A subtype-specific gene regulatory program controls differential circuit integration of deep CA3 pyramidal neurons
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.
Authors
- