Molecular Psychiatry最新文献

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition with multifactorial etiologies. Although much research has historically focused on neurons, growing evidence indicates that multiple cell types within the central nervous system (CNS), particularly glial cells, also play critical roles. Importantly, glial cells express most of the high-confidence ASD (hc-ASD) genes, and mutations in these genes are strongly associated with an increased risk of ASD. These cells also play a crucial role in the development, refinement and maturation of circuits. This review highlights the central role of oligodendrocytes (OLs) and myelin in ASD pathophysiology. Individuals with ASD frequently exhibit impairments in white matter development and integrity, particularly in brain regions associated with sociability, stereotyped behaviors, and decision-making. These findings are supported by advanced CNS imaging and postmortem analyses, including structural, proteomic, and transcriptomic studies. Rodent models that replicate core ASD symptoms, such as social disinterest and restricted/repetitive behaviors, demonstrate that aberrant myelination profoundly affects these behavioral traits. Moreover, perturbations in oligodendroglial development directly alter CNS architecture, leading to neuronal morphological abnormalities and disruptions in excitation/inhibition balance. The correlation between OL dysfunction, altered brain architecture, and ASD symptoms underscores the importance of studying OLs in the context of ASD. A comprehensive understanding of the interplay between OL function and ASD pathophysiology could inform the development of targeted therapeutic strategies aimed at restoring white matter integrity and improving functional outcomes.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by core behavioral symptoms. We previously showed that nitric oxide (NO) plays a key role in ASD. However, the precise molecular mechanism through which NO acts via its posttranslational modification, S-nitrosylation (SNO), in ASD remains largely unknown. Emerging evidence, including our previous studies, suggests that the mechanistic target of the rapamycin (mTOR) signaling pathway plays a critical role in ASD pathophysiology. Our SNO-proteome systems biology analysis showed the enrichment of the mTOR pathway. In this study, we deciphered a novel mechanism of the cross talk between NO and mTOR pathway using two well-established mouse models as well as clinical samples of children with ASD. To assess changes in the SNO-proteome, we used the SNOTRAP method, revealing increased S-nitrosylation of tuberous sclerosis complex 2 (TSC2) in Shank3^Δ4-22 and Cntnap2^(-/-) mutant mice. We proved that this modification led to the loss of TSC2 protein via ubiquitination, resulting in dysregulated mTOR signaling in both excitatory and inhibitory neurons. Pharmacological inhibition of neuronal nitric oxide synthase (nNOS) successfully prevented TSC2 S-nitrosylation, mTOR overactivation, and altered protein translation in ASD models, highlighting NO's role in modulating mTOR function. To further validate the role of TSC2 S-nitrosylation in ASD, we generated a cysteine-to-serine mutation (C203S) in TSC2 to prevent its S-nitrosylation. Intracranial injection of the mutant TSC2 (C203S) in Shank3^Δ4-22 mice in the prefrontal cortex prevented ASD-like behaviors, confirming the pathogenic role of NO-mediated TSC2 modification. Critically, analysis of clinical samples from children with ASD, including those with SHANK3 mutations and idiopathic ASD, revealed reduced TSC2 levels and increased mTOR signaling activity, further validating our findings. Collectively, this study uncovers a novel molecular mechanism by which S-nitrosylation disrupts TSC2 function, leading to aberrant mTOR signaling and ASD-like phenotypes. By revealing a unique SNO-TSC2-mTOR axis, our work deciphers the novel nitric oxide-mediated mTOR activation and opens new avenues for targeted therapeutic strategies in ASD, including those carrying SHANK3 mutations.

The authors describe trends in stimulant prescribing to US adults and characterize stimulant-treated adults by use of three modalities: telehealth only, in-person only, or mixed (hybrid) behavioral healthcare. Among US adults in the 2018-2023 Medical Expenditure Panel Survey (n = 119,138), annual stimulant treatment rates are presented with age- and sex-adjusted marginal 2018-2023 differences across sociodemographic and clinical strata. Characteristics of stimulant-treated adults are also presented by reason for stimulant use (attention-deficit/hyperactivity disorder vs. other) and behavioral healthcare modality. Between 2018 and 2023, medical stimulant use increased from 1.8% to 2.2% of adults, including greater increases for adults with household incomes >400% than <100% of the Federal Poverty Level and employed adults than non-employed adults over age 65. However, the percentage of patients receiving ADHD visits who were treated with stimulants declined from 81.6% in 2018 to 74.6% in 2023. In 2021-2023, 48.4% of stimulant-treated patients received all their behavioral healthcare as in-person visits rather than hybrid (30.9%) or telehealth only (20.7%). These three groups did not differ in the percentage who received stimulants for ADHD, the number of stimulant prescriptions they received, or benzodiazepine or opioid prescriptions. In summary, between 2018 and 2023, adult stimulant use increased, particularly among higher-income and employed adults, while the share of ADHD patients treated with stimulants declined. Approximately one-half of stimulant-treated patients received teletherapy, and service modality was not related to ADHD treatment, stimulant prescription counts, or benzodiazepine or opioid prescriptions.