tretinoin and Autism-Spectrum-Disorder

Autism spectrum disorder (ASD) is a complex neurodevelopmental disease with an unclear underlying pathogenesis. Disruption of retinoic acid (RA)-retinoic acid receptor α (RARα) signaling and aberrant microglial activation were reported to be involved in the pathogenesis of ASD. However, the effect of RA-RARα signaling on microglial activation in ASD and the underlying mechanisms are unknown. Herein, we found inhibited RA-RARα signaling and increased microglial activation in valproic acid (VPA)-induced autism rats. Furthermore, we administered RA to VPA rats and found that RA ameliorated autism-like behaviors, inhibited microglial activation and normalized microglial polarization in VPA rats. Additionally, the expression levels of RARα and triggering receptor expressed on myeloid cells 2 (TREM2) were increased in the prefrontal cortex (PFC) of VPA rats given RA. Chromatin immunoprecipitation (ChIP) and dual luciferase reporter assays confirmed that RARα can regulate the transcriptional activity of the TREM2 gene by binding to its promoter. We conclude that RA administration ameliorates autism-like behaviors in VPA rats by inhibiting microglial activation and normalizing microglial polarization through the regulation of TREM2 transcription by RARα.

Topics: Animals; Autism Spectrum Disorder; Autistic Disorder; Microglia; Prefrontal Cortex; Rats; Retinoic Acid Receptor alpha; Tretinoin; Valproic Acid

In addition to their core symptoms, most individuals with autism spectrum disorder (ASD) also experience motor impairments. These impairments are often linked to the cerebellum, which is the focus of the current study. Herein, we utilized a prenatal valproic acid (VPA)-induced rat model of autism and performed RNA sequencing in the cerebellum. Relative to control animals, the VPA-treated offspring demonstrated both abnormal motor coordination and impaired dendritic arborization of Purkinje cells (PCs). Concurrently, we observed a decrease in the cerebellar expression of retinoic acid (RA) synthesis enzymes (RDH10, ALDH1A1), metabolic enzyme (CYP26A2), and lower levels of RA, retinoic acid receptor α (RARα), and Cerebellin2 (CBLN2) in the VPA-treated offspring. However, RA supplementation ameliorated these deficits, restoring motor coordination, normalizing PCs dendritic arborization, and increasing the expression of RA, RARα, and CBLN2. Further, ChIP assays confirmed that RA supplementation enhanced RARα's binding capacity to CBLN2 promoters. Collectively, these findings highlight the therapeutic potential of RA for treating motor incoordination in VPA-induced autism, acting through the RARα-CBLN2 pathway.

Topics: Animals; Ataxia; Autism Spectrum Disorder; Autistic Disorder; Cerebellum; Dietary Supplements; Disease Models, Animal; Female; Humans; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Tretinoin; Valproic Acid

Topics: Animals; Autism Spectrum Disorder; Behavior, Animal; Female; Maternal Exposure; Neuronal Plasticity; Neurons; Prefrontal Cortex; Pregnancy; Rats; Rats, Sprague-Dawley; Risk Factors; Signal Transduction; Tretinoin; Triclosan

The autism spectrum disorders (ASDs) are a collection of human neurological disorders with heterogeneous etiologies. Hyperactivity of E3 ubiquitin (Ub) ligase UBE3A, stemming from 15q11-q13 copy number variations, accounts for 1%-3% of ASD cases worldwide, but the underlying mechanisms remain incompletely characterized. Here we report that the functionality of ALDH1A2, the rate-limiting enzyme of retinoic acid (RA) synthesis, is negatively regulated by UBE3A in a ubiquitylation-dependent manner. Excessive UBE3A dosage was found to impair RA-mediated neuronal homeostatic synaptic plasticity. ASD-like symptoms were recapitulated in mice by overexpressing UBE3A in the prefrontal cortex or by administration of an ALDH1A antagonist, whereas RA supplements significantly alleviated excessive UBE3A dosage-induced ASD-like phenotypes. By identifying reduced RA signaling as an underlying mechanism in ASD phenotypes linked to UBE3A hyperactivities, our findings introduce a new vista of ASD etiology and facilitate a mode of therapeutic development against this increasingly prevalent disease.

