Journal of Neurodevelopmental Disorders最新文献

Background: Prader-Willi syndrome (PWS) is a neurodevelopmental disorder caused by loss of paternally expressed genes on chromosome 15q11-13, including NDN, which encodes necdin. Necdin deficiency has been linked to impaired visuospatial memory, social recognition, and stress regulation-features also seen in PWS. Previous work showed that necdin-deficient (Ndn + m/-p) mice exhibit reduced activity of noradrenergic neurons in the locus coeruleus (LC), a nucleus essential for arousal and stress responses. However, the mechanisms underlying LC hypoactivity remain unclear. Because GABAergic signaling is critical for LC excitability, this study examined the role of GABA_A ​and GABA_B ​receptor-mediated inhibition in Ndn + m/-p mice.

Methods: Electrophysiological recordings from brainstem slices of wild-type (WT) and Ndn + m/-p mice were used to measure spontaneous firing rates (SFRs) of LC noradrenergic neurons. The effects of bicuculline (GABA_A​ antagonist) and CGP54626 (GABA_B​ antagonist) were tested. Whole-cell patch-clamp recordings assessed receptor-mediated currents. Western blotting quantified receptor subunit expression in peri-LC tissue. Immunocytochemistry and ELISA examined GABA_B​ receptor expression and GABA release in cultured astrocytes.

Results: LC-NE neurons in Ndn + m/-p mice exhibited significantly reduced baseline SFR compared with WT. Bicuculline did not alter firing in either genotype, whereas CGP54626 significantly increased SFR in WT but not in Ndn + m/-p neurons, indicating impaired GABA_B receptor-mediated tonic inhibition. Whole-cell patch-clamp experiments confirmed intact GABA_A receptor-mediated inward currents in both genotypes, while no GABA_B receptor-mediated phasic currents were detected. Western blot analysis revealed comparable expression of GABA_A receptor α2 subunit and GABA_BR1 in peri-LC tissue between WT and Ndn + m/-p mice, suggesting functional rather than expression-level deficits. GFAP-positive cell density in the LC region was unchanged in vivo; however, in astrocyte cultures, Ndn + m/-p astrocytes exhibited greater proliferation by DIV 19 and consistently secreted higher levels of GABA, with significant elevations at later culture stages.

Conclusion: Necdin deficiency selectively disrupts GABA_B receptor-mediated tonic inhibition of LC-NE neurons while preserving GABA_A receptor function. Elevated astrocytic proliferation and GABA release may further enhance ambient inhibition, contributing to LC hypoactivity and the neurobehavioral phenotypes of PWS. These findings identify GABA_B receptor dysfunction and astrocytic dysregulation as potential mechanistic targets for therapeutic intervention in PWS.

Fragile X Syndrome (FXS), the leading known inherited cause of atypical behaviors associated with autism spectrum disorders (ASD), arises due to the reduced expression or absence of the Fragile X Messenger Ribonucleoprotein 1 (FMRP). Individuals with ASD and FXS often experience atypical sensory processing across modalities such as touch, hearing, and/or vision. The consequences of altered sensory processing can be debilitating, leading to impairments in sensory discrimination and an inability to filter out irrelevant sensory stimuli such as innocuous sounds, smells, sights, or touches. Currently, there is a significant knowledge gap in the field of FXS regarding the circuit mechanisms that drive atypical sensory processing and how these contribute to hypersensitivity and secondary effects, such as learning impairments and increased anxiety. Animal models of FXS mirror many of the sensory hypersensitivity issues observed in humans, exhibiting heightened anxiety, as well as learning and social impairments. Here, we discuss the dysfunctional neural dynamics underlying atypical sensory processing across modalities in FXS, potential therapeutic interventions targeting specific ion channels, receptors, and circuits, and propose future research directions that could pave the way for circuit-targeted therapies.

Background: Jacobsen Syndrome (JS), also known as 11q Deletion Syndrome (del11q), is a rare genetic disorder affecting approximately 1 in 100,000 births that presents with varied clinical manifestations and severities including intellectual disability, psychomotor delays, and distinctive physical traits. This study offers a detailed analysis of the clinical and cognitive profiles of individuals with JS and examines how these characteristics are related to each other and to genetic variables.

Methods: Twenty-nine participants with JS (20 female, mean age 12.48 years, SD = 9.13) underwent standardized assessments assessing cognitive functioning, adaptive behavior, autistic traits, and general psychopathology. A CGH array was used to assess genetic deletions. We employed descriptive and inferential statistical analyses to explore the association between clinical and cognitive characteristics and deletion size.

Results: Sixty percent of participants had verbal language. Mean intelligence quotient was 50.18, the range of adaptive functioning was very broad, and 43% showed behaviors exceeding the ADOS-2 cutoff for autism spectrum classification. A higher cognitive performance was associated with better adaptive skills, including more advanced language skills and with more depressive symptoms or a diagnosis of depression. Larger deletions were associated with more delays in developmental milestones and poorer cognitive functioning. No significant association was found between haploinsufficiency of the KIRREL3 and ARHGAP32 genes and cognitive functioning or autistic characteristics.

Conclusions: Our findings provide deeper insights into the complex relationship between genetic factors and clinical attributes in individuals with JS, revealing notable clinical variability within the JS population. This information may help predict developmental difficulties as genetic findings emerge.

Background: Emotion regulation (ER) difficulties are common in autistic individuals and may contribute to co-occurring psychopathology during adolescence. However, age-group heterogeneity in existing research limits understanding of ER processes in autistic adolescents. Therefore, this mixed methods systematic review synthesizes current knowledge on ER in autistic adolescents aged 10-24 years.

Methods: We systematically searched MEDLINE, PsycINFO, Web of Science, and Scopus for empirical studies on ER in autistic adolescents. 32 studies (including two qualitative) met inclusion criteria and were synthesized using a convergent integrated approach.

Results: Autistic adolescents consistently exhibited more ER difficulties than non-autistic peers, which were associated with internalizing and externalizing symptoms. Greater autism symptom severity, lower theory of mind, and social challenges were frequently linked to lower ER, while no consistent associations with age, gender, or IQ were found. Few studies examined physiological or neurobiological factors, but evidence suggested associations between ER difficulties, lower heart rate variability, and atypical neural responses. Cognitive-behavioral and mindfulness-based interventions generally led to improvements in ER, though results varied and discrepancies between self- and proxy-reports were common.

Conclusion: ER challenges are pronounced in autistic adolescents and are closely associated with mental health symptoms. While interventions show promise, future research should address measurement heterogeneity, examine neurobiological underpinnings, and include more longitudinal and ecologically valid designs.

Trial registration: CRD42024529184 (registered April 06, 2024).

Background: Importance: The neurodevelopmental outcomes of children born after medically assisted reproduction remain incompletely characterized on a population level. We were to assess the incidence and relative risk of neurodevelopmental delay in the children of infertile women born after unassisted conception, intrauterine insemination (IUI), and in vitro fertilization (IVF).

Method: We conducted a retrospective cohort study using the National Health Insurance Service database of South Korea from October 2017 through December 2023. The study included 115 839 singleton, full-term, non-low-birthweight children born to women aged 20-49 years with a diagnosis of female infertility. The exposure was mode of conception-spontaneous, IUI, or IVF-balanced by propensity score matching on preconceptional maternal factors. Outcome measure was neurodevelopmental delay, defined as scoring below the cutoff in any of six functional domains on the Korean Developmental Screening Test across six consecutive rounds. Crude incidence rate ratios (IRRs) and adjusted hazard ratios (aHRs) were estimated using Cox proportional hazards models.

Results: Among 115 839 children, 6 575 (5.7%) exhibited delay in at least one domain. Crude IRRs for any delay were 1.19 (95% confidence interval [CI]: 1.07, 1.61) for IUI and 1.10 (95% CI: 1.03, 1.17) for IVF versus unassisted conception. In the survival models, higher risks persisted for both IUI (aHR = 1.19; 95% CI: 1.06, 1.34) and IVF (1.09, 95% CI: 1.02, 1.06) compared with unassisted conception. When comparing IVF and IUI, IVF conferred a lower risk of fine motor delay than IUI (0.84, 95% CI: 0.72, 0.99). Among IVF births, risk of developmental delay was similar across all six domains for frozen and fresh embryo transfers.

Conclusions: Children conceived via IUI or IVF demonstrated a modest but significant increase in screen-positive neurodevelopmental delay compared with those conceived spontaneously. These findings highlight the need for neurodevelopmental monitoring in this population.