1. Barón-Mendoza I, Maqueda-Martínez E, Martínez-Marcial M, De la Fuente-Granada M, Gómez-Chavarin M, González-Arenas A. Changes in the Number and Morphology of Dendritic Spines in the Hippocampus and Prefrontal Cortex of the C58/J Mouse Model of Autism. Frontiers in cellular neuroscience. 2021; 15: 726501.

Autism spectrum disorder (ASD) has a broad range of neurobiological characteristics, including alterations in dendritic spines, where approximately 90% of excitatory synapses occur. Therefore, changes in their number or morphology would be related to atypical brain communication. The C58/J inbred mouse strain displays low sociability, impaired communication, and stereotyped behavior; hence, it is considered among the animal models suitable for the study of idiopathic autism. Thus, this study aimed to evaluate the dendritic spine differences in the hippocampus and the prefrontal cortex of C58/J mice. We found changes in the number of spines and morphology in a brain region-dependent manner: a subtle decrease in spine density in the prefrontal cortex, higher frequency of immature phenotype spines characterized by filopodia-like length or small morphology, and a lower number of mature phenotype spines with mushroom-like or wide heads in the hippocampus. Moreover, an in silico analysis showed single nucleotide polymorphisms (SNPs) at genes collectively involved in regulating structural plasticity with a likely association with ASD, including MAP1A (Microtubule-Associated Protein 1A), GRM7 (Metabotropic Glutamate Receptor, 7), ANKRD11 (Ankyrin Repeat Domain 11), and SLC6A4 (Solute Carrier Family 6, member 4), which might support the relationship between the C58/J strain genome, an autistic-like behavior, and the observed anomalies in the dendritic spines.

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2. Coppedè F. The diagnostic potential of the epigenome in autism spectrum disorders. Epigenomics. 2021; 13(20): 1587-90.

Tweetable abstract The diagnostic application of genome-wide methylation signatures is increasing in various syndromic forms of autism, but further studies are warranted to clarify whether epigenetic biomarkers can be of diagnostic utility in idiopathic ASD.

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3. Klei L, McClain LL, Mahjani B, Panayidou K, De Rubeis S, Grahnat AS, Karlsson G, Lu Y, Melhem N, Xu X, Reichenberg A, Sandin S, Hultman CM, Buxbaum JD, Roeder K, Devlin B. How rare and common risk variation jointly affect liability for autism spectrum disorder. Molecular autism. 2021; 12(1): 66.

BACKGROUND: Genetic studies have implicated rare and common variations in liability for autism spectrum disorder (ASD). Of the discovered risk variants, those rare in the population invariably have large impact on liability, while common variants have small effects. Yet, collectively, common risk variants account for the majority of population-level variability. How these rare and common risk variants jointly affect liability for individuals requires further study. METHODS: To explore how common and rare variants jointly affect liability, we assessed two cohorts of ASD families characterized for rare and common genetic variations (Simons Simplex Collection and Population-Based Autism Genetics and Environment Study). We analyzed data from 3011 affected subjects, as well as two cohorts of unaffected individuals characterized for common genetic variation: 3011 subjects matched for ancestry to ASD subjects and 11,950 subjects for estimating allele frequencies. We used genetic scores, which assessed the relative burden of common genetic variation affecting risk of ASD (henceforth « burden »), and determined how this burden was distributed among three subpopulations: ASD subjects who carry a potentially damaging variant implicated in risk of ASD (« PDV carriers »); ASD subjects who do not (« non-carriers »); and unaffected subjects who are assumed to be non-carriers. RESULTS: Burden harbored by ASD subjects is stochastically greater than that harbored by control subjects. For PDV carriers, their average burden is intermediate between non-carrier ASD and control subjects. Both carrier and non-carrier ASD subjects have greater burden, on average, than control subjects. The effects of common and rare variants likely combine additively to determine individual-level liability. LIMITATIONS: Only 305 ASD subjects were known PDV carriers. This relatively small subpopulation limits this study to characterizing general patterns of burden, as opposed to effects of specific PDVs or genes. Also, a small fraction of subjects that are categorized as non-carriers could be PDV carriers. CONCLUSIONS: Liability arising from common and rare risk variations likely combines additively to determine risk of any individual diagnosed with ASD. On average, ASD subjects carry a substantial burden of common risk variation, even if they also carry a rare PDV affecting risk.

