Hussman Institute for Autism

ABCA7 (ATP-binding cassette sub-family A member 7) encodes a lipid transporter linked to Alzheimers disease (AD). While common variants confer modest risk in Europeans, a 44-base pair deletion (rs142076058; p.Arg578Alafs) is a strong risk factor in African Americans (AA). Despite this, the biological consequences of this ancestry-specific variant are not well understood. We expressed the truncated ABCA7 protein in HEK and HepG2 cells to assess localization and lipid metabolism. Additionally, induced pluripotent stem cell (iPSC)-derived neurons carrying the deletion were compared with isogenic controls. The truncated ABCA7 localized to the plasma membrane similarly to wild type but induced significant lipid droplet accumulation in HepG2 cells and iPSC-derived neurons. These findings show that the AA-specific ABCA7 deletion disrupts lipid regulation despite normal localization, suggesting a mechanistic link between impaired lipid homeostasis and increased AD risk. This work underscores the importance of ancestry-specific studies in AD research.

EDITORIAL article Front. Cell. Neurosci., 28 September 2021 | https://doi.org/10.3389/fncel.2021.760994

During postnatal development of the visual cortex between eye-opening to puberty, visual experience promotes a gradual increase in the strength of inhibitory synaptic connections from parvalbumin-positive interneurons (PV-INs) onto layer 2/3 pyramidal cells. However, the detailed connectivity properties and molecular mechanisms underlying these developmental changes are not well understood. Using dual-patch clamp in brain slices from G42 mice, we revealed that both connection probability and the number of synaptic release sites contributed to the enhancement of synaptic strength. The increase of release site number was hindered by dark rearing from eye-opening and rescued by 3-days re-exposure to the normal visual environment. The effect of light re-exposure on restoring synaptic release sites in dark reared mice was mimicked by the agonist of cannabinoid-1 (CB1) receptors and blocked by an antagonist of these receptors, suggesting a role for endocannabinoid signaling in light-induced maturation of inhibitory connectivity from PV-INs to pyramidal cells during postnatal development.

Abstract Autism spectrum disorder (ASD) is a neurological condition characterized by alterations in social interaction and communication, and restricted and/or repetitive behaviors. The classical type II cadherins cadherin-8 (Cdh8, CDH8) and cadherin-11 (Cdh11, CDH11) have been implicated as autism risk gene candidates. To explore the role of cadherins in the etiology of autism, we investigated their expression patterns during mouse brain development and in autism-specific human tissue. In mice, expression of cadherin-8 and cadherin-11 was developmentally regulated and enriched in the cortex, hippocampus, and thalamus/striatum during the peak of dendrite formation and synaptogenesis. Both cadherins were expressed in synaptic compartments but only cadherin-8 associated with the excitatory synaptic marker neuroligin-1. Induced pluripotent stem cell (iPSC)-derived cortical neural precursor cells (NPCs) and cortical organoids generated from individuals with autism showed upregulated CDH8 expression levels while CDH11 expression levels were downregulated. We used Cdh11 knockout mice of both sexes to analyze the function of cadherin-11, which could help explain phenotypes observed in autism. Cdh11-/- hippocampal neurons exhibited increased dendritic complexity along with altered neuronal and synaptic activity. Similar to the expression profiles in human tissue, levels of cadherin-8 were significantly elevated in Cdh11 knockout brains. Additionally, excitatory synaptic markers neuroligin-1 and PSD-95 were both increased. Together, these results strongly suggest that cadherin-11 is involved in regulating the development of neuronal circuitry and that alterations in the expression levels of cadherin-11 may contribute to the etiology of autism.Significance StatementAutism is a neurodevelopmental condition with high genetic and phenotypic heterogeneity. Multiple genes have been implicated in autism, including the cadherin superfamily of adhesion molecules, cadherin-8 and cadherin-11. This study first characterizes the expression profiles of cadherin-8 and cadherin-11 to understand the potential roles they play in the development of neurons. The study further describes novel contributions of cadherin-11 in neural circuit formation. Loss of cadherin-11 in mice results in altered levels of several synaptic proteins, including PSD-95, neuroligin-1, and cadherin-8, and changes the morphology and activity of excitatory neurons. The levels of cadherin-8 and cadherin-11 in human cells of autistic individuals are both altered, strengthening the hypothesis that these two cadherins may involve in aspects of autism etiology.

