The Role of Parvalbumin Interneurons in Autism Spectrum Disorder

Yao, Yiwei; Li, Qian

doi:10.1002/jnr.25391

Cited by 2 publications

References 111 publications

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Human stem cell-derived GABAergic interneuron development reveals early emergence of subtype diversity followed by gradual electrochemical maturation

Bershteyn,

Zhou,

Fuentealba

et al. 2024

Preprint

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Medial ganglionic eminence-derived inhibitory GABAergic pallial interneurons (MGE-pINs) are essential regulators of cortical circuits; their dysfunction is associated with numerous neurological disorders. We developed human (h) MGE-pINs from pluripotent stem cells for the treatment of drug-resistant epilepsy. Here, we analyzed xenografted hMGE-pINs over the lifespan of host mice using single nuclei RNA sequencing. Comparative transcriptomics against endogenous human brain datasets revealed that 97% of grafted cells developed into somatostatin (SST) and parvalbumin (PVALB) subtypes, including populations that exhibit selective vulnerability in Alzheimer′s disease. Transplanted hMGE-pINs demonstrated rapid emergence of subclass features, progressing through distinct transcriptional states sequentially involving neuronal migration, synapse organization, and membrane maturation. We present molecular, electrophysiological, and morphological data that collectively confirm the derivation of diverse bona-fide human SST and PVALB subtypes, providing a high-fidelity model to study human MGE-pIN development and functional maturation as well as a compositional atlas for regenerative cell therapy applications.

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Human stem cell-derived GABAergic interneuron development reveals early emergence of subtype diversity followed by gradual electrochemical maturation

Bershteyn,

Zhou,

Fuentealba

et al. 2024

Preprint

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Calcium Signaling and Molecular Adhesion Processes May Hold the Key to Genetic Risk for Autism: A Molecular Pathway Analysis on Two Independent Samples

Drago,

Calabro,

Crisafulli

2024

Genes

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Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by limited interests, difficulties in social interactions, repetitive behaviors, and impairments in social communication. ASD tends to run in families, and twin studies suggest a strong genetic basis for the disorder. However, the definition of a genetic profile that indicates a risk for ASD remains unclear. Methods: This analysis includes an investigation (Autism Dataset 4 from the NIMH repository, n = 2890) and a replication (Autism Dataset 3 from the NIMH repository, n = 1233) of trio samples with GWAS data. In Phase 1, a molecular pathway analysis is conducted on the investigation sample to test for the enrichment of specific Gene Ontology (GO) terms associated with autism. In Phase 2, the identified pathways are tested for enrichment in the replication sample. Permutation tests are performed to reduce the risk of false-positive findings. Quality assessment is conducted using QQ-plots and λ values, with Plink and R utilized for the Transmission Disequilibrium Test (TDT) and permutation tests. Results: The GO term GO:0007417 was found to be enriched in both the investigation and replication samples. SNPs associated with this pathway were observed at a frequency higher than expected in the replication sample. Conclusions: The GO term GO:0007417 (development of the nervous system) was associated with autism in both trio samples. Variations in the genes TMPRSS4, TRPC4, and PCDH9 were consistently linked to autism across the two independent samples, highlighting the role of calcium signaling and cell adhesion molecules in the risk of autism-related disorders. The pathways and variations associated with autism are described in detail, which can contribute to the engineering of new pharmacological treatments for ASD.

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The Role of Parvalbumin Interneurons in Autism Spectrum Disorder

Cited by 2 publications

References 111 publications

Human stem cell-derived GABAergic interneuron development reveals early emergence of subtype diversity followed by gradual electrochemical maturation

Human stem cell-derived GABAergic interneuron development reveals early emergence of subtype diversity followed by gradual electrochemical maturation

Calcium Signaling and Molecular Adhesion Processes May Hold the Key to Genetic Risk for Autism: A Molecular Pathway Analysis on Two Independent Samples

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