronger among participants who were homozygous for the T (minor) allele of the MTHFR 677C>T SNP (; 95% CI: , 3.1) than those without the T allele (; 95% CI: , 0.7), but the difference was not statistically significant (). Folate may modify the associations between gestational lead exposure and childhood autistic-like behaviors, suggesting that it mitigates the neurotoxic effects of prenatal lead exposure. https://doi.org/10.1289/EHP14479.

Comparative effect of atorvastatin and risperidone on modulation of TLR4/NF-κB/NOX-2 in a rat model of valproic acid-induced autism

BackgroundAutism spectrum disorder (ASD) is a complex neurodevelopmental condition that is significantly increasing, resulting in severe distress. The approved treatment for ASD only partially improves the sympoms, but it does not entirely reverse the symptoms. Developing novel disease-modifying drugs is essential for the continuous improvement of ASD. Because of its pleiotropic effect, atorvastatin has been garnered attention for treating neuronal degeneration. The present study aimed to investigate the therapeutic effects of atorvastatin in autism and compare it with an approved autism drug (risperidone) through the impact of these drugs on TLR4/NF-κB/NOX-2 and the apoptotic pathway in a valproic acid (VPA) induced rat model of autism.MethodsOn gestational day 12.5, pregnant rats received a single IP injection of VPA (500 mg/kg), for VPA induced autism, risperidone and atorvastatin groups, or saline for control normal group. At postnatal day 21, male offsprings were randomly divided into four groups (n = 6): control, VPA induced autism, risperidone, and atorvastatin. Risperidone and atorvastatin were administered from postnatal day 21 to day 51. The study evaluated autism-like behaviors using the three-chamber test, the dark light test, and the open field test at the end of the study. Biochemical analysis of TLR4, NF-κB, NOX-2, and ROS using ELISA, RT-PCR, WB, histological examination with hematoxylin and eosin and immunohistochemical study of CAS-3 were performed.ResultsMale offspring of prenatal VPA-exposed female rats exhibited significant autism-like behaviors and elevated TLR4, NF-κB, NOX-2, ROS, and caspase-3 expression. Histological analysis revealed structural alterations. Both risperidone and atorvastatin effectively mitigated the behavioral, biochemical, and structural changes associated with VPA-induced rat model of autism. Notably, atorvastatin group showed a more significant improvement than risperidone group.ConclusionsThe research results unequivocally demonstrated that atorvastatin can modulate VPA-induced autism by suppressing inflammation, oxidative stress, and apoptosis through TLR4/NF-κB/NOX-2 signaling pathway. Atorvastatin could be a potential treatment for ASD.Graphical

Animal Models of Autistic-like Behavior in Rodents: A Scoping Review and Call for a Comprehensive Scoring System

Appropriate animal models of human diseases are a cornerstone in the advancement of science and medicine. To create animal models of neuropsychiatric and neurobehavioral diseases such as autism spectrum disorder (ASD) necessitates the development of sufficient neurobehavioral measuring tools to translate human behavior to expected measurable behavioral features in animals. If possible, the severity of the symptoms should also be assessed. Indeed, at least in rodents, adequate neurobehavioral and neurological tests have been developed. Since ASD is characterized by a number of specific behavioral trends with significant severity, animal models of autistic-like behavior have to demonstrate the specific characteristic features, namely impaired social interactions, communication deficits, and restricted, repetitive behavioral patterns, with association to several additional impairments such as somatosensory, motor, and memory impairments. Thus, an appropriate model must show behavioral impairment of a minimal number of neurobehavioral characteristics using an adequate number of behavioral tests. The proper animal models enable the study of ASD-like-behavior from the etiologic, pathogenetic, and therapeutic aspects. From the etiologic aspects, models have been developed by the use of immunogenic substances like polyinosinic-polycytidylic acid (PolyIC), lipopolysaccharide (LPS), and propionic acid, or other well-documented immunogens or pathogens, like Mycobacterium tuberculosis. Another approach is the use of chemicals like valproic acid, polychlorinated biphenyls (PCBs), organophosphate pesticides like chlorpyrifos (CPF), and others. These substances were administered either prenatally, generally after the period of major organogenesis, or, especially in rodents, during early postnatal life. In addition, using modern genetic manipulation methods, genetic models have been created of almost all human genetic diseases that are manifested by autistic-like behavior (i.e., fragile X, Rett syndrome, SHANK gene mutation, neuroligin genes, and others). Ideally, we should not only evaluate the different behavioral modes affected by the ASD-like behavior, but also assess the severity of the behavioral deviations by an appropriate scoring system, as applied to humans. We therefore propose a scoring system for improved assessment of ASD-like behavior in animal models.

