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  3. Human microglia in brain assembloids display region-specific diversity and respond to hyperexcitable neurons carrying SCN2A mutation: Microglial diversity and response in assembloids

Human microglia in brain assembloids display region-specific diversity and respond to hyperexcitable neurons carrying SCN2A mutation: Microglial diversity and response in assembloids

  • bioRxiv. 2025 Jun 4:2025.06.04.657874. doi: 10.1101/2025.06.04.657874.
Jiaxiang Wu 1 2 3,  Xiaoling Chen 1 2 3,  Jingliang Zhang 1 2 3,  Kyle Wettschurack 1 2 3,  Morgan Robinson 1 2 4,  Weihao Li 5,  Yuanrui Zhao 1 2,  Ye-Eun Yoo 1 2,  Brody A Deming 1 2,  Akila D Abeyaratna 1 2,  Zhefu Que 1 2,  Dongshu Du 6,  Matthew Tegtmeyer 2 7,  Chongli Yuan 4,  William C Skarnes 8,  Jean-Christophe Rochet 1 2,  Long-Jun Wu 9,  Yang Yang 1 2 10
Affiliations

Affiliations

  • 1 Borch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, IN 47907, USA.
  • 2 Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, IN 47907, USA.
  • 3 These authors contributed equally.
  • 4 Davidson School of Chemical Engineering, College of Engineering, Purdue University, West Lafayette, IN 47907, USA.
  • 5 ENT Institute and Department of Otorhinolaryngology, Eye & ENT Hospital, Fudan University, Shanghai 200031, China.
  • 6 School of Life Sciences, Shanghai University, Shanghai 200444, China.
  • 7 Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA.
  • 8 The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA.
  • 9 Center for Neuroimmunology and Glial Biology, Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
  • 10 Lead contact.
PMID: 40501840 DOI: 10.1101/2025.06.04.657874
Abstract

Microglia critically shape neuronal circuit development and function, yet their region-specific properties and roles in distinct circuits of the human brain remain poorly understood. In this study, we generated region-specific brain organoids (cortical, striatal, and midbrain), each integrated with human microglia, to fill this critical gap. Single-cell RNA Sequencing uncovered six distinct microglial subtypes exhibiting unique regional signatures, including a subtype highly enriched for the GABAB receptor gene within striatal organoids. To investigate the contributions of microglia to neural circuitry, we created microglia-incorporated midbrain-striatal assembloids, modeling a core circuit node for many neuropsychiatric disorders including autism. Using chemogenetics to activate this midbrain-striatal circuit, we observed increased calcium signaling in microglia involving GABAB receptors. Leveraging this model, we examined microglial responses within neural circuits harboring an SCN2A nonsense (C959X) mutation associated with profound autism. Remarkably, microglia displayed heightened calcium responses to SCN2A mutation-mediated neuronal hyperactivity, and engaged in excessive synaptic pruning. These pathological effects were reversed by pharmacological inhibition of microglial GABAB receptors. Collectively, our findings establish an advanced platform to dissect human neuroimmune interactions in sub-cortical regions, highlighting the important role of microglia in shaping critical circuitry related to neuropsychiatric disorders.

Keywords

NaV1.2; assembloid; brain organoid; microglia; midbrain-striatal circuit.

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