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4. Laporta ML, Sprung J, Fejedelem CA, Henning DT, Weaver AL, Hanson AC, Schroeder DR, Myers SM, Voigt RG, Weingarten TN, Flick RP, Warner DO. Association Between Exposure of Children to General Anesthesia and Autism Spectrum Disorder. Journal of autism and developmental disorders. 2021.

This study tested the hypothesis that exposure of children prior to their third birthday to procedures requiring general anesthesia is associated with an increased incidence of autism spectrum disorder (ASD) in later life. This study employed a nested, 1:2 matched-case control study design using ASD cases identified in a population-based birth cohort of children born in Olmsted County, MN from 1976 to 2000. Matching variables included sex, date of birth, and mother’s age in conditional logistic regression including 499 ASD cases and 998 controls. After adjusting for birth weight and health status, there was no significant association between exposure and ASD (OR 1.27 [95% CI 0.92-1.76]), indicating that general anesthesia is not associated with an increased risk of ASD.

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5. Liu S, Pei P, Li L, Wu H, Zheng X, Wang S, Xiao Y, Pan H, Bao X, Qi Y, Ma Y. Mitochondrial DNA Copy Number in Rett Syndrome Caused by Methyl-CpG-Binding Protein-2 Variants. The Journal of pediatrics. 2022; 241: 154-61.

OBJECTIVE: To determine changes in mitochondrial DNA (mtDNA) copy number in peripheral blood in Rett syndrome caused by methyl-CpG-binding protein-2 (MECP2) variants and explore the mechanism of mitochondrial dysfunction in Rett syndrome. STUDY DESIGN: Female patients who were diagnosed with Rett syndrome and had an MECP2 variant (n = 142) were recruited in this study, along with the same number of age- and sex-matched healthy controls. MtDNA copy number was quantified by real-time quantitative polymerase chain reaction with TaqMan probes. The differences in mtDNA copy number between the Rett syndrome group and the control group were analyzed using the independent-samples t test. Linear regression, biserial correlation analysis, and one-way ANOVA were applied for the correlations between mtDNA copy number and age, clinical severity, variant types, functional domains, and hot-spot variants. RESULTS: MtDNA copy number was found to be significantly increased in the patients with Rett syndrome with MECP2 gene variants compared with the control subjects. Age, clinical severity, variant types, functional domains, and hot-spot variants were not related to mtDNA copy number in patients with Rett syndrome. CONCLUSIONS: MtDNA copy number is increased significantly in patients with Rett syndrome, suggesting that changes in mitochondrial function in Rett syndrome trigger a compensatory increase in mtDNA copy number and providing new possibilities for treating Rett syndrome, such as mitochondria-targeted therapies.

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6. Mahjani B, De Rubeis S, Gustavsson Mahjani C, Mulhern M, Xu X, Klei L, Satterstrom FK, Fu J, Talkowski ME, Reichenberg A, Sandin S, Hultman CM, Grice DE, Roeder K, Devlin B, Buxbaum JD. Prevalence and phenotypic impact of rare potentially damaging variants in autism spectrum disorder. Molecular autism. 2021; 12(1): 65.

BACKGROUND: The Autism Sequencing Consortium identified 102 high-confidence autism spectrum disorder (ASD) genes, showing that individuals with ASD and with potentially damaging single nucleotide variation (pdSNV) in these genes had lower cognitive levels and delayed age at walking, when compared to ASD participants without pdSNV. Here, we made use of a Swedish sample of individuals with ASD (called PAGES, for Population-Based Autism Genetics & Environment Study) to evaluate the frequency of pdSNV and their impact on medical and psychiatric phenotypes, using an epidemiological frame and universal health reporting. We then combine findings with those for potentially damaging copy number variation (pdCNV). METHODS: SNV and CNV calls were generated from whole-exome sequencing and chromosome microarray data, respectively. Birth and medical register data were used to collect phenotypes. RESULTS: Of 808 individuals assessed by sequencing, 69 (9%) had pdSNV in the 102 ASC genes, and 144 (18%) had pdSNV in the 102 ASC genes or in a larger set of curated neurodevelopmental genes (from the Deciphering Developmental Disorders study, the gene2phenotype database, and the Radboud University gene lists). Three or more individuals had pdSNV in GRIN2B, POGZ, SATB1, DYNC1H1, SCN8A, or CREBBP. In comparison, out of the 996 individuals from whom CNV were called, 105 (11%) carried one or more pdCNV, including four or more individuals with CNV in the recurrent 15q11q13, 22q11.2, and 16p11.2 loci. Carriers of pdSNV were more likely to have intellectual disability (ID) and epilepsy, while carriers of pdCNV showed increased rates of congenital anomalies and scholastic skill disorders. Carriers of either pdSNV or pdCNV were more likely to have ID, scholastic skill disorders, and epilepsy. LIMITATIONS: The cohort only included individuals with autistic disorder, the more severe form of ASD, and phenotypes are defined from medical registers. Not all genes studied are definitively ASD genes, and we did not have de novo information to aid in classification. CONCLUSIONS: In this epidemiological sample, rare pdSNV were more common than pdCNV and the combined yield of potentially damaging variation was substantial at 27%. The results provide compelling rationale for the use of high-throughout sequencing as part of routine clinical workup for ASD and support the development of precision medicine in ASD.