Childhood anaesthesia and autism risk: population and murine study.

Early childhood exposure to general anaesthesia has been linked to potential changes in infant brain morphology and behaviour in preclinical studies, contributing to long-term behaviours associated with autism spectrum disorder. This study investigates the association between early childhood exposure to general anaesthesia and the risk of autism, using a population-based cohort study with matching for baseline characteristics and evaluates the effect of sevoflurane exposure on autism-like behaviour in mice, using the Taiwan Maternal and Child Health Database. Children aged 0-3 who received at least one exposure to general anaesthesia between 2004 and 2014 were matched 1:1 with children who were not exposed. Risk ratios and confidence intervals were used to assess the relationship between general anaesthesia and the occurrence of autism. Additionally, mice were exposed to sevoflurane for 2 h on postnatal days 5-7, and changes in behaviour related to autism were evaluated. Propensity score matching resulted in 7530 children in each group. The incidence rates (IRs) of autism were 11.26 and 6.05 per 100 000 person-years in the exposed and unexposed groups, respectively. The incidence ratio for autism following exposure to general anaesthesia was 1.86 (95% confidence interval, 1.34-2.59). In mice, sevoflurane exposure induced autism-like behaviours and led to the downregulation of high-risk autism genes, including ARID1B, GABRA5, GABRB3, GRIN2B, SHANK3 and SUV420H1. Early childhood exposure to general anaesthesia is associated with an increased risk of autism. Repeated exposure to sevoflurane in mice induces autism-like behaviours, suggesting a potential link between anaesthesia and the development of autism.

Intranasal Insulin Eases Autism in Rats via GDF-15 and Anti-Inflammatory Pathways.

In rat models, it is well-documented that chronic administration of propionic acid (PPA) leads to autism-like behaviors. Although the intranasal (IN) insulin approach is predominantly recognized for its effects on food restriction, it has also been shown to enhance cognitive memory by influencing various proteins, modulating anti-inflammatory pathways in the brain, and reducing signaling molecules such as interleukins. This study seeks to explore the potential therapeutic benefits of IN insulin in a rat model of autism induced by PPA. Thirty male Wistar albino rats were categorized into three cohorts: the control group, the PPA-induced autism (250 mg/kg/day intraperitoneal PPA dosage for five days) group, treated with saline via IN, and the PPA-induced autism group, treated with 25 U/kg/day (250 µL/kg/day) insulin via IN. All treatments were administered for 15 days. After behavioral testing, all animals were euthanized, and brain tissue and blood samples were collected for histopathological and biochemical assessments. Following insulin administration, a substantial reduction in autism symptoms was observed in all three social behavior tests conducted on the rats. Moreover, insulin exhibited noteworthy capabilities in decreasing brain MDA, IL-2, IL-17, and TNF-α levels within autism models. Additionally, there is a notable elevation in the brain nerve growth factor level (p < 0.05) and GDF-15 (p < 0.05). The assessment of cell counts within the hippocampal region and cerebellum revealed that insulin displayed effects in decreasing glial cells and inducing a significant augmentation in cell types such as the Purkinje and Pyramidal cells. The administration of insulin via IN exhibits alleviating effects on autism-like behavioral, biochemical, and histopathological alterations induced by PPA in rats. Insulin-dependent protective effects show anti-inflammatory, anti-oxidative, and neuroprotective roles of insulin admitted nasally.

