1. Chen X, Zhang J, Wu J, Robinson MJ, Kothandaraman H, Yoo YE, Gonzalez Dopeso-Reyes IM, Buffenoir TD, Halurkar MS, Yang H, Zhang Z, Wang M, Creager EN, Giles HD, Zhao Y, Olivero-Acosta MI, Wettschurack KW, Que Z, Liu J, Yuan C, Schaser AJ, Lanman NA, Rochet JC, Skarnes WC, Kremer EJ, Yang Y. Autism-associated SCN2A deficiency disrupts cortico-striatal circuitry in human brain assembloids. Neuron. 2026.

Profound autism spectrum disorder (ASD) is frequently attributable to single-gene mutations, with SCN2A, encoding the voltage-gated sodium channel Na(V)1.2, among the most penetrant. Cortico-striatal circuitry is a key node implicated in ASD, yet how SCN2A deficiency alters human neural circuits remains unclear. Using a human cortico-striatal assembloid model, we show that autism-causing heterozygous SCN2A protein-truncating variants (PTVs) impair long-range cortical axonal projections, reduce striatal spine density, and attenuate excitatory cortico-striatal synaptic transmission. Genotype-defined assembloids reveal contributions from both impaired cortical projections and intrinsic striatal vulnerability. Paradoxically, despite these connectivity deficits, SCN2A-deficient neurons exhibit increased intrinsic excitability, and assembloids show elevated spontaneous network firing, suggesting a potentially distinctive feature of human neural models. Notably, canine adenovirus type 2-mediated delivery of human SCN2A rescued cellular and circuit deficits. Collectively, our study unveils human circuit dysfunction caused by SCN2A deficiency and supports the therapeutic potential of targeted gene replacement for SCN2A-related ASD.

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2. Coffman MC, Scheer A, Engelhard M, Franz L, Maslow G, Dawson G, Goldstein BA, Huang WA. Characterizing the Prevalence of Co-Occurring Neurodevelopmental Conditions and Associations With the Timing of Diagnosis in Autism in Medicaid Claims Data. Autism Res. 2026: e70365.

Autism commonly co-occurs with other neurodevelopmental conditions (NDCs), although diagnostic trajectories of an autism diagnosis relative to other NDCs are not well understood. We sought to examine the prevalence of NDCs within autistic children and how co-occurrence is associated with the timing of autism diagnoses. All children born between January 1, 2014 and December 31, 2015, and who had continuous enrollment in North Carolina Medicaid between less than 1 month old through autism diagnosis were included. This time period was chosen because follow-up data is available through December 31, 2022, which allowed inclusion of children to at least 8 years of age. From a cohort of 91,907 children, we identified 2694 children (77% boys) diagnosed with autism spectrum disorder. We found language (82%) and global developmental (52%) delays the most prevalent co-occurring NDCs. Within the most common combinations of co-occurring NDCs, over half (55%) of autistic children were diagnosed with three combinations of NDCs (24% with motor, language, and global developmental delays; 16% with language delay only; 16% with language and global developmental delays). Diagnoses of NDCs are associated with earlier autism diagnoses, with autism diagnoses occurring 10.8 months earlier for developmental, 8.4 months for language, and 7.2 months earlier for motor delays than children without these co-occurring diagnoses. Earlier autism diagnoses were especially evident in children who received neurodevelopmental delay diagnoses between 1.5 and 2 years of age. These findings are clinically relevant for developmental screening in children with neurodevelopmental disorders and intervention recommendations for autistic children. In a sample of 2694 autistic children, we found only 10% did not have a co‐occurring NDC. Being diagnosed with a NDC generally resulted in earlier autism diagnoses, particularly when NDCs were diagnosed between 1.5 and 2 years of age. Results indicate clinically significant challenges for autistic children that often extend beyond their autism diagnosis, which has implications for intervention service delivery. eng.

