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Autism spectrum disorder (ASD) is a multifactorial disorder with characteristic synaptic and gene expression changes. Early intervention during childhood is thought to benefit prognosis. Here, we examined the changes in cortical synaptogenesis, synaptic function, and gene expression from birth to the juvenile stage in a marmoset model of ASD induced by valproic acid (VPA) treatment. Early postnatally, synaptogenesis was reduced in this model, while juvenile-age VPA-treated marmosets showed increased synaptogenesis, similar to observations in human tissue. During infancy, synaptic plasticity transiently increased and was associated with altered vocalization. Synaptogenesis-related genes were downregulated early postnatally. At three months of age, the differentially expressed genes were associated with circuit remodeling, similar to the expression changes observed in humans. In summary, we provide a functional and molecular characterization of a non-human primate model of ASD, highlighting its similarity to features observed in human ASD. Non-human primate models of autism spectrum disorder (ASD) are few and not well characterised. Here, the authors describe synaptic function and gene expression changes in a marmoset model of ASD from birth to juvenile, highlighting its similarity to features observed in human ASD.

Individuals with autism spectrum disorder (ASD) are exposed to a variety of stressors owing to their behavioral traits. Cortisol is a hormone typically associated with stress, and its concentration and response to stress are higher in individuals with ASD than in controls. The mechanisms underlying cortisol dysregulation in ASD have been explored in rodents. Although rodent models have successfully replicated the major symptoms of autism (i.e., impaired vocal communication, social interaction deficits, and restricted/repetitive patterns of behavior), evidence suggests that the hypothalamic-pituitary-adrenal (HPA) axis system differs between rodents and primates. We developed an ASD model in the common marmoset (Callithrix jacchus), a New World monkey, utilizing prenatal exposure to valproic acid (VPA). In this study, we collected the salivary cortisol levels in VPA-exposed and unexposed marmosets in the morning and afternoon. Our results revealed that both VPA-exposed and unexposed marmosets showed similar diurnal changes in cortisol levels, which were lower in the afternoon than in the morning. However, heightened cortisol levels were observed in VPA-exposed marmosets in the morning, but not in the afternoon. These results are consistent with those of ASD in humans. Our results suggest that VPA-exposed marmosets show similarities not only in their behavioral patterns and brain pathologies, which we have reported previously but also in hormonal regulation, validating the usefulness of VPA-exposed marmosets also as a tool for ASD stress research.

Hyperactivity is frequently observed in individuals with autism spectrum disorder (ASD) and significantly affects various aspects of life. This underscores the critical need for effective intervention methods tailored to the needs of individuals with ASD. Non-human primate models offer a promising avenue for elucidating the intricate interplay between ASD characteristics and developing individualized therapeutic strategies. This study examined the activity levels and behavioral dynamics in a prenatal valproic acid-induced (VPA) common marmoset model of ASD using ultraminiature data loggers, employing a more detailed approach to behavioral pattern analysis than is traditionally utilized. Although the overall activity levels showed no significant differences, the VPA group exhibited increased activity during specific hours, which is consistent with human ASD studies. Sample Entropy, a statistical measure used to quantify the regularity and unpredictability of time-series data, was higher during daytime in the VPA group, indicating reduced regularity in activity patterns akin to impulsive behavior in ASD. Subtle patterns that were not discernible through simple group comparisons were identified, highlighting the potential of this method as a valuable tool for the behavioral analysis of human ASD. Associations between erratic activity patterns, brief resting intervals, and elevated cortisol levels were observed, all of which correspond to stress phenotypes in individuals with ASD. The findings revealed variations in activity among the adult VPA groups, potentially linked to stress responses. Additionally, VPA juvenile marmosets showed increased locomotor activity in the social interaction test, complementing the adult behavioral findings and suggesting age-dependent manifestations of hyperactivity in this model. This non-human primate model effectively replicates real-world scenarios encountered by individuals with ASD exhibiting hyperactivity, thus holding significant implications for the advancement of personalized therapeutic strategies.