Cognitive behavioral phenotyping of DSCAM heterozygosity as a model for autism spectrum disorder.

It is estimated that 1 in 36 children are affected by autism spectrum disorder (ASD) in the United States, which is nearly a twofold increase from a decade ago. Recent genetic studies have identified de novo loss-of-function (dnLoF) mutations in the Down Syndrome Cell Adhesion Molecule (DSCAM) as a strong risk factor for ASD. Previous research has shown that DSCAM ablation confers social interaction deficits and perseverative behaviors in mouse models. However, it remains unknown to what extent DSCAM underexpression captures the full range of behaviors, specifically cognitive phenotypes, presented in ASD. Here, we conducted a comprehensive cognitive behavioral phenotyping which revealed that loss of one copy of DSCAM, as in the DSCAM2J+/-, that is, DSCAM heterozygous mice, displayed hyperactivity, increased anxiety-like behavior, and motor coordination deficits. Additionally, hippocampal-dependent learning and memory was affected, including impairments in working memory, long-term memory, and contextual fear learning. Interestingly, implicit learning processes remained intact. Therefore, DSCAM LoF produces autistic-like behaviors that are similar to those observed in human cases of ASD. These findings further support a role for DSCAM dnLoF mutations in ASD and suggest DSCAM2J+/- as a suitable model for ASD research.

Sortilin is associated with progranulin deficiency and autism-like behaviors in valproic acid-induced autism rats.

Neuroinflammation and microglial activation-related dendritic injury contribute to the pathogenesis of Autism Spectrum Disorder (ASD). Previous studies show that Progranulin (PGRN) is a growth factor associated with inflammation and synaptic development, but the role of PGRN in autism and the mechanisms underlying changes in PGRN expression remain unclear. To investigate the impact of PGRN in autism, we stereotactically injected recombinant PGRN into the hippocampus of ASD model rats. Additionally, we explored the possibility that sortilin may be the factor behind the alterations in PGRN by utilizing SORT1 knockdown. Ultimately, we aimed to identify potential targets for the treatment of autism. PGRN could alleviate inflammatory responses, protect neuronal dendritic spines, and ameliorate autism-like behaviors. Meanwhile, elevated expression of sortilin and decreased levels of PGRN were observed in both ASD patients and rats. Enhanced sortilin levels facilitated PGRN internalization into lysosomes. Notably, suppressing SORT1 expression amplified PGRN levels, lessened microglial activation, and mitigated inflammation, thereby alleviating autism-like behaviors. Collectively, our findings highlight elevated sortilin levels in ASD rat brains, exacerbating dendrite impairment by affecting PGRN expression. PGRN supplementation and SORT1 knockdown hold potential as therapeutic strategies for ASD.

Gasdermin D Mediated Mitochondrial Metabolism Orchestrate Neurogenesis Through LDHA During Embryonic Development.

Regulatory cell death is an important way to eliminate the DNA damage that accompanies the rapid proliferation of neural stem cells during cortical development, including pyroptosis, apoptosis, and so on. Here, the study reports that the absence of GSDMD-mediated pyroptosis results in defective DNA damage sensor pathways accompanied by aberrant neurogenesis and autism-like behaviors in adult mice. Furthermore, GSDMD is involved in organizing the mitochondrial electron transport chain by regulating the AMPK/PGC-1α pathway to target Aifm3. This process promotes a switch from oxidative phosphorylation to glycolysis. The perturbation of metabolic homeostasis in neural progenitor cells increases lactate production which acts as a signaling molecule to regulate the p38MAPK pathway. And activates NF-𝜿B transcription to disrupt cortex development. This abnormal proliferation of neural progenitor cells can be rescued by inhibiting glycolysis and lactate production. Taken together, the study proposes a metabolic axis regulated by GSDMD that links pyroptosis with metabolic reprogramming. It provides a flexible perspective for the treatment of neurological disorders caused by genotoxic stress and neurodevelopmental disorders such as autism.