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3. Dawson A, Street A, Flower RL. ‘For the First Time, I Felt Seen’: Understanding What Helps Autistic Emerging Adults Feel Safe and Included on Social Media. Autism. 2026: 13623613261489306.

Social media is a prominent part of everyday life and is used regularly to connect users with a diverse network of content and people from around the world. Research on social media among autistic individuals has largely focused on online risks (e.g., cyberbullying) among children and adolescents, with limited attention to the perspectives of autistic emerging adults (i.e., aged 18-29), particularly regarding social media safety and inclusion. The aim of this qualitative study was to understand what helps autistic emerging adults feel safe and included on social media, focusing on their lived experience and recommendations for improvement. Data was collected from 50 autistic emerging adults (M(age) = 24.57, SD = 3.01) through an online open-ended survey. Using reflexive thematic analysis, we generated three key themes: (a) Welcomed by a community of allies, (b) Curating my experience and (c) Communicating in ways that work for me. The findings offer insight into the features and strategies used by autistic emerging adults to feel safe and included when using social media, and provides practical recommendations to foster a safer and more inclusive online environment for neurodivergent individuals.Lay AbstractSocial media is a part of everyday life and is used by many people to connect with others around the world. To our knowledge, no research has looked at what helps autistic emerging adults (people aged between 18-29 years) feel safe and included on social media. We wanted to understand this. We created an online survey with open-ended questions about social media use, asking 50 autistic emerging adults questions regarding their thoughts on what helps them to feel safe and included when using social media. We also asked for their ideas about what could be improved. We used a type of process called reflexive thematic analysis to look at patterns in what people said. We created three themes that we feel represented these patterns, which we called (a) Welcomed by a community of allies, (b) Curating my experience and (c) Communicating in ways that work for me. Participants spoke about feeling seen and accepted among others who shared they were autistic online. They also spoke about strategies they used to control what they experienced, and appreciated the different ways in which they could interact with others using social media. Participants felt more autism education was needed online, and made suggestions relating to more safety and custom settings on social media platforms. The findings of this study give insight into what helps autistic emerging adults feel safe and included when using social media.

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4. Goncalo AK. The role of neuroinflammation in the connections between autism spectrum disorder and Alzheimer’s disease and related dementias: A review. J Alzheimers Dis. 2026: 13872877261491809.

Recent evidence suggests a link between autism spectrum disorder (ASD) and early-onset Alzheimer’s disease and related dementias (AD/ADRD), yet the mechanisms underlying this association remain poorly understood. This narrative review investigates whether early management of ASD may reduce the risk of developing AD/ADRD by targeting shared biological pathways. A literature search was conducted using PubMed and included English-language studies published from 1996 to 2026. Eligible studies addressed ASD, AD/ADRD, neuroinflammation, aging, or dementia, and included systematic reviews, meta-analyses, narrative reviews, clinical trials, randomized controlled trials, and translational animal studies. Studies lacking discussion of mechanisms relevant to ASD, neuroinflammation, aging, or dementia were excluded. Search terms included AD, dementia, ASD, inflammation, pregnenolone, omega-3, prednisolone, celecoxib, minocycline, N-acetylcysteine, sulforaphane, histamine receptor agonists, and GABA. Additional studies were identified through reference list screening. Of 170 records identified, 133 met the inclusion criteria and formed the basis for the review. Findings indicate that neuroinflammation is a central mechanism linking ASD-related comorbidities with established AD/ADRD risk factors. The evidence suggests that reducing neuroinflammation, particularly through interventions targeting microglial activation during childhood or early adulthood, may lower the likelihood of early-onset AD/ADRD in individuals with ASD. Although current evidence is primarily theoretical and indirect, it supports further investigation of anti-inflammatory strategies as potential preventive interventions. The review concludes by proposing future empirical studies to test whether early neuroinflammation-targeted treatment in ASD can reduce the incidence of early-onset AD/ADRD.