Abstract BackgroundDuring brain development, a multitude of neuronal networks form as neurons find their correct position within the brain and send out axons to synapse onto specific targets. Altered neuronal connectivity within these complex networks has been reported in Autism Spectrum Disorder (ASD), leading to alterations in brain function and multisensory integration. Semaphorins (also referred to as Semas), a large protein family of about 30 members, have been shown to play an important role in neuronal circuit formation and have been implicated in the etiology of ASD. The purpose of the current study is to investigate howSema6Amutation affects neuronal connectivity in ASD. SinceSema6Ais involved in cell migration, we hypothesized that during brain development the migration of GABAergic interneurons is affected by the loss ofSema6Agene, leading to alterations in Excitatory/Inhibitory (E/I) balance.MethodsSema6Atransgenic mice were crossed with either GAD65-GFP mice or GAD67-GFP mice to allow for both a reliable and robust staining of the GABAergic interneuron population within theSema6Amouse line. Using histological techniques we studies the expression of interneurons subtypes in the Sema6A mutant mice.ResultsAnalysis ofSema6Amutant mice crossed with either GAD65-GFP or GAD67-GFP knock-in mice revealed a reduced number of GABAergic interneurons in the primary somatosensory cortex, hippocampus, and reticular thalamic nucleus (RTN) in adultSema6Amutant mice. This reduction in cell number appeared to be targeted to the Parvalbumin (PV) interneuron cell population since neither the Calretinin nor the Calbindin expressing interneurons were affected by theSema6Amutation.LimitationsAlthough the use of animal models has been crucial for understanding the biological basis of autism, the complexity of the human brain can never truly be replicated by these models.ConclusionsTaken together, these findings suggest thatSema6Agene loss affects only the fast spiking-PV population and reveal the importance of an axon guidance molecule in the formation of GABAergic neuronal networks and provide insight into the molecular pathways that may lead to altered neuronal connectivity and E/I imbalance in ASD.

Results of recent genome-wide association studies (GWAS) and whole genome sequencing (WGS) highlighted type II cadherins as risk genes for autism spectrum disorders (ASD). To determine whether these cadherins may be linked to the morphogenesis of ASD-relevant brain regions, in situ hybridization (ISH) experiments were carried out to examine the mRNA expression profiles of two ASD-associated cadherins, Cdh9 and Cdh11, in the developing cerebellum. During the first postnatal week, both Cdh9 and Cdh11 were expressed at high levels in segregated sub-populations of Purkinje cells in the cerebellum, and the expression of both genes was declined as development proceeded. Developmental expression of Cdh11 was largely confined to dorsal lobules (lobules VI/VII) of the vermis as well as the lateral hemisphere area equivalent to the Crus I and Crus II areas in human brains, areas known to mediate high order cognitive functions in adults. Moreover, in lobules VI/VII of the vermis, Cdh9 and Cdh11 were expressed in a complementary pattern with the Cdh11-expressing areas flanked by Cdh9-expressing areas. Interestingly, the high level of Cdh11 expression in the central domain of lobules VI/VII was correlated with a low level of expression of the Purkinje cell marker calbindin, coinciding with a delayed maturation of Purkinje cells in the same area. These findings suggest that these two ASD-associated cadherins may exert distinct but coordinated functions to regulate the wiring of ASD-relevant circuits in the cerebellum.

Potentially pathogenic alterations have been identified in individuals with autism spectrum disorders (ASDs) within a variety of key neurodevelopment genes. While this hints at a common ASD molecular etiology, gaps persist in our understanding of the neurodevelopmental mechanisms impacted by genetic variants enriched in ASD patients. Induced pluripotent stem cells (iPSCs) can model neurodevelopment in vitro, permitting the characterization of pathogenic mechanisms that manifest during corticogenesis. Taking this approach, we examined the transcriptional differences between iPSC-derived cortical neurons from patients with idiopathic ASD and unaffected controls over a 135-day course of neuronal differentiation. Our data show ASD-specific misregulation of genes involved in neuronal differentiation, axon guidance, cell migration, DNA and RNA metabolism, and neural region patterning. Furthermore, functional analysis revealed defects in neuronal migration and electrophysiological activity, providing compelling support for the transcriptome analysis data. This study reveals important and functionally validated insights into common processes altered in early neuronal development and corticogenesis and may contribute to ASD pathogenesis.