Dietary L-proline supplementation ameliorates autism-like behaviors and modulates gut microbiota in the valproic acid-induced mouse model of autism spectrum disorder

Dietary L-proline supplementation ameliorates autism-like behaviors and modulates gut microbiota in the valproic acid-induced mouse model of autism spectrum disorder

Embryonic exposure to environmental factors drives transmitter switching in the neonatal mouse cortex causing autistic-like adult behavior

Autism spectrum disorders (ASD) can be caused by environmental factors. These factors act early in the development of the nervous system and induce stereotyped repetitive behaviors and diminished social interactions, among other outcomes. Little is known about how these behaviors are produced. In pregnant women, delivery of valproic acid (VPA) (to control seizure activity or stabilize mood) or immune activation by a virus increases the incidence of ASD in offspring. We found that either VPA or Poly Inosine:Cytosine (which mimics a viral infection), administered at mouse embryonic day 12.5, induced a neurotransmitter switch from GABA to glutamate in PV- and CCK-expressing interneurons in the medial prefrontal cortex by postnatal day 10. The switch was present for only a brief period during early postnatal development, observed in male and female mice at postnatal day 21 and reversed in both males and females by postnatal day 30. At postnatal day 90, male mice exhibited stereotyped repetitive behaviors and diminished social interaction while female mice exhibited only stereotyped repetitive behavior. Transfecting GAD1 in PV- and CCK-expressing interneurons at postnatal day 10, to reintroduce GABA expression, overrode the switch and prevented expression of autistic-like behavior. These findings point to an important role of neurotransmitter switching in mediating the environmental causes of autism.

Exogenous PD-L1 binds to PD-1 to alleviate and prevent autism-like behaviors in maternal immune activation-induced male offspring mice

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder caused by the interaction of multiple pathogenic factors. Epidemiological studies and animal experiments indicate that maternal immune activation (MIA) is closely related to the development of ASD in offspring. A large number of pro-inflammatory cytokines are transferred from the placenta to the fetal brain during MIA, which impedes fetal neurodevelopment and is accompanied by activation of immune cells and microglia. Programmed cell death protein 1 (PD-1) can be highly expressed on the surface of various activated immune cells, when combined with programmed cell death-ligand 1 (PD-L1), it can activate the PD-1/PD-L1 pathway and exert powerful immunosuppressive effects, suggesting that this immune checkpoint may have the potential to treat MIA-induced ASD. This study combined bioinformatics analysis and experimental validation to explore the efficacy of Fc-fused PD-L1 (PD-L1-Fc) in treating MIA-induced ASD. Bioinformatics analysis results showed that in human placental inflammation, IL-6 was upregulated, T cells proliferated significantly, and the PD-1/PD-L1 pathway was significantly enriched. The experimental results showed that intraperitoneal injection of poly(I:C) induced MIA in pregnant mice resulted in significant expression of IL-6 in their serum, placenta, and fetal brain. At the same time, the expression of PD-1 and PD-L1 in the placenta and fetal brain increased, CD4+ T cells in the spleen were significantly activated, and PD-1 expression increased. Their offspring mice exhibited typical ASD-like behaviors. In vitro experiments on primary microglia of offspring mice have confirmed that the expression of IL-6, PD-1, and PD-L1 is significantly increased, and PD-L1-Fc effectively reduced their expression levels. In the prefrontal cortex of MIA offspring mice, there was an increase in the expression of IL-6, PD-1, and PD-L1; activation of microglial cells, and colocalization with PD-1. Then we administered brain stereotaxic injections of PD-L1-Fc to MIA offspring mice and intraperitoneal injections to MIA pregnant mice. The results indicated that PD-L1-Fc effectively suppressed neuroinflammation in the frontal cortex of offspring mice and partially ameliorated ASD-like behaviors; MIA in pregnant mice was significantly alleviated, and the offspring mice they produced did not exhibit neuroinflammation or ASD-like behaviors. In summary, we have demonstrated the therapeutic ability of PD-L1-Fc for MIA-induced ASD, aiming to provide new strategies and insights for the treatment of ASD.