Autism spectrum disorder (ASD) is a synapse-related disorder that is diagnosed at around 3 years of age. Earlier intervention is desirable for better ASD prognosis; however, there is limited biological literature regarding early-age ASD. This study aimed to assess altered cortical synapses and gene expression in the ASD model marmoset. There were distinct phenotypes in the model animals across the neonate, childhood, and mature stages in the dorsomedial prefrontal cortex (Brodmann area 8b/9). At the neonate stage, synapses were underdeveloped and modulated genes were enriched with synaptogenesis- and ASD-related genes. At the childhood stage, synaptic features and gene expressions associated with experience-dependent circuit remodeling were altered in model animals. At the mature stage, there were synapse overdevelopment and altered gene expression similar to those in human ASD. These early synaptic phenotypes and altered gene expressions could be novel targets of efficient therapy from a young age. Competing Interest Statement The authors have declared no competing interest.

Recent studies have focused on the effects of low doses of Bisphenol A (BPA) on the central nervous system, which may prevent sexual dimorphism of the brain in rodents. To assess sensitivity to BPA, mother–infant behaviors in the cynomolgus monkey were studied longitudinally after treating the mothers with low-dose BPA during pregnancy. Mother–infant interaction was observed for 6 months after the birth of the infants. In conclusion, male offspring of BPA-treated females showed female-like behavior patterns. Prenatal BPA exposure altered infant behavior in the early stages of mother–infant interaction, and male infants were affected more seriously than females.

Hyperactivity is frequently observed in individuals with autism spectrum disorder (ASD) and significantly affects various aspects of life. This underscores the critical need for effective intervention methods tailored to the needs of individuals with ASD. Non-human primate models offer a promising avenue for elucidating the intricate interplay between ASD characteristics and developing individualized therapeutic strategies. This study examined the activity levels and behavioral dynamics in a prenatal valproic acid-induced (VPA) common marmoset model of ASD using ultraminiature data loggers, employing a more detailed approach to behavioral pattern analysis than is traditionally utilized. Although the overall activity levels showed no significant differences, the VPA group exhibited increased activity during specific hours, which is consistent with human ASD studies. Sample Entropy, a statistical measure used to quantify the regularity and unpredictability of time-series data, was higher during daytime in the VPA group, indicating reduced regularity in activity patterns akin to impulsive behavior in ASD. Subtle patterns that were not discernible through simple group comparisons were identified, highlighting the potential of this method as a valuable tool for the behavioral analysis of human ASD. Associations between erratic activity patterns, brief resting intervals, and elevated cortisol levels were observed, all of which correspond to stress phenotypes in individuals with ASD. The findings revealed variations in activity among the adult VPA groups, potentially linked to stress responses. Additionally, VPA juvenile marmosets showed increased locomotor activity in the social interaction test, complementing the adult behavioral findings and suggesting age-dependent manifestations of hyperactivity in this model. This non-human primate model effectively replicates real-world scenarios encountered by individuals with ASD exhibiting hyperactivity, thus holding significant implications for the advancement of personalized therapeutic strategies.

Individuals with autism spectrum disorder (ASD) are exposed to a variety of stressors owing to their behavioral traits. Cortisol is a hormone typically associated with stress, and its concentration and response to stress are higher in individuals with ASD than in controls. The mechanisms underlying cortisol dysregulation in ASD have been explored in rodents. Although rodent models have successfully replicated the major symptoms of autism (i.e., impaired vocal communication, social interaction deficits, and restricted/repetitive patterns of behavior), evidence suggests that the hypothalamic-pituitary-adrenal (HPA) axis system differs between rodents and primates. We developed an ASD model in the common marmoset (Callithrix jacchus), a New World monkey, utilizing prenatal exposure to valproic acid (VPA). In this study, we collected the salivary cortisol levels in VPA-exposed and unexposed marmosets in the morning and afternoon. Our results revealed that both VPA-exposed and unexposed marmosets showed similar diurnal changes in cortisol levels, which were lower in the afternoon than in the morning. However, heightened cortisol levels were observed in VPA-exposed marmosets in the morning, but not in the afternoon. These results are consistent with those of ASD in humans. Our results suggest that VPA-exposed marmosets show similarities not only in their behavioral patterns and brain pathologies, which we have reported previously but also in hormonal regulation, validating the usefulness of VPA-exposed marmosets also as a tool for ASD stress research.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social and communication impairments and restricted and repetitive behavior. Although currently no established cure exists for ASD, early intervention to the deficits of attention to other individuals is expected to reduce the progression of ASD symptoms in later life. In order to confirm this hypothesis and improve early therapeutic interventions, it is desirable to develop an animal model of ASD in which social attention is impaired in childhood and ASD-like social behavior is observed in adulthood. However, rodent models of ASD have difficulty in recapitulating the deficit of gaze-based social attention. In this study, we examined the direction of gaze towards other conspecifics during childhood and puberty in a three-chamber test setting using an ASD model of marmoset produced by maternal exposure to valproic acid (VPA). We also conducted a reversal learning test in an adult VPA-exposed marmoset as an indicator of perseveration, a core symptom of ASD that has not previously been investigated in this model. The results showed that time spent gazing at other conspecifics was reduced in VPA-exposed marmosets in childhood, and adults displayed rigidity of response. In a longitudinal study using the same animals, deficits in social attention in childhood correlated well with ASD-like social disturbance (inequity aversion and third-party reciprocity) and inflexible behavior in adulthood. Since VPA-exposed marmosets exhibit these diverse ASD-like behaviors that are coherent from childhood to adulthood, VPA-exposed marmosets will provide a valuable opportunity to elucidate mechanisms for early intervention and contribute to the development of early therapies. Competing Interest Statement The authors have declared no competing interest.

