Uncovering convergence and divergence between autism and schizophrenia using genomic tools and patients’ neurons

Romanovsky, Eva; Choudhary, Ashwani; Peles, David; Akel, Ahmad Abu; Stern, Shani

doi:10.1101/2023.08.11.552921

Cited by 3 publications

(2 citation statements)

References 57 publications

(117 reference statements)

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“…Interestingly, this gene encodes a postsynaptic protein kinase substrate that binds to calmodulin in the absence of calcium. This gene was reported also as a key associated gene for both schizophrenia and Autism Spectrum Disorder [19,20]. Figure 3D presents the shared DEGs between control and schizophrenia-affected patients.…”

Section: Resultsmentioning

confidence: 93%

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Monozygotic twins discordant for schizophrenia differ in maturation and synaptic transmission

Stern,

Zhang,

Wang

et al. 2024

Mol Psychiatry

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Schizophrenia affects approximately 1% of the world population. Genetics, epigenetics, and environmental factors are known to play a role in this psychiatric disorder. While there is a high concordance in monozygotic twins, about half of twin pairs are discordant for schizophrenia. To address the question of how and when concordance in monozygotic twins occur, we have obtained fibroblasts from two pairs of schizophrenia discordant twins (one sibling with schizophrenia while the second one is unaffected by schizophrenia) and three pairs of healthy twins (both of the siblings are healthy). We have prepared iPSC models for these 3 groups of patients with schizophrenia, unaffected co-twins, and the healthy twins. When the study started the co-twins were considered healthy and unaffected but both the co-twins were later diagnosed with a depressive disorder. The reprogrammed iPSCs were differentiated into hippocampal neurons to measure the neurophysiological abnormalities in the patients. We found that the neurons derived from the schizophrenia patients were less arborized, were hypoexcitable with immature spike features, and exhibited a significant reduction in synaptic activity with dysregulation in synapse-related genes. Interestingly, the neurons derived from the co-twin siblings who did not have schizophrenia formed another distinct group that was different from the neurons in the group of the affected twin siblings but also different from the neurons in the group of the control twins. Importantly, their synaptic activity was not affected. Our measurements that were obtained from schizophrenia patients and their monozygotic twin and compared also to control healthy twins point to hippocampal synaptic deficits as a central mechanism in schizophrenia.

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Section: Resultsmentioning

confidence: 93%

“…Genome-wide association studies (GWAS) have been performed in schizophrenia with an approach to better understand the etiology of the disease. Many genes have been associated with schizophrenia [15][16][17][18][19][20]. Some of the associated genes include CACNA1C, DGCR8, DRD2, MIR137, NOS1AP, and NRXN1.…”

Section: Introductionmentioning

confidence: 99%

Monozygotic twins discordant for schizophrenia differ in maturation and synaptic transmission

Stern,

Zhang,

Wang

et al. 2024

Mol Psychiatry

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Genetic Overlap Between Inflammatory Bowel Disease and Neurological Disorders: Insights from GWAS and Gene Expression Analysis

Tripathi,

Stern,

Dagan

et al. 2024

Preprint

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Inflammatory Bowel Disease (IBD), which includes Crohn’s disease (CD) and Ulcerative Colitis (UC), is a complex and multifactorial condition marked by chronic inflammation of the gastrointestinal tract. This study leverages genome-wide association studies (GWAS) and gene expression data from the Genotype-Tissue Expression (GTEx) project to investigate IBD’s genetic and expression profiles and subtypes. We examined 207 studies related to IBD, 71 specific to CD, and 66 focused on UC, identifying both shared and unique genetic factors among these conditions. GWAS meta-analysis revealed the top IBD-associated genes, which include IL23R, NOD2, ATG16L1, HLA-DRB9, and more. Pathway enrichment analyses identified consistently enriched pathways such as the NF-kappa B signaling pathway, JAK-STAT signaling pathway, and cytokine-cytokine receptor interaction, all of which play critical roles in immune responses and inflammation. Gene Ontology (GO) term analysis highlighted processes like cytokine production, cell activation, and leukocyte activation, reinforcing their involvement in the pathogenesis of IBD. Gene expression analysis showed that genes associated with IBD are expressed not only in the gastrointestinal tract but also in various regions of the brain, suggesting potential links between IBD and neurological functions. Our study further explored the genetic overlap between IBD and several neurological disorders, including schizophrenia, depression, autism spectrum disorder, and attention-deficit/hyperactivity disorder, uncovering a shared genetic architecture. These findings emphasize the systemic nature of IBD and its potential neurological implications, paving the way for targeted therapeutic strategies that address both gastrointestinal and neurological aspects of the disease.

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Exosomes can modulate the early hyperexcitability in cortical neurons with ASD-associatedShank3mutation

Choudhary,

Rosh,

Hussein

et al. 2024

Preprint

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Shank3, a scaffolding protein, is critical for synaptic structure and function, particularly for the formation and maintenance of dendritic spines.Shank3mutations are strongly implicated in autism spectrum disorder (ASD) and related neuropsychiatric conditions such as Phelan-McDermid Syndrome (PMS) also known as the 22q13.3 deletion syndrome. Previous work has recognized early hyperexcitability in cortical neurons derived from ASD patients with various gene mutations as a potential common endophenotype. In this study, we examined the effects of exosomes extracted from several cell types on the neurophysiological properties of cortical neurons derived fromShank3(c.3679insG mutation) induced pluripotent stem cells (iPSCs). First, we sought to understand the implications of exosome-based intercellular communication on the neurophysiology ofShank3mutant and control neurons by switching their respective exosomes. We found that while control neuron-derived exosomes do not change the neurophysiology ofShank3neurons, theShank3neuron-derived exosomes transfer the early hyperexcitability and other ASD-related phenotypes to control neurons. Next, we also explored the therapeutic potential of mesenchymal stem cells (MSC) and iPSC-derived exosomes from healthy donors in theShank3cortical neurons. We demonstrate that both MSC and iPSC-derived exosomes rescue the early hyperexcitability and accelerated maturation ofShank3neurons. Proteomic analysis of exosomes derived fromShank3mutant and control neurons, as well as from exosomes derived from MSCs and iPSCs, revealed distinct protein cargoes that may cause changes in the neurophysiological properties of the recipient neurons. Our results hence provide novel insights into the pathophysiology of ASD emphasizing the importance of exosomes in intercellular communication and their potential to influence intrinsic and network properties of neurons. Moreover, our findings support the need for further exploration of exosome-based interventions as potential therapeutics for treating neurodevelopmental disorders.

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Uncovering convergence and divergence between autism and schizophrenia using genomic tools and patients’ neurons

Cited by 3 publications

References 57 publications

Monozygotic twins discordant for schizophrenia differ in maturation and synaptic transmission

Monozygotic twins discordant for schizophrenia differ in maturation and synaptic transmission

Genetic Overlap Between Inflammatory Bowel Disease and Neurological Disorders: Insights from GWAS and Gene Expression Analysis

Exosomes can modulate the early hyperexcitability in cortical neurons with ASD-associatedShank3mutation

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