Acetyl-l-carnitine alleviates valproate-induced autism-like behaviors through attenuation of hippocampal mitochondrial dysregulation

This study aimed to evaluate the potential benefits of acetyl-L-carnitine (ALCAR) in the context of valproate-induced autism. After prenatal exposure to valproate (VPA; 600 mg/kg, i.p.) on embryonic day 12.5, followed by ALCAR treatment (300 mg/kg on postnatal days 21–49, p.o.), assessment of oxidative stress, mitochondrial membrane potential (MMP), mitochondrial biogenesis, parvalbumin interneurons, and hippocampal volume was conducted. These assessments were carried out subsequent to the evaluation of autism-like behaviors. Hippocampal analysis of oxidative factors (reactive oxygen species and malondialdehyde) and antioxidants (superoxide dismutase, catalase, and glutathione) revealed a burden of oxidative stress in VPA rats. Additionally, mitochondrial biogenesis and MMP were elevated, while the number of parvalbumin interneurons decreased. These changes were accompanied by autism-like behaviors observed in the three-chamber maze, marble burring test, and Y-maze, as well as a learning deficit in the Barnes maze. In contrast, administrating ALCAR attenuated behavioral deficits, reduced oxidative stress, improved parvalbumin-positive neuronal population, and properly modified MMP and mitochondrial biogenesis. Collectively, our results indicate that oral administration of ALCAR ameliorates autism-like behaviors, partly through its targeting oxidative stress and mitochondrial biogenesis. This suggests that ALCAR may have potential benefits ASD managing.

Loss of Zmiz1 in mice leads to impaired cortical development and autistic-like behaviors.

De novo mutations in transcriptional regulators are emerging as key risk factors contributing to the etiology of neurodevelopmental disorders. Human genetic studies have recently identified ZMIZ1 and its de novo mutations as causal of a neurodevelopmental syndrome strongly associated with intellectual disability, autism, ADHD, microcephaly, and other developmental anomalies. However, the role of ZMIZ in brain development or how ZMIZ1 mutations cause neurological phenotypes is unknown. Here, we generated a forebrain-specific Zmiz1 mutant mouse model that develops brain abnormalities, including cortical microcephaly, corpus callosum dysgenesis, and abnormal differentiation of upper-layer cortical neurons. Behaviorally, Zmiz1 mutant mice show alterations in motor activity, anxiety, communication, and social interactions with strong sex differences, resembling phenotypes associated with autism. Molecularly, Zmiz1 deficiency leads to transcriptomic changes disrupting neurogenesis, neuron differentiation programs, and synaptic signaling. We identified Zmiz1-mediated downstream regulation of key neurodevelopmental factors, including Lhx2, Auts2, and EfnB2. Importantly, reactivation of the EfnB2 pathway by exogenous EFNB2 recombinant protein rescues the dendritic outgrowth deficits in Zmiz1 mutant cortical neurons. Overall, our in vivo findings provide insight into Zmiz1 function in cortical development and reveal mechanistic underpinnings of ZMIZ1 syndrome, thereby providing valuable information relevant to future studies on this neurodevelopmental disorder.