Senotherapy targeting for senescent cells is designed to attenuate age-related dysfunction. Senescent T cells, defined as CD4 + CD44 high CD62L low PD-1 + CD153 + cells, accumulate in visceral adipose tissues (VAT) in obese individuals. Here, we show the long-lasting effect of using CD153 vaccination to remove senescent T cells from high-fat diet (HFD)-induced obese C57BL/6J mice. We administered a CD153 peptide-KLH (keyhole limpet hemocyanin) conjugate vaccine with Alhydrogel (CD153-Alum) or CpG oligodeoxynucleotide (ODN) 1585 (CD153-CpG) and confirmed an increase in anti-CD153 antibody levels that was sustained for several months. After being fed a HFD for 10–11 weeks, adipose senescent T cell accumulation was significantly reduced in the VAT of CD153-CpG-vaccinated mice, accompanied by glucose tolerance and insulin resistance. A complement-dependent cytotoxicity (CDC) assay indicated that the mouse IgG2 antibody produced in the CD153-CpG-vaccinated mice successfully reduced the number of senescent T cells. The CD153-CpG vaccine is an optional tool for senolytic therapy. Senotherapy, the removal of aged T cells, is an effective approach to attenuate age-related diseases. Here the authors report a CD153 targeting vaccine that prevents the accumulation of senescent adipose tissue T cells in mice on high-fat diet, which is associated with improved glucose tolerance.

Osteoprotegerin (OPG) is a soluble secreted protein and a decoy receptor, which inhibits a receptor activator of nuclear factor κB (NF-κB) ligand (RANKL)/the receptor activator of NF-κB (RANK) signaling. Recent clinical studies have shown that a high-serum-OPG level is associated with unfavorable outcome in ischemic stroke, but it is unclear whether OPG is a culprit or an innocent bystander. Here we demonstrate that enhanced RANKL/RANK signaling in OPG ⁻/⁻ mice or recombinant RANKL-treated mice contributed to the reduction of infarct volume and brain edema via reduced postischemic inflammation. On the contrary, infarct volume was increased by reduced RANKL/RANK signaling in OPG ⁻/⁻ mice and WT mice treated with anti-RANKL neutralizing antibody. OPG, RANKL, and RANK mRNA were increased in the acute stage and were expressed in activated microglia and macrophages. Although enhanced RANKL/RANK signaling had no effects in glutamate, CoCl ₂, or H ₂O ₂-stimulated neuronal culture, enhanced RANKL/RANK signaling showed neuroprotective effects with reduced expression in inflammatory cytokines in LPS-stimulated neuron-glia mixed culture, suggesting that RANKL/RANK signaling can attenuate inflammation through a Toll-like receptor signaling pathway in microglia. Our findings propose that increased OPG could be a causal factor of reducing RANKL/RANK signaling and increasing postischemic inflammation. Thus, the OPG/RANKL/RANK axis plays critical roles in controlling inflammation in ischemic brains.