Autism-associatedSCN2Adeficiency disrupts cortico-striatal circuitry in human brain assembloids

  1. Xiaoling Chen
  2. Jingliang Zhang
  3. Jiaxiang Wu
  4. Morgan J. Robinson
  5. Harish Kothandaraman
  6. Ye-Eun Yoo
  7. Iria M. Gonzalez Dopeso-Reyes
  8. Thomas D. Buffenoir
  9. Manasi S. Halurkar
  10. Zaiyang Zhang
  11. Muhan Wang
  12. Erin N. Creager
  13. Yuanrui Zhao
  14. Maria I. Olivero-Acosta
  15. Kyle W. Wettschurack
  16. Zhefu Que
  17. Chongli Yuan
  18. Allison J. Schaser
  19. Nadia A. Lanman
  20. Jean-Christophe Rochet
  21. William C. Skarnes
  22. Eric J. Kremer
  23. Yang Yang
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Abstract

Profound autism spectrum disorder (ASD) is frequently attributable to single-gene mutations, withSCN2A(voltage-gated sodium channel NaV1.2) protein-truncating variants (PTVs) being one of the most penetrant. Although cortico-striatal circuitry is implicated as a key node in ASD, the impact ofSCN2Adeficiency on human neural circuits is unknown. Using the human cortico-striatal assembloid model, we show that the autism-causing PTVSCN2A-C959Ximpairs long-range cortical axonal projections, reduces striatal spine density, and attenuates excitatory cortical-striatal synaptic transmission. Surprisingly, these assembloids carrying the heterozygousSCN2Anonsense mutation exhibited pronounced network hyperexcitability, a human cell-specific phenotype not observed inScn2a+/-mice, highlighting a human-specific circuit vulnerability. Collectively, our study unveils human circuit-specific dysfunctions ofSCN2Adeficiency andSCN2A-mediated ASD.

Highlights

  • Axonal projections facilitate synapse formation and functional connectivity in human brain assembloids.

  • NaV1.2 is expressed along neuronal axons, extending to soma and dendrites in human brain assembloids.

  • SCN2A-C959Xdisrupts axonal projection patterns, impairs excitatory synaptic transmission, reduces spine density, and results in elevated neuronal excitability.

Graphical abstract

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In brief

SCN2Ahaploinsufficiency impairs cortico-striatal circuitry.

SCN2Ahaploinsufficiency disrupts axon initial segment (AIS) integrity, leading to hyperexcitability (red arrow), reduced axon projections, and impaired synaptic transmission (decreased sEPSCs and altered network firing). These deficits result in dysfunction within the cortico-striatal circuitry.

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