Assessment of Probiotics' Impact on Neurodevelopmental and Behavioral Responses in Zebrafish Models: Implications for Autism Spectrum Disorder Therapy.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder; the prevalence of which has been on the rise with unknown causes. Alterations in the gut-brain axis have been widely recognized in ASD patients, and probiotics are considered to potentially benefit the rescuing of autism-like behaviors. However, the effectiveness and mechanisms of multiple probiotics on zebrafish models are still not clearly revealed. This study aims to use the germ-free (GF) and conventionally raised (CR) AB wild-type zebrafish and the mutant Tbr1b-/- and Katnal2-/- lines as human-linked ASD animal models to evaluate the effects of multiple probiotics on mitigating developmental and behavioral defects. Results showed that the addition of probiotics increased the basic important developmental indexes, such as body length, weight, and survival rate of treated zebrafish. Moreover, the Lactobacillus plantarum and Lactobacillus rhamnosus affected the behavior of CR zebrafish by increasing their mobility, lowering the GF zebrafish manic, and mitigating transgenic zebrafish abnormal behavior. Moreover, the expression levels of key genes related to gamma-aminobutyric acid (GABA), dopamine (DA), and serotonin (5-HT) as important neuropathways to influence the appearance and development of autism-related disorders, including gad1b, tph1a, htr3a, th, and slc6a3, were significantly activated by some of the probiotics' treatment at some extent. Taken together, this study indicates the beneficial effects of different probiotics, which may provide a novel understanding of probiotic function in related diseases' therapy.

Vagus nerve stimulation for the therapy of Dravet syndrome: a systematic review and meta-analysis.

Dravet syndrome (DS) is a refractory developmental and epileptic encephalopathy characterized by seizures, developmental delay and cognitive impairment with a variety of comorbidities, including autism-like behavior, speech dysfunction, and ataxia. Vagus nerve stimulation (VNS) is one of the common therapies for DS. Here, we aim to perform a meta-analysis and systematic review of the efficacy of VNS in DS patients. We systematically searched four databases (PubMed, Embase, Cochrane and CNKI) to identify potentially eligible studies from their inception to January 2024. These studies provided the effective rate of VNS in treating patients with DS. The proportions of DS patients achieving ≥50% reduction of seizure frequency were extracted from these studies. Meta-analyses were performed to respectively evaluate the efficacy of VNS for DS after 3, 6, 12, 18, 24 and 36 months. Sixteen trials with a total of 173 patients were included. Meta-analyses showed that the pooled efficiency was 0.54 (95% CI 0.43-0.65) in the DS patients treated with VNS (p < 0.05). Meanwhile, the pooled efficiency respectively was 0.42 (95% CI 0.25-0.61), 0.54 (95% CI 0.39-0.69), 0.51 (95% CI 0.39-0.66), and 0.49 (95% CI 0.36-0.63) in the DS patients treated with VNS after 3, 6, 12 and 24 months (p < 0.05). This study suggests that VNS is effective in the treatment of DS. However, few studies have focused on VNS for DS, and there is a lack of high-quality evidence. Thus, high-quality randomized controlled trials are needed to confirm the efficacy of VNS in DS.

Effects of Memantine on Cognitive Flexibility in a Valproic Acid Rat Model of Autism

Abstract Autistic children frequently struggle with cognitive flexibility. The potential molecular mechanism underlying cognitive inflexibility remains unclear. Decreased level of brain-derived neurotrophic factor (BDNF), which plays a vital role in neural development and synaptic plasticity may have a role. This study aimed to investigate the effects of memantine on (BDNF) expression in hippocampus of prenatal VPA exposed rats, and its consequent effects on cognitive flexibility. Pregnant female rats received a single intraperitoneal injection of VPA (600 mg/kg) on gestational day 12.5 to induce autistic-like behaviors in their offspring. Afterwards, the 23-day-old male Wistar rat pups received daily intraperitoneal injections of memantine (20 mg/kg) for 4 weeks. The prenatal VPA-exposed rats exhibited reduced cognitive flexibility in the attentional set- shifting task (ASST) reflecting ASD-associated cognitive flexibility deficits, a common ASD- associated problem with accompanied reduction in hippocampal BDNF. The defective performance in ASST was more prominent in the reversal stages. Memantine associated increased hippocampal BDNF could alleviate cognitive inflexibility in ASD. This study draws attention to the potential favorable effect of memantine on cognitive performance in autistic subjects.