Can biomarkers that measure things like visual social attention be a good proxy for an in person behavioral diagnosis? Why would this be important? This week’s podcast explores two new studies the the Journal of the American Medical Association that show a simple device called EarliPoint can be used to shorten the wait times to receive a diagnostic evaluation. Currently autism can be diagnosed at 18 months but most families do not get into an appointment until 4-5 years of age. That can change. Families were able to easily complete it, it predicted things like not just a diagnosis but behavioral features and cognitive ability. It’s been deployed in 6 speciality centers, been approved by the FDA, and hopefully coming to a clinic near you soon.
Podcast: Now you know the reason for decades of eye tracking research
Abstract
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.
Abstract
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.
Abstract
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.
Abstract
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.
Abstract
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.
This week’s podcast covers two new papers of interest to the autism community. First, another study showing increase in self harm and suicide in those with autism – no new news there – but a new discovery this week showed a vulnerability of females with a diagnosis. The study also explores the lower rate of suicide in those with IDD but higher rate of self harm in this same group. Second, the mystery of autism genetics is slowly unveiled. Why is rare variation so influential in an autism diagnosis? As it turns out those with rare variation also have common variation, piling on the genetic liability in this group. Common variation is also uniquely linked to language delay in autism, so is this a core feature? Links below are the scientific articles as well as resources to support those dealing with mental health problems in the autistic community.
Mental health links:
https://vkc.vumc.org/assets/files/resources/mental-health-toolkit.pdf
https://www.camh.ca/-/media/files/cundill-centre/depression-and-autism-full-pdf.pdf
https://www.azrieli-anc.com/autism-mental-healthhttps://www.autism.org.uk/advice-and-guidance/topics/mental-health/suicide#How%20do%20I%20get%20help%20and%20support
Articles:
https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2808056
Genetics study is OPEN ACCESS: https://www.pnas.org/doi/abs/10.1073/pnas.2215632120?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub++0pubmed
On this week’s ASF podcast: there are dozens of good reasons why scientists need to study the brains of people with autism. One is to understand what happens in the brain as people with autism get older and see how the brain changes over time. Another is to identify mechanisms of autism to help all neuroscientists figure out how the brain works. A third is improve medicine by determining what helps what people at what age. Scientists @UCDavis, @Penn and @UCLA examined the individual brain cells of people with autism to address these three questions, revealing that the autistic brain shows some similarities to brains of people with Alzheimer’s Disease. In addition, inflammation seen in the brain may be caused by too much activity of cells talking to each other. Studying the brains of people with autism is essential to better understanding and is made possible by families who are committed to research.
The title gets you, right? Well, on this week’s podcast we report on a new study that examines epigenetic profiles of sperm and how they related to child outcomes. Do some of the marks on bio-dad’s sperm match to those found in kids with ASD? what about genes related to autism? Also, can parents be good proxies of their child’s intellectual ability? For the most part yes, but sometimes they tend to overestimate this ability. This means they are good, but not perfect reporters. How could they be if the child has a severe intellectual disability?
Defects in interneuron migration can disrupt the assembly of cortical circuits and lead to neuropsychiatric disease. Using forebrain assembloids derived by integration of cortical and ventral forebrain organoids, we have previously discovered a cortical interneuron migration defect in Timothy syndrome (TS), a severe neurodevelopmental disease caused by a mutation in the L-type calcium channel (LTCC) Cav1.2. Here, we find that acute pharmacological modulation of Cav1.2 can regulate the saltation length, but not the frequency, of interneuron migration in TS. Interestingly, the defect in saltation length is related to aberrant actomyosin and myosin light chain (MLC) phosphorylation, while the defect in saltation frequency is driven by enhanced γ-aminobutyric acid (GABA) sensitivity and can be restored by GABA-A receptor antagonism. Finally, we describe hypersynchronous hCS network activity in TS that is exacerbated by interneuron migration. Taken together, these studies reveal a complex role of LTCC function in human cortical interneuron migration and strategies to restore deficits in the context of disease.
Keywords: GABA; Timothy syndrome; assembloids; calcium; interneurons; organoids.
Background: Fragile X syndrome (FXS) is the most prevalent form of inherited intellectual disability and is commonly associated with autism. Previous studies have linked the structural and functional alterations in FXS with impaired sensory processing and sensory hypersensitivity, which may hinder the early development of cognitive functions such as language comprehension. In this study, we compared the P1 response of the auditory evoked potential and its habituation to repeated auditory stimuli in male children (2-7 years old) with and without FXS, and examined their association with clinical measures in these two groups.
Methods: We collected high-density electroencephalography (EEG) data in an auditory oddball paradigm from 12 male children with FXS and 11 age- and sex-matched typically developing (TD) children. After standardized EEG pre-processing, we conducted a spatial principal component (PC) analysis and identified two major PCs-a frontal PC and a temporal PC. Within each PC, we compared the P1 amplitude and inter-trial phase coherence (ITPC) between the two groups, and performed a series of linear regression analysis to study the association between these EEG measures and several clinical measures, including assessment scores for language abilities, non-verbal skills, and sensory hypersensitivity.
Results: At the temporal PC, both early and late standard stimuli evoked a larger P1 response in FXS compared to TD participants. For temporal ITPC, the TD group showed greater habituation than the FXS group. However, neither group showed significant habituation of the frontal or temporal P1 response. Despite lack of habituation, exploratory analysis of brain-behavior associations observed that within the FXS group, reduced frontal P1 response to late standard stimuli, and increased frontal P1 habituation were both associated with better language scores.
Conclusion: We identified P1 amplitude and ITPC in the temporal region as a contrasting EEG phenotype between the FXS and the TD groups. However, only frontal P1 response and habituation were associated with language measures. Larger longitudinal studies are required to determine whether these EEG measures could be used as biomarkers for language development in patients with FXS.
Keywords: EEG; ERP; Fragile X syndrome; autism; language; neural habituation; phase coherence.
What do anxiety, prevalence, ketamine, other neurodevelopmental disorders, siblings, genetics, brain imaging and the autistic researcher committee at INSAR all have in common? They were all topics at the last Day of Learning. You can hear a 20 minute summary of the talks on this week’s ASFpodcast.