Topics: Aldehyde Dehydrogenase 1 Family; Animals; Autism Spectrum Disorder; Child, Preschool; HEK293 Cells; Humans; Male; Mice, Inbred C57BL; Molecular Targeted Therapy; Neuronal Plasticity; Neurons; Retinal Dehydrogenase; Signal Transduction; Tretinoin; Ubiquitin-Protein Ligases; Ubiquitination

Previous studies framed a possible link of retinoic acid (RA) regulation in brain to autism spectrum disorders (ASD) etiology. The aim of this study was to measure serum levels of RA in relation to the degree of the severity of autism. Serum RA levels were measured by enzyme-linked immunosorbent assay (ELISA) colorimetric detection Kit in 81 children with autism and 81 age-sex matched typical development children. The severity of autistic symptomatology was measured by the Childhood Autism Rating Scale (CARS) score using the Chinese version. The serum levels of RA in the children with ASD (1.68 ± 0.52 ng/ml) were significantly lower than those of control subjects (2.13 ± 0.71 ng/ml) (P < 0.001). At admission, 57 children (70.4%) had a severe autism. In those children, the mean serum RA levels were lower than in those children with mild to moderate autism (1.57 ± 0.47 ng/ml VS. 1.95 ± 0.55 ng/ml; P = 0.003). Furthermore, in multivariate model, low RA level was associated with having/the presence of ASD (adjusted odd ratio[OR] 0.516; P = 0.003) and severe ASD (OR 0.415; P = 0.015) after adjusted for confounding factors. The data suggested that serum RA levels were reduced in the group with ASD, and the levels negative correlated significantly with the severity of autism.

Topics: Autism Spectrum Disorder; Case-Control Studies; Child; Child, Preschool; China; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Odds Ratio; Severity of Illness Index; Tretinoin

Autism spectrum disorder (ASD) comprises a group of neurodevelopmental disorders for which various theories have been proposed. Each theory brings valuable insights and has experimental evidence backing it, yet none provides an overarching explanation for each of the pathological aspects involved in ASD. Here we present an integrative theory of ASD, centered on a sequence of events spanning from the molecular to the behavioral level. We propose that an abnormality in the interplay between retinoic acid and sex hormones predisposes an individual to specific molecular malfunctions. In turn, this molecular syndrome generates an altered brain connectivity between the cerebellum, the midbrain dopaminergic areas, and the prefrontal cortex. Lastly, this disconnection would generate specific behavioral traits traditionally involved in ASD. Therefore, this paper represents a step forward in unifying different levels of pathological features into novel integrated testable hypotheses.

Topics: Animals; Autism Spectrum Disorder; Behavior; Cerebellum; Dopamine; Gonadal Steroid Hormones; Humans; Mesencephalon; Mice; Models, Theoretical; Phenotype; Prefrontal Cortex; Purkinje Cells; Retinoic Acid Receptor alpha; Testosterone; Tretinoin

Autism spectrum disorders (ASDs) are a range of complex neurodevelopmental conditions principally characterized by dysfunctions linked to mental development. Previous studies have shown that there are more than 1000 genes likely involved in ASD, expressed mainly in brain and highly interconnected among them. We applied whole exome sequencing in Colombian-South American trios. Two missense novel SNVs were found in the same child: ALDH1A3 (RefSeq NM_000693: c.1514T>C (p.I505T)) and FOXN1 (RefSeq NM_003593: c.146C>T (p.S49L)). Gene expression studies reveal that Aldh1a3 and Foxn1 are expressed in ~E13.5 mouse embryonic brain, as well as in adult piriform cortex (PC; ~P30). Conserved Retinoic Acid Response Elements (RAREs) upstream of human ALDH1A3 and FOXN1 and in mouse Aldh1a3 and Foxn1 genes were revealed using bioinformatic approximation. Chromatin immunoprecipitation (ChIP) assay using Retinoid Acid Receptor B (Rarb) as the immunoprecipitation target suggests RA regulation of Aldh1a3 and Foxn1 in mice. Our results frame a possible link of RA regulation in brain to ASD etiology, and a feasible non-additive effect of two apparently unrelated variants in ALDH1A3 and FOXN1 recognizing that every result given by next generation sequencing should be cautiously analyzed, as it might be an incidental finding.

Topics: Adult; Aldehyde Oxidoreductases; Animals; Autism Spectrum Disorder; Base Sequence; Brain; Child; Cohort Studies; Colombia; Embryo, Mammalian; Exome; Female; Forkhead Transcription Factors; Gene Expression Regulation, Developmental; High-Throughput Nucleotide Sequencing; Humans; Male; Mice; Mice, Inbred C57BL; Molecular Sequence Data; Pedigree; Psychological Tests; Receptors, Retinoic Acid; Response Elements; Signal Transduction; Tretinoin