Elevated levels of FMRP-target MAP1B impair human and mouse neuronal development and mouse social behaviors via autophagy pathway


Fragile X messenger ribonucleoprotein 1 protein (FMRP) binds many mRNA targets in the brain. The contribution of these targets to fragile X syndrome (FXS) and related autism spectrum disorder (ASD) remains unclear. Here, we show that FMRP deficiency leads to elevated microtubule-associated protein 1B (MAP1B) in developing human and non-human primate cortical neurons. Targeted MAP1B gene activation in healthy human neurons or MAP1B gene triplication in ASD patient-derived neurons inhibit morphological and physiological maturation. Activation of Map1b in adult male mouse prefrontal cortex excitatory neurons impairs social behaviors. We show that elevated MAP1B sequesters components of autophagy and reduces autophagosome formation. Both MAP1B knockdown and autophagy activation rescue deficits of both ASD and FXS patients’ neurons and FMRP-deficient neurons in ex vivo human brain tissue. Our study demonstrates conserved FMRP regulation of MAP1B in primate neurons and establishes a causal link between MAP1B elevation and deficits of FXS and ASD.

Purpose: Daily mood can be influenced by a range of experiences. Identifying everyday life experiences that make autistic adults happy and unhappy holds potential to foster positive mood and tackle mental health problems amongst this group.

Methods: A total of 293 autistic adults between the ages of 18 to 35 years old (mean age of 26.51 years old (SD = 4.62); 43.3% female gender, 4.8% nonbinary) provided open-text responses regarding everyday sources of happiness and unhappiness. Using an iterative process of inductive coding, 14 happy themes and 22 unhappy themes of mood-changing life experiences were identified based on self-report qualitative data.

Results: Common themes across the happy and unhappy domain involved social partners, social interactions, and engagement in recreational and employment activities, with additional distinct themes specific to happy or unhappy mood. Top themes identified in the happy domain emphasizes encouraging quality relationships and positive interactions with others and cultivating supportive work/societal environments to build a sense of achievement and value. Meanwhile, emotional tolls accompanied negative relationships and interactions, underscoring the necessity to provide autistic adults with conflict resolution and coping skills to increase feelings of happiness.

Conclusion: Overall, the wide range of sources of happy and unhappy everyday experiences highlights the importance of considering personal preferences in engagement with others and activities in treatment.

Keywords: Adulthood; Autism; Daily life experiences; Happiness; Mood; Qualitative study.


Social motivation is critical to the development of typical social functioning. Social motivation, specifically one or more of its components (e.g., social reward seeking or social orienting), could be relevant for understanding phenotypes related to autism. We developed a social operant conditioning task to quantify effort to access a social partner and concurrent social orienting in mice. We established that mice will work for access to a social partner, identified sex differences, and observed high test-retest reliability. We then benchmarked the method with two test-case manipulations. Shank3B mutants exhibited reduced social orienting and failed to show social reward seeking. Oxytocin receptor antagonism decreased social motivation, consistent with its role in social reward circuitry. Overall, we believe that this method provides a valuable addition to the assessment of social phenotypes in rodent models of autism and the mapping of potentially sex-specific social motivation neural circuits.

Keywords: Shank3b; autism; behavioral assay; mice; operant conditioning; oxytocin; sex differences; sociability; social motivation.


Understanding the neural processes underpinning individual differences in early language development is of increasing interest, as it is known to vary in typical development and to be quite heterogeneous in neurodevelopmental conditions. However, few studies to date have tested whether early brain measures are indicative of the developmental trajectory of language, as opposed to language outcomes at specific ages. We combined recordings from two longitudinal studies, including typically developing infants without a family history of autism, and infants with increased likelihood of developing autism (infant-siblings) (N = 191). Electroencephalograms (EEG) were recorded at 6 months, and behavioral assessments at 6, 12, 18, 24 and 36 months of age. Using a growth curve model, we tested whether absolute EEG spectral power at 6 months was associated with concurrent language abilities, and developmental change in language between 6 and 36 months. We found evidence of an association between 6-month alpha-band power and concurrent, but not developmental change in, expressive language ability in both infant-siblings and control infants. The observed association between 6-month alpha-band power and 6-month expressive language was not moderated by group status, suggesting some continuity in neural mechanisms.


The COVID-19 pandemic elicited increases in anxiety and depression in youth, and youth on the autism spectrum demonstrate elevations in such symptoms pre-pandemic. However, it is unclear whether autistic youth experienced similar increases in internalizing symptoms after the COVID-19 pandemic onset or whether decreases in these symptoms were present, as speculated in qualitative work. In the current study, longitudinal changes in anxiety and depression during the COVID-19 pandemic in autistic youth were assessed in comparison to nonautistic youth. A well-characterized sample of 51 autistic and 25 nonautistic youth (ageM = 12.8, range = 8.5-17.4 years, IQ > 70) and their parents completed the Revised Children’s Anxiety and Depression Scale (RCADS), a measure of internalizing symptoms, repeatedly, representing up to 7 measurement occasions from June to December 2020 (N ~ 419 occasions). Multilevel models were used to evaluate changes in internalizing symptoms over time. Internalizing symptoms did not differ between autistic and nonautistic youth in the summer of 2020. As reported by youth themselves, internalizing symptoms decreased in autistic youth, both overall and compared to nonautstic peers. This effect was driven by decreases in generalized anxiety, social anxiety, and depression symptoms in autistic youth. Reductions in generalized anxiety, social anxiety, and depression in autistic youth may be due to COVID-19 pandemic-specific differences in response to social, environmental, and contextual changes that unfolded in 2020. This highlights the importance of understanding unique protective and resilience factors that may be evident in autistic individuals in response to broad societal shifts such as those seen in response to COVID-19.

Keywords: adolescents; anxiety; co-morbid conditions; depression; longitudinal data analysis.


Advancing from gene discovery in autism spectrum disorders (ASDs) to the identification of biologically relevant mechanisms remains a central challenge. Here, we perform parallel in vivo functional analysis of 10 ASD genes at the behavioral, structural, and circuit levels in zebrafish mutants, revealing both unique and overlapping effects of gene loss of function. Whole-brain mapping identifies the forebrain and cerebellum as the most significant contributors to brain size differences, while regions involved in sensory-motor control, particularly dopaminergic regions, are associated with altered baseline brain activity. Finally, we show a global increase in microglia resulting from ASD gene loss of function in select mutants, implicating neuroimmune dysfunction as a key pathway relevant to ASD biology.

Keywords: CP: Neuroscience; autism spectrum disorder; dopaminergic neurons; genetics; microglia; neurodevelopment; zebrafish.


Chromatin dysregulation has emerged as a major hallmark of neurodevelopmental disorders such as intellectual disability (ID) and autism spectrum disorders (ASD). The prevalence of ID and ASD is higher in males compared to females, with unknown mechanisms. Intellectual developmental disorder, X-linked syndromic, Claes-Jensen type (MRXSCJ), is caused by loss-of-function mutations of lysine demethylase 5C (KDM5C), a histone H3K4 demethylase gene. KDM5C escapes X-inactivation, thereby presenting at a higher level in females. Initially, MRXSCJ was exclusively reported in males, while it is increasingly evident that females with heterozygous KDM5C mutations can show cognitive deficits. The mouse model of MRXSCJ, male Kdm5c-hemizygous knockout animals, recapitulates key features of human male patients. However, the behavioral and molecular traits of Kdm5c-heterozygous female mice remain incompletely characterized. Here, we report that gene expression and behavioral abnormalities are readily detectable in Kdm5c-heterozygous female mice, demonstrating the requirement for a higher KDM5C dose in females. Furthermore, we found both shared and sex-specific consequences of a reduced KDM5C dose in social behavior, gene expression, and genetic interaction with the counteracting enzyme KMT2A. These observations provide an essential insight into the sex-biased manifestation of neurodevelopmental disorders and sex chromosome evolution.

Keywords: chromatin regulators; histone demethylase; learning and memory; neurodevelopmental disorders; x-linked intellectual disability.

Background: Fidelity, or the degree to which an intervention is implemented as designed, is essential for effective implementation. There has been a growing emphasis on assessing fidelity of evidence-based practices for autistic children in schools. Fidelity measurement should be multidimensional and focus on core intervention components and assess their link with program outcomes. This study evaluated the relation between intervention fidelity ratings from multiple sources, tested the relation between fidelity ratings and child outcomes, and determined the relations between core intervention components and child outcomes in a study of an evidence-based psychosocial intervention designed to promote inclusion of autistic children at school, Remaking Recess.

Method: This study extends from a larger randomized controlled trial examining the effect of implementation support on Remaking Recess fidelity and child outcomes. Schools were randomized to receive the intervention or the intervention plus implementation support. Observers, intervention coaches, and school personnel completed fidelity measures to rate completion and quality of intervention delivery. A measure of peer engagement served as the child outcome. Pearson correlation coefficients were calculated to determine concordance between raters. Two sets of hierarchical linear models were conducted using fidelity indices as predictors of peer engagement.

Results: Coach- and self-rated completion and quality scores, observer- and self-rated quality scores, and observer- and coach-rated quality fidelity scores were significantly correlated. Higher observer-rated completion and quality fidelity scores were predictors of higher peer engagement scores. No single intervention component emerged as a significant predictor of peer engagement.

Conclusions: This study demonstrates the importance of using a multidimensional approach for measuring fidelity, testing the link between fidelity and child outcomes, and examining how core intervention components may be associated with child outcomes. Future research should clarify how to improve multi-informant reports to provide “good enough” ratings of fidelity that provide meaningful information about outcomes in community settings.