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7. Moseley RL, Turner-Cobb JM, Spahr CM, Shields GS, Slavich GM. Lifetime and perceived stress, social support, loneliness, and health in autistic adults. Health psychology : official journal of the Division of Health Psychology, American Psychological Association. 2021; 40(8): 556-68.

OBJECTIVES: Although the health consequences of life stress exposure in the general population are well known, how different stressors occurring over the lifetime cause morbidity and mortality in autism is unclear, as are the factors that moderate and mediate these associations. The few studies that have compared autistic and nonautistic individuals have used instruments that yield few stress exposure indices and assess stressors occurring over short time periods. METHOD: To address these issues, we used the Stress and Adversity Inventory to assess lifetime stressor exposure and perceived stressor severity in 127 autistic and 104 nonautistic adults. Moderated mediation analysis examined associations between stressor exposure and physical and mental ill-health with respect to the hypothesized mediating role of stressor perception, and moderation effects of loneliness and social support. RESULTS: Autistic adults experienced more lifetime stressors and generally perceived stressors as being more severe. Greater perceived stressor severity was related to poorer physical and mental health and to greater loneliness and lower social support for both groups. An additional post hoc analysis of the association between diagnostic status and mental ill-health revealed that loneliness mediated the relation between being autistic and having poorer mental health. CONCLUSION: Autistic individuals experienced more lifetime stressors, and their impact on physical and mental health was mediated by perceived stressor severity. Moreover, loneliness and low social support were associated with greater negative impact of lifetime stress exposure on mental health. Interventions that reduce cognitive-perceptual stress appraisals, and that target loneliness and social support, may help reduce risk for stress-related disease in autistic individuals. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

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8. Naguy A, Pridmore S, Alamiri B. Autism and COVID-19: Clinical Considerations. The primary care companion for CNS disorders. 2021; 23(5).

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9. Quan L, Xu X, Cui Y, Han H, Hendren RL, Zhao L, You X. A systematic review and meta-analysis of the benefits of a gluten-free diet and/or casein-free diet for children with autism spectrum disorder. Nutrition reviews. 2022; 80(5): 1237-46.

CONTEXT: It has been suggested that a gluten-free and casein-free (GFCF) diet may alleviate the symptoms of autism spectrum disorder (ASD) and facilitate neurodevelopment of children with ASD. Studies to date have been inconclusive. OBJECTIVE: This study aimed to evaluate (through quantitative meta-analysis) the efficacy and safety of a GFCF diet for children with ASD. To our knowledge, this is the first time such an analysis has been carried out. DATA SOURCES: Eight electronic databases were searched, from the establishment of each database up to March 27, 2020: PubMed, Web of Science, Embase (Ovid), PsycINFO (Ovid), Cochrane Library, CNKI, Wanfang, and VIP databases. DATA EXTRACTION: Two authors independently performed the data extraction and risk-of-bias assessment. DATA ANALYSIS: A quantitative meta-analysis was performed with standard procedures by using Stata SE 15 software. Within the total of 8 studies, with 297 participants, 5 studies reported significant reductions in stereotypical behaviors [standard mean difference (SMD) = -0.41, 95% confidence interval (CI): -0.68 to -0.15], and 3 studies reported improvements in cognition (SMD = -0.46, 95% CI: -0.91 to -0.01) following GFCF dietary intervention . No statistically significant changes were observed in other symptomatic categories (all P > 0.05). CONCLUSION: The current meta-analysis showed that a GFCF diet can reduce stereotypical behaviors and improve the cognition of children with ASD. Though most of the included studies were single-blind, the benefits of a GFCF diet that have been indicated are promising. Additional studies on a larger scale are warranted. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration no. CRD42020177619.

