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PreprintCC BY-NC-NDbioRxiv

A subtype-specific gene regulatory program controls differential circuit integration of deep CA3 pyramidal neurons

  • J. de Wit1
  • D. Daaboul
  • J. Vandensteen
  • D. Dascenco
  • B. Lorente-Echeverria
  • J. Vandenbempt
  • E. Leysen
  • M. Reverendo
  • I. Vlaeminck
  • L. Vervloessem
  • N. Alcaraz
  • M. Wojno
8 more authors
  • S. Poovathingal
  • K. Davie
  • P. Magalhaes
  • N. Kempynck
  • G. Michel
  • N. Spruston
  • K. Wierda
  • S. Aerts
  1. 1VIB Center for Neuroscience
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Abstract

How closely related neuronal subtypes integrate into different circuits remains poorly understood. Deep and superficial hippocampal CA3 pyramidal neurons (PNs) differ in intrinsic firing and mossy fiber (MF) input at specialized postsynaptic structures termed thorny excrescences (TEs). Combining developmental single-nucleus multiomics with genetic targeting, morphological analysis and electrophysiology, we identify the transcription factor ST18 as a regulator of deep CA3 subtype identity. ST18 marks sparsely thorny and burst-firing neurons, and gene regulatory analyses predict that it represses a superficial-associated program involved in dendritic spine development, synaptic organization, and electrophysiological properties. Postnatal ST18 loss shifts the transcriptional and chromatin landscape of deep CA3 PNs toward a superficial-like state. These molecular changes are accompanied by increased TE elaboration approaching superficial levels, enhanced excitatory synaptic activity, and reduced burst-firing. Together, these findings identify ST18-dependent restriction of an alternative subtype program as a mechanism linking molecular identity to distinct input connectivity patterns and intrinsic firing properties during postnatal circuit maturation.

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Cite

BibTeXRIS
BibTeX
@misc{wit2026subtypespecific,
  title = {{A subtype-specific gene regulatory program controls differential circuit integration of deep CA3 pyramidal neurons}},
  author = {J. de Wit and D. Daaboul and J. Vandensteen and D. Dascenco and B. Lorente-Echeverria and J. Vandenbempt and E. Leysen and M. Reverendo and I. Vlaeminck and L. Vervloessem and N. Alcaraz and M. Wojno and S. Poovathingal and K. Davie and P. Magalhaes and N. Kempynck and G. Michel and N. Spruston and K. Wierda and S. Aerts},
  howpublished = {bioRxiv},
  year = {2026},
  month = nov,
  doi = {10.64898/2026.11.03.763963},
  url = {https://www.biorxiv.org/content/10.64898/2026.11.03.763963v1},
  note = {CC BY-NC-ND},
}
RIS
TY  - UNPB
TI  - A subtype-specific gene regulatory program controls differential circuit integration of deep CA3 pyramidal neurons
AU  - J. de Wit
AU  - D. Daaboul
AU  - J. Vandensteen
AU  - D. Dascenco
AU  - B. Lorente-Echeverria
AU  - J. Vandenbempt
AU  - E. Leysen
AU  - M. Reverendo
AU  - I. Vlaeminck
AU  - L. Vervloessem
AU  - N. Alcaraz
AU  - M. Wojno
AU  - S. Poovathingal
AU  - K. Davie
AU  - P. Magalhaes
AU  - N. Kempynck
AU  - G. Michel
AU  - N. Spruston
AU  - K. Wierda
AU  - S. Aerts
PY  - 2026
DA  - 2026/11/03
PB  - bioRxiv
DO  - 10.64898/2026.11.03.763963
UR  - https://www.biorxiv.org/content/10.64898/2026.11.03.763963v1
AB  - How closely related neuronal subtypes integrate into different circuits remains poorly understood. Deep and superficial hippocampal CA3 pyramidal neurons (PNs) differ in intrinsic firing and mossy fiber (MF) input at specialized postsynaptic structures termed thorny excrescences (TEs). Combining developmental single-nucleus multiomics with genetic targeting, morphological analysis and electrophysiology, we identify the transcription factor ST18 as a regulator of deep CA3 subtype identity. ST18 marks sparsely thorny and burst-firing neurons, and gene regulatory analyses predict that it represses a superficial-associated program involved in dendritic spine development, synaptic organization, and electrophysiological properties. Postnatal ST18 loss shifts the transcriptional and chromatin landscape of deep CA3 PNs toward a superficial-like state. These molecular changes are accompanied by increased TE elaboration approaching superficial levels, enhanced excitatory synaptic activity, and reduced burst-firing. Together, these findings identify ST18-dependent restriction of an alternative subtype program as a mechanism linking molecular identity to distinct input connectivity patterns and intrinsic firing properties during postnatal circuit maturation.
ER  -