Plain language summary: Fidelity is defined as how closely an intervention is administered in the way the creators intended. Fidelity is important because it allows researchers to determine what exactly is leading to changes. In recent years, there has been an interest in examining fidelity of interventions for autistic children who receive services in school. This study looked at the relationship between fidelity ratings from multiple individuals, the relationship between fidelity and child outcomes, and the relationship between individual intervention component and child changes in a study of Remaking Recess, an intervention for autistic children at school. Schools were randomly selected to receive the intervention only or the intervention plus implementation support from the research team. Observers, intervention coaches, and individuals delivering the intervention themselves completed fidelity measures. Child engagement with peers was measured before and after the intervention. Several measures of self-, coach-, and observer-report fidelity were associated with each other. Higher observer-reported fidelity was associated with higher child peer engagement scores. No single intervention step was linked to child peer engagement and both treatment groups had similar outcomes in terms of fidelity. This study shows the importance of having multiple raters assess different parts of intervention fidelity, looking at the link between fidelity and child outcomes, and seeing how individual intervention steps may be related to outcomes. Future research should aim to find out which types of fidelity ratings are “good enough” to lead to positive changes following treatment so that those aspects can be used and targeted in the future.

Keywords: autism spectrum disorder; fidelity; implementation; school-based; social engagement intervention.

Objectives: Autism spectrum disorder (autism) is a heterogeneous condition that poses challenges in describing the needs of individuals with autism and making prognoses about future outcomes. We applied a newly proposed definition of profound autism to surveillance data to estimate the percentage of children with autism who have profound autism and describe their sociodemographic and clinical characteristics.

Methods: We analyzed population-based surveillance data from the Autism and Developmental Disabilities Monitoring Network for 20 135 children aged 8 years with autism during 2000-2016. Children were classified as having profound autism if they were nonverbal, were minimally verbal, or had an intelligence quotient <50.

Results: The percentage of 8-year-old children with profound autism among those with autism was 26.7%. Compared with children with non-profound autism, children with profound autism were more likely to be female, from racial and ethnic minority groups, of low socioeconomic status, born preterm or with low birth weight; have self-injurious behaviors; have seizure disorders; and have lower adaptive scores. In 2016, the prevalence of profound autism was 4.6 per 1000 8-year-olds. The prevalence ratio (PR) of profound autism was higher among non-Hispanic Asian/Native Hawaiian/Other Pacific Islander (PR = 1.55; 95 CI, 1.38-1.73), non-Hispanic Black (PR = 1.76; 95% CI, 1.67-1.86), and Hispanic (PR = 1.50; 95% CI, 0.88-1.26) children than among non-Hispanic White children.

Conclusions: As the population of children with autism continues to change, describing and quantifying the population with profound autism is important for planning. Policies and programs could consider the needs of people with profound autism across the life span to ensure their needs are met.

Keywords: autism; public health; surveillance.

Best practice for the assessment of autism spectrum disorder (ASD) symptom severity relies on clinician ratings of the Autism Diagnostic Observation Schedule, 2nd Edition (ADOS-2), but the association of these ratings with objective measures of children’s social gaze and smiling is unknown. Sixty-six preschool-age children (49 boys, M = 39.97 months, SD = 10.58) with suspected ASD (61 confirmed ASD) were administered the ADOS-2 and provided social affect calibrated severity scores (SA CSS). Children’s social gaze and smiling during the ADOS-2, captured with a camera contained in eyeglasses worn by the examiner and parent, were obtained via a computer vision processing pipeline. Children who gazed more at their parents (p = .04) and whose gaze at their parents involved more smiling (p = .02) received lower social affect severity scores, indicating fewer social affect symptoms, adjusted R2 = .15, p = .003.

Keywords: Autism diagnostic observation schedule; Autism spectrum disorder; Objective measurement; Smiling; Social gaze.

Individuals diagnosed with autism spectrum disorder (ASD) present with a highly diverse set of challenges, disabilities, impairments and strengths. Recently, it has been suggested that researchers and practitioners avoid using certain words to describe the difficulties and impairments experienced by individuals with ASD to reduce stigma. The proposed limitations on terminology were developed by only a subset of the autism community, and the recommendations are already causing negative consequences that may be harmful to future scientific and clinical endeavors and, ultimately, to people with ASD. No one should have the power to censor language to exclude the observable realities of autism. Scientists and clinicians must be able to use any scientifically accurate terms necessary to describe the wide range of autistic people they study and support, without fear of censure or retribution.

Keywords: Vocabulary; autism spectrum disorder; bias; language.

Literature examining emotional regulation in infants with autism spectrum disorder (ASD) has focused on parent report. We examined behavioral and physiological responses during an emotion-evoking task designed to elicit emotional states in infants. Infants at an increased likelihood for ASD (IL; have an older sibling with ASD; 96 not classified; 29 classified with ASD at age two) and low likelihood (LL; no family history of ASD; n = 61) completed the task at 6, 12, and 18 months. The main findings were (1) the IL-ASD group displayed higher levels of negative affect during toy removal and negative tasks compared to the IL non-ASD and LL groups, respectively, (2) the IL-ASD group spent more time looking at the baseline task compared to the other two groups, and (3) the IL-ASD group showed a greater increase in heart rate from baseline during the toy removal and negative tasks compared to the LL group. These results suggest that IL children who are classified as ASD at 24 months show differences in affect, gaze, and heart rate during an emotion-evoking task, with potential implications for understanding mechanisms related to emerging ASD.

Keywords: ASD; affect; autism; baby sibling; gaze; heart rate; physiology.