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10. Real-López M, Peraire M, Ramos-Vidal C, Nath D, Hervás A, Cortés X. [Involvement of intestinal dysbiosis in the etiopathogenesis and treatment of autism spectrum disorder: a bibliographic review]. Revista de neurologia. 2021; 73(8): 282-95.

INTRODUCTION: Autism spectrum disorder is a neurodevelopmental disorder with phenotypic heterogeneity and variable symptomatic course of partly unknown etiology. The prevalence of gastrointestinal disorders in autism leads to investigate the role that intestinal microbiota may have as a causal factor and to propose specific therapeutic interventions. The role of microbiota in brain development and function, demonstrated in animal models, justifies its investigation in this neuropsychiatric disorder. OBJECTIVE: The aim was to investigate the relationship between altered microbiota composition and autism spectrum disorder, and to assess the therapeutic role of prebiotics, probiotics and fecal transplantation in this neurodevelopmental disorder. DEVELOPMENT: A literature review was conducted in PubMed, Cochrane Library and Google Scholar to select relevant articles related to the topic that were published between January 2012 and April 2020. Thirty-five relevant articles were selected. In 23 of them, significant differences were found in the composition and diversity of the microbiota in children with ASD, as well as in the biomolecules involved in certain metabolic pathways. The other 12 investigations reported gastrointestinal and behavioral improvements after therapeutic intervention. CONCLUSIONS: It is reasonable to state that there is enough evidence to support the existence of a relationship between intestinal microbiota and autism spectrum disorders. This fact should be explored in depth to assess the etiopathogenic burden of dysbiosis and the possible therapeutic tools.

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11. Sacrey LR, Zwaigenbaum L, Brian JA, Smith IM, Armstrong V, Raza S, Vaillancourt T, Schmidt LA. Affect and gaze responses during an Emotion-Evoking Task in infants at an increased likelihood for autism spectrum disorder. Molecular autism. 2021; 12(1): 63.

BACKGROUND: The majority of research examining emotional difficulties in autism spectrum disorder (ASD) prior to age 2 relies on parent report. METHODS: We examined behavioral responses (affect and gaze) during emotionally salient tasks designed to elicit mildly positive and negative emotional states in infants. At 12 and 18 months, infants at an increased likelihood for an ASD diagnosis (IL; have an older sibling with ASD; n = 60) and low likelihood (LL; no family history of ASD; n = 21) completed the Emotion-Evoking (EE) Task and parents completed the Infant Behavior Questionnaire-Revised (IBQ-R). All children received an Autism Diagnostic Observation Scale-second Edition assessment for ASD symptomatology at 24 months. RESULTS: The main findings were (1) the IL group displayed higher rates of negative affect and spent less time looking at the task objects compared to the LL group, and (2) affect and gaze scores at 12 and 18 months, but not scores on the IBQ-R, predicted ASD symptoms at 24 months. LIMITATIONS: The data were drawn from an IL sample and may not be generalizable to the general ASD population, and the children were not followed to determine a diagnosis of ASD. CONCLUSION: These results suggest that behavioral responses can provide important information that complements parent reports of emotional regulation in IL infants as early as 12 months of age.

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12. Sapey-Triomphe LA, Temmerman J, Puts NAJ, Wagemans J. Prediction learning in adults with autism and its molecular correlates. Molecular autism. 2021; 12(1): 64.

BACKGROUND: According to Bayesian hypotheses, individuals with Autism Spectrum Disorder (ASD) have difficulties making accurate predictions about their environment. In particular, the mechanisms by which they assign precision to predictions or sensory inputs would be suboptimal in ASD. These mechanisms are thought to be mostly mediated by glutamate and GABA. Here, we aimed to shed light on prediction learning in ASD and on its neurobiological correlates. METHODS: Twenty-six neurotypical and 26 autistic adults participated in an associative learning task where they had to learn a probabilistic association between a tone and the rotation direction of two dots, in a volatile context. They also took part in magnetic resonance spectroscopy (MRS) measurements to quantify Glx (glutamate and glutamine), GABA + and glutathione in a low-level perceptual region (occipital cortex) and in a higher-level region involved in prediction learning (inferior frontal gyrus). RESULTS: Neurotypical and autistic adults had their percepts biased by their expectations, and this bias was smaller for individuals with a more atypical sensory sensitivity. Both groups were able to learn the association and to update their beliefs after a change in contingency. Interestingly, the percentage of correct predictions was correlated with the Glx/GABA + ratio in the occipital cortex (positive correlation) and in the right inferior frontal gyrus (negative correlation). In this region, MRS results also showed an increased concentration of Glx in the ASD group compared to the neurotypical group. LIMITATIONS: We used a quite restrictive approach to select the MR spectra showing a good fit, which led to the exclusion of some MRS datasets and therefore to the reduction of the sample size for certain metabolites/regions. CONCLUSIONS: Autistic adults appeared to have intact abilities to make predictions in this task, in contrast with the Bayesian hypotheses of ASD. Yet, higher ratios of Glx/GABA + in a frontal region were associated with decreased predictive abilities, and ASD individuals tended to have more Glx in this region. This neurobiological difference might contribute to suboptimal predictive mechanisms in ASD in certain contexts.