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5. Gray L, Hall E, Hearne B, Zhang Y, Stern S, Stewart GR, Stott J, John A. Subjective and objective cognitive differences in adults in mid-life and older age with autism or high autistic traits: a systematic review and meta-analysis. Neurosci Biobehav Rev. 2026: 107011.

BACKGROUND: Research examining ageing in autistic populations, once largely neglected, has expanded in recent years. Cognitive decline and dementia are key public health concerns, and it remains unclear whether autism is related to atypical cognitive ageing. A synthesis of quantitative evidence on cognition in autistic adults in mid- to later-life is needed. This systematic review and meta-analysis is the first to do this. METHODS: Studies comparing objective and subjective cognition in autistic and neurotypical adults aged 50+ were included. Given the underdiagnosis of autism in this age group, autistic samples defined using validated measures of autistic traits were included alongside formally diagnosed samples. Online databases (PubMed, Scopus, CINAHL, PsychINFO) were searched. Risk of bias was assessed using AXIS. RESULTS: Fifteen cross-sectional studies were included, examining 13 cognitive constructs. Additional analyses compared effect sizes between diagnosed and trait-defined populations. Autistic individuals reported significantly greater subjective cognitive difficulty (d = 0.90), although this was not reflected in objective performance. Small group differences were observed in processing speed, verbal fluency, and working memory (d = -0.28 – -0.38), across which autistic samples performed more poorly. Other cognitive domains did not significantly differ. Heterogeneity was high across several analyses. DISCUSSION: Results suggest broadly similar cognitive ageing in autistic and neurotypical adults. However, interpretation is limited by underrepresentation of participants over 65, and the absence of longitudinal studies. The discrepancy between objective and subjective cognition was a striking finding, with implications for clinical investigation of self-reported cognitive concerns amongst adults on the autism spectrum.

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6. Iliff S, Richard Williams N, Collins S, Gilliam M, Hill A, Knox T, Randall A. Person-Environment-Occupation Fit in Autistic College Students: A Mixed-Methods Study of Social Participation. Am J Occup Ther. 2026: 19437676261487169.

ImportanceSocial participation is a core occupation influencing health, identity, and belonging in college students. Limited research examines participation among autistic students within a person-environment-occupation (PEO) framework.ObjectiveTo examine social participation among autistic and non-autistic college students by comparing participation rates, satisfaction, motivations, and perceived barriers and exploring differences in lived experience and PEO fit.DesignMixed-methods convergent parallel design integrating quantitative survey data and qualitative content analysis.SettingA mid-sized, private university in the southeastern United States.ParticipantsA convenience sample of undergraduate students living on campus (N = 49; 23 autistic, 26 non-autistic).Outcomes and MeasuresAn anonymous survey of self-reported participation hours, satisfaction ratings, activity involvement, motivations, and barriers. Analyses included Welch’s t-tests and a chi-square test; qualitative data were analyzed inductively and integrated.ResultsGroups reported similar activity types, participation rates (p = .14), satisfaction (p = .63), and barriers (p = .61). Overall, 62% reported at least one barrier, most commonly time. Qualitative findings revealed differences in experience: autistic students more often described internal barriers (e.g., anxiety, difficulty identifying activities), whereas non-autistic students emphasized interpersonal challenges. Both groups desired greater campus engagement.Conclusions and RelevanceComparable participation outcomes may mask differences in experience and PEO fit. Occupational therapy can support meaningful engagement through neurodiversity-affirming, contextually responsive approaches that enhance accessibility, fit, and a sense of belonging. This study was done to better understand how autistic and non-autistic college students take part in social activities and how those experiences feel. Social activities help students build friendships, feel included, and support well-being. The study found that both groups spent about the same amount of time in social activities and felt similarly satisfied. However, their experiences were different. Autistic students more often reported feeling anxious or having trouble finding activities that matched their interests. Other students more often described challenges with fitting into social groups. These results show that participation is not just about how often someone joins activities, but also how comfortable and meaningful those experiences are. Occupational therapists can use this information to design activities and environments that better match students’ needs. This can improve participation, increase belonging, and support more inclusive college communities. eng.

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7. Keller PC, Sappok T. [Brief Evaluation of the Adapted Autism Diagnostic Observation Schedule (A-ADOS) in Adults with Intellectual Disability]. Psychiatr Prax. 2026.

OBJECTIVE: The study aims to assess the application of the adapted Autism Diagnostic Observation Schedule (A-ADOS) in adults with intellectual disabilities and suspected autism spectrum disorder. METHODS: In 14 individuals from this cohort, guideline-compliant autism diagnostics were conducted. The diagnosis was established in in a multidisciplinary consensus conference, considering all collected findings. The A-ADOS was additionally administered in a non-blinded manner; sensitivity and specificity were evaluated based on the case conference decisions. RESULTS: The A-ADOS was feasible in 12 out of 14 individuals (86%). The A-ADOS showed a sensitivity of 70% and a specificity of 100%. CONCLUSION: The A-ADOS proves to be feasible and diagnostically promising. Due to methodological limitations, the results are preliminary; a prospective, blinded study is required to validate the instrument.

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8. Kumazaki H, Kamide H, Miyashita T, Sumioka H, Yoshikawa Y, Ishiguro H. Social Role-Based Training Using a Computer Graphics Avatar in a Real-World Commercial Setting for Individuals With Autism Spectrum Disorder: Quasi-Experimental Study. J Med Internet Res. 2026; 28: e93549.

BACKGROUND: The lack of social role-based behaviors, such as guiding and assisting others, is a barrier to employment success and community participation for individuals with autism spectrum disorder (ASD). Enhancing self-efficacy is essential for improving these behaviors. To enhance self-efficacy in social role-based behaviors, we developed a training system that enables users to perform social role-based behaviors, including guiding and assisting others, called TCR (a training system that enables users to perform role-based behaviors using a computer graphics avatar in a real, bustling commercial facility). OBJECTIVE: We aimed to evaluate the feasibility of TCR and its potential to reduce anxiety and enhance self-confidence, motivation, metacognition, and self-efficacy in performing social role-based behaviors during real-world interactions among individuals with ASD. METHODS: We assigned 38 adults with ASD to either the TCR group (n=20), which received TCR alongside communication guidance from teachers (CGT), or the control group (n=18), which received only CGT, based on the chronological order of enrollment. Both groups underwent a 5-session intervention (days 14, 21, 28, 35, and 42). Anxiety, self-confidence, motivation, metacognition, and self-efficacy related to social role-based behaviors were assessed on days 0, 14, 28, 42, and 56 using self-report and observer ratings. RESULTS: Linear mixed model analyses showed group × time interactions for self-reported self-efficacy at day 56 (t(144.016)=2.670; P=.008; 95% CI 0.349-2.340). Nominally significant group × time interactions were also observed for self-reported anxiety, self-confidence, motivation, and metacognition, suggesting greater improvements in the TCR group than in the control group. Observer-reported outcomes demonstrated significant group × time interactions for self-efficacy at day 56 (t(144.016)=4.500; P<.001; 95% CI 0.405-1.039), anxiety at day 56 (t(144.016)=-3.593; P<.001; 95% CI -1.425 to -0.414), and self-confidence at day 56 (t(144.016)=3.321; P=.001; 95% CI 0.269-1.059), indicating greater improvement in the TCR group than in the control group. Nominally significant group × time interactions were additionally observed for observer-reported motivation at day 56 (t(144.016)=2.471; P=.02; 95% CI 0.103-0.930). Possible group × time interactions were also observed for observer-reported metacognition at day 56 (t(144.016)=1.858; P=.06; 95% CI -0.023 to 0.751). CONCLUSIONS: This study is innovative in that TCR enables users to perform social role-based behaviors. Unlike previous studies, TCR integrates opportunities for observing peers and role models, along with real-time encouragement, feedback, and verbal persuasion from a trainer, thereby incorporating multiple sources of self-efficacy. By demonstrating the feasibility of TCR and its potential to enhance self-efficacy in social role-based behaviors, this study contributes to the development of more effective interventions targeting functional social outcomes in individuals with ASD. TCR may support the development of skills relevant to employment and social participation in real-world settings and represents a potential scalable approach for community-based ASD interventions.

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9. Megari K, Genova KD. Complex needs, overlooked anxiety: A narrative review of neuropsychological assessment and treatment of anxiety in children with co-occurring autism spectrum disorder and intellectual developmental disorder. J Int Neuropsychol Soc. 2026: 1-17.

OBJECTIVE: Recent studies indicate that anxiety is one of the most prevalent mental health challenges faced by children and adolescents diagnosed with autism spectrum disorder (ASD). METHODS: For young individuals with concurrent Intellectual disability disorder, these rates are projected to be significantly elevated. RESULTS: Despite the estimated high prevalence of anxiety among young individuals with co-occurring ASD and intellectual developmental disorder (IDD), significant uncertainty remains in the field about the most effective methods for identifying, diagnosing, and treating anxiety in this distinct group. CONCLUSIONS: The main objective of this narrative review is to examine the current literature on effective strategies and adjustments for evaluating and treating anxiety in children and adolescents who have co-occurring ASD and IDD, aiming to support professionals engaged with this significantly neglected group.

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10. Ouellette J, Warsi S, Romero P, Khare P, Naz S, Aubert-Tandon L, Freitas-Andrade M, Pileggi C, Yandiev S, Raman-Nair J, Yee J, Blakeley N, Govindaswamy B, Comin CH, Harper ME, Soundara Manickam D, Dabertrand F, Saghatelyan A, Lacoste B. Purinergic receptor activation rectifies autism-associated endothelial dysfunction. Neuron. 2026.

Recent evidence in a 16p11.2 deletion mouse model of autism spectrum disorder (ASD) revealed brain endothelial abnormalities postnatally, but the endothelial alterations eliciting these changes remained unknown. Using 14-day-old and adult 16p11.2-deficient and wild-type male mice, we now show that the 16p11.2 deletion causes a bioenergetic failure selectively in endothelial cells (ECs) with reduced intracellular ATP levels. Intra- or extracellular ATP supplementation rescued the function of 16p11.2-deficient ECs in vitro via P2 purinergic receptor activation, specifically P2Y2 receptors. Activating P2Y2 receptors restored cerebrovascular reactivity in 16p11.2-deficient arterioles ex vivo, activity-dependent cerebral blood flow in vivo, and rescued 16p11.2 deletion-associated mouse behaviors. Taken together, this study demonstrates that metabolic reprogramming of brain ECs via purinergic receptor engagement represents a promising therapeutic avenue for ASD.

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11. Rahmati Y, van Jaarsveldt IEM, Jarrold C. Domains of self-regulation in autism, Down syndrome, and Williams syndrome: Condition-specific or transdiagnostic?. Res Dev Disabil. 2026; 178: 105390.

BACKGROUND: This questionnaire study examined regulatory control in the conditions of autism, Down syndrome, and Williams syndrome by assessing effortful control and executive function across cognitive, emotional, social, and sensory domains. METHOD: A bespoke parent-report questionnaire was developed. Parents of children aged 5-13 with these conditions and neurotypical peers participated (n = 231). Factor analysis was used to identify regulatory structures across groups, and Bayesian analyses compared group factor scores. Cluster analysis explored whether profiles grouped by diagnosis or regulatory pattern. RESULTS: Factor analysis identified a four-factor structure of self-regulation comprising Cognitive Regulation, Sensory Regulation, Emotional Regulation, and Social Regulation. Subsequent analyses showed that all neurodiverse children scored lower than neurotypical children on Cognitive Regulation, with no meaningful differences between the neurodiverse groups. All neurodiverse groups also scored lower than neurotypical children on Sensory Regulation, although autistic children scored meaningfully lower than both the Down syndrome and Williams syndrome groups. For Emotional Regulation, autistic children and children with Williams syndrome scored lower than neurotypical children, whereas children with Down syndrome did not; within the neurodiverse groups, the only meaningful difference was that autistic children scored lower than children with Down syndrome. For Social Regulation, only autistic children scored meaningfully lower than neurotypical children. Cluster analysis indicated that children tended to group according to shared patterns of self-regulation rather than by diagnostic category, although some diagnostic clustering was also evident. CONCLUSIONS: These findings highlight both shared and condition-specific challenges, suggesting that diagnosis provides an initial guide to an individual’s regulatory profile but should be supplemented by a needs-based assessment to better inform personalized intervention.

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12. Rivard M, Boulé M, Mello C, Hastings R, Abouzeid N, Chatenoud C, Bradshaw J, Gore N, Parent-Poisson N, Comtois G, Morin D. The perceived utility, acceptability, and impact of Early Positive Approaches to Support (E-PAtS) in routine services for families of young children with developmental disabilities. Res Dev Disabil. 2026; 178: 105386.

OBJECTIVES: To examine the social validity of the Early Positive Approaches to Support (E-PAtS) program. E-PAtS is a group-based psychoeducational and support intervention designed for parents of children with developmental disabilities (DD) in the early stages of their service trajectory. METHODS: We used semi-structured interviews and post-session measures to explore parents’ perceptions of the adequacy program’s goals, acceptability of its procedures, and its perceived effects. RESULTS: Findings indicated strong alignment between parents’ motivations for participation, program goals, and perceived outcomes across family members. Thematic analysis identified five features supporting the social validity of E-PAtS: 1) learning about DD and practical strategies, 2) accessing and navigating services, 3) engaging in group discussions, 4) developing self-care practices, and 5) experiencing co-facilitation. Parents also reported improvements in child behavior and an increased capacity to navigate services and identify needs. CONCLUSIONS: These findings underscore the importance of socially valid, family-centered approaches. They also position E-PAtS as a complementary early support to enhance readiness for subsequent interventions, and support its integration within a continuum of services for families of children with DD.

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13. Sato A. Intermediary Relational Coordination in Fragmented Child Developmental Support Systems: An Early Implementation Evaluation of a Multi-Agency Network in Japan. Child Care Health Dev. 2026; 52(6): e70358.

BACKGROUND: Fragmentation across healthcare, education, welfare and community-based services creates persistent challenges for coordinating support for children with developmental difficulties. Formal integration across these sectors may be difficult to achieve. This study explored how participating professionals perceived cross-sectoral collaboration during the early implementation of a paediatrician-initiated multi-agency network operating within existing institutional structures. METHODS: An exploratory early implementation evaluation was conducted using a retrospective pre-post survey design. An anonymous questionnaire was distributed to 116 network members, of whom 32 responded. Participants retrospectively rated their pre-network experiences and their current experiences across four study-specific domains of collaboration: ease of consultation, understanding of roles across sectors, adoption of a needs-based perspective and confidence in cross-sectoral referral and collaboration. Quantitative data were analysed descriptively, and free-text responses were analysed thematically by two reviewers. RESULTS: Participants reported higher current than retrospective pre-network ratings across all four collaboration domains, with the largest perceived changes in understanding of roles and confidence in cross-sectoral referral and collaboration. Thematic analysis identified four themes: accessible consultation pathways, shared language and mutual understanding, confidence through relational trust and persistent structural constraints. Participants described the value of identifiable consultation contacts and repeated cross-sectoral interaction, while also noting limitations in network reach and continuing institutional barriers. CONCLUSIONS: This exploratory evaluation provides preliminary insight into how professionals participating in a voluntary multi-agency network perceived cross-sectoral collaboration during early implementation. Building on these findings, we propose the M-MEW (Mesh-in-Dome) model as a practice-derived conceptualisation of a bidirectional and multidirectional relational mesh developing across existing institutional structures. The model envisages an initial facilitating hub supporting network formation, with the potential for coordination to become increasingly distributed as reciprocal relationships develop. Prospective evaluation is required to determine whether this model improves collaboration or outcomes for children and families.

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14. Sterner EF, Demler VF, Lenz R, MacGregor LJ, Mathys C, Knolle F. Altered semantic prediction error processing with increasing schizotypal and autistic traits. Transl Psychiatry. 2026; 16(1).

Predictive processing has been proposed as a framework for symptom development in autism (ASD) and schizophrenia (SSD) spectrum disorders, with ASD being associated with an overweighting of (low-level) sensory evidence whereas SSD is characterized by an overweighting of (high-level) prior beliefs, both resulting in altered prediction error processing. This study investigated these hypotheses and their electrophysiological correlates in subclinical expressions of ASD and SSD during language processing. Participants completed an auditory comprehension task that manipulated the precision of high-level semantic prior beliefs and low-level sensory evidence. Hierarchical Bayesian belief-updating modeling and electroencephalography were used to examine whether imbalances in the weighting of prior beliefs and sensory evidence were reflected in altered processing of semantic prediction errors, characterized by mean N400 amplitudes. Computational modeling revealed that increasing schizotypal traits were associated with significant overweighting of prior beliefs, while autistic traits did not show a significant shift. Linear mixed-effect models of mean N400 amplitudes indicated that schizotypy-related overweighting of semantic prior beliefs was reflected in a reduced semantic prediction error signal, indexed by smaller N400 differences between high predictability sentences and both low predictability and high predictability mismatch sentences. A similar but weaker and less distinct pattern emerged for increasing autistic traits. These findings provide converging computational and electrophysiological support for overweighting of semantic prior beliefs with increasing subclinical schizotypy. In contrast, increasing autistic traits were not associated with overweighting of sensory evidence, with electrophysiological results instead suggesting subtle alterations in the weighting of semantic prior beliefs.

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15. Wang Z, Chen H, Wang C, Mu C, Qiao D, Zhang Z, Li D, Cui C, Wang M, Wang X, Zhang R, Wang C, Cui H, Li S. FMRP Regulates NrCAM Expression via β-catenin and Modulates PSD95, Dendritic Spines and Autism-like Behaviors. Neurosci Bull. 2026.

Fragile X mental retardation protein (FMRP) and β-catenin play essential roles in dendritic development and neurobehavior, whereas the neuronal cell adhesion molecule (NrCAM) is closely involved in synapse formation and remodeling. However, whether FMRP regulates NrCAM through β-catenin to influence hippocampal dendritic development and neurobehavior remains unclear. Here, transcriptomic analysis of Fmr1 knockout (KO) mice identified Ctnnb1 as a key differentially expressed gene associated with aberrant dendritic development. FMRP directly binds to β-catenin mRNA in HT22 cells. Fmr1 knockdown upregulated β-catenin, NrCAM, and PSD95 expression at both the mRNA and protein levels and promoted the nuclear accumulation of β-catenin. NrCAM was required for the FMRP deficiency-induced upregulation of PSD95, and simultaneous knockdown of Fmr1 and Nrcam reduced PSD95 expression. Furthermore, Fmr1 knockdown enhanced the interaction between NrCAM and PSD95. In vivo hippocampal Nrcam knockdown in Fmr1 KO mice decreased PSD95 expression, whereas Ctnnb1 knockdown rescued dendritic spine abnormalities and ameliorated autism-like behaviors. These findings demonstrate that FMRP regulates NrCAM through β-catenin to modulate PSD95 expression, thereby influencing hippocampal dendritic spine development and autism-like behaviors. This study provides new mechanistic insights into the neuropathology of hereditary mental retardation.

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