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13. Sprong MCA, Broeders W, van der Net J, Breur J, de Vries LS, Slieker MG, van Brussel M. Motor Developmental Delay After Cardiac Surgery in Children With a Critical Congenital Heart Defect: A Systematic Literature Review and Meta-analysis. Pediatric physical therapy : the official publication of the Section on Pediatrics of the American Physical Therapy Association. 2021; 33(4): 186-97.

PURPOSE: To systematically review evidence regarding the severity and prevalence of motor development in children with a critical congenital heart defect (CCHD) without underlying genetic anomalies. SUMMARY OF KEY POINTS: Twelve percent of all included studies reported abnormal mean motor developmental scores, and 38% reported below average motor scores. Children with single-ventricle physiology, especially those with hypoplastic left heart syndrome, had the highest severity and prevalence of motor delay, particularly at 0 to 12 months. Most included studies did not differentiate between gross and fine motor development, yet gross motor development was more affected. RECOMMENDATIONS FOR CLINICAL PRACTICE: We recommend clinicians differentiate between the type of heart defect, fine and gross motor development, and the presence of genetic anomalies. Furthermore, increased knowledge about severity and prevalence will enable clinicians to tailor their interventions to prevent motor development delays in CCHD.

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14. Stagg S, Tan LH, Kodakkadan F. Emotion Recognition and Context in Adolescents with Autism Spectrum Disorder. Journal of autism and developmental disorders. 2021.

Emotion recognition research in autism has provided conflicting results and has ignored the role of context. We examined if autistic adolescents use context to identify displayed and felt emotion. Twenty adolescents with autism and 20 age-matched neurotypical adolescents identified emotions from a standardised set of images. The groups also viewed videos scenes with actors displaying a feigned emotion masking their true feelings. Participants identified the displayed and felt emotions. Both groups identified emotions from static images equally well. In the video condition, the autism group was unable to distinguish between the displayed and felt emotions. Emotion research is often divorced from context. Our findings suggest that autistic individuals have difficulty integrating contextual cues when processing emotions.

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15. Thakur A, Pereira C, Hardy J, Bobbette N, Sockalingam S, Lunsky Y. Virtual Education Program to Support Providers Caring for People With Intellectual and Developmental Disabilities During the COVID-19 Pandemic: Rapid Development and Evaluation Study. JMIR mental health. 2021; 8(10): e28933.

BACKGROUND: People with intellectual and developmental disabilities are at increased health-related risk due to the COVID-19 pandemic. Virtual training programs that support providers in caring for the physical and mental health needs of this population, as well provide psychological support to the providers themselves, are needed during the pandemic. OBJECTIVE: This paper describes the design, delivery, and evaluation of a virtual educational COVID-19-focused Extension for Community Healthcare Outcomes program to support providers during the COVID-19 pandemic in caring for the mental health of people with intellectual and developmental disabilities. METHODS: A rapid design thinking approach was used to develop a 6-session program that incorporates mindfulness practice, a wellness check, COVID-19-related research and policy updates, a didactic presentation on a combination mental health and COVID-19 related topic, and a case-based discussion to encourage practical learning. We used the first 5 outcome levels of Moore’s evaluation framework-focusing on participation, satisfaction, learning, self-efficacy, and change in practice-which were rated (out of 5) by care providers from health and disability service sectors, as well as additional reflection measures about innovations to the program. Qualitative feedback from open-text responses from participants were analyzed using modified manifest content analysis. RESULTS: A total of 104 care providers from health and disability service sectors participated in the program. High levels of engagement (81 participants per session on average) and satisfaction (overall satisfaction score: mean 4.31, SD 0.17) were observed. Self-efficacy (score improvement: 19.8%), support, and coping improved. Participants also rated the newly developed COVID-19 program and its innovative components highly. Open text feedback showed participants felt that the Extension for Community Healthcare Outcomes program expanded their knowledge and competency and created a sense of being part of a community of practice; provided value for the COVID-19 innovations; supported resource-sharing within and beyond program participants; and facilitated changes to participants’ approaches to client care in practice and increased participants’ confidence in supporting clients and families. CONCLUSIONS: The Extension for Community Healthcare Outcomes program is an effective model for capacity-building programs with a shared-learning approach. Future iterations should include targeted evaluation of long-term outcomes such as staff burnout.

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16. Volkmar FR. Celebrating 40 years since DSM-III. Journal of autism and developmental disorders. 2021; 51(12): 4251-2.

This special section celebrates the first official recognition of Autism as a diagnostic concept in 1980 in the third edition of the American Psychiatric Association’s Diagnostic and Statistical Manual. The articles in this special section note the many areas of significant progress made as well as areas that remain important topics for continued and future research. The official recognition of autism as a diagnostic concept has significantly advanced both clinical work and research.

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17. Wieckowski AT, Thomas RP, Chen CA, Zitter A, Fein DA, Barton ML, Adamson LB, Robins DL. Effect of Brief Training to Identify Autism Spectrum Disorder During Toddler Well-Child Care Visits. Journal of developmental and behavioral pediatrics : JDBP. 2021; 42(8): 666-71.

OBJECTIVE: To examine the effect of a brief Enhanced training using the information-motivation-behavior (IMB) change model on improving providers’ surveillance rates and accuracy of autism spectrum disorder (ASD) detection. METHOD: Toddlers (n = 5,672) were screened for ASD during their pediatric well-child visits. Pediatric providers (n = 120) were randomized to receive Enhanced (incorporating components of the IMB model) or Control training. Providers indicated whether they had an ASD concern at each well-child visit. Toddlers who were positive on any screener and/or whose provider indicated ASD concern were invited for a diagnostic evaluation. Differences in provider-indicated ASD concerns before and after training were evaluated using log-linear analyses. RESULTS: The Enhanced training did not have a significant effect on provider-endorsed ASD concerns (p = 0.615) or accuracy of endorsing concerns (p = 0.619). Providers in the Control training showed a significant reduction in indicating whether or not they had concerns after the training (from 71.9% to 64.3%), which did not occur in the Enhanced group. The Enhanced training led to more frequent endorsements of language (χ2 = 8.772, p = 0.003) and restricted and repetitive behavior (χ2 = 7.918, p = 0.005) concerns for children seen after training. CONCLUSION: Provider training had limited impact on ASD surveillance, indicating the importance of using formal screening instruments that rely on parent report during well-child visits to complement developmental surveillance. Future research should examine whether providers who indicate specific concerns are more likely to accurately refer children for ASD evaluations.

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18. Zhang Z, Gibson JR, Huber KM. Experience-dependent weakening of callosal synaptic connections in the absence of postsynaptic FMRP. eLife. 2021; 10.

Reduced structural and functional interhemispheric connectivity correlates with the severity of Autism Spectrum Disorder (ASD) behaviors in humans. Little is known of how ASD-risk genes regulate callosal connectivity. Here, we show that Fmr1, whose loss-of-function leads to Fragile X Syndrome (FXS), cell autonomously promotes maturation of callosal excitatory synapses between somatosensory barrel cortices in mice. Postnatal, cell-autonomous deletion of Fmr1 in postsynaptic Layer (L) 2/3 or L5 neurons results in a selective weakening of AMPA receptor- (R), but not NMDA receptor-, mediated callosal synaptic function, indicative of immature synapses. Sensory deprivation by contralateral whisker trimming normalizes callosal input strength, suggesting that experience-driven activity of postsynaptic Fmr1 KO L2/3 neurons weakens callosal synapses. In contrast to callosal inputs, synapses originating from local L4 and L2/3 circuits are normal, revealing an input-specific role for postsynaptic Fmr1 in regulation of synaptic connectivity within local and callosal neocortical circuits. These results suggest direct cell autonomous and postnatal roles for FMRP in development of specific cortical circuits and suggest a synaptic basis for long-range functional underconnectivity observed in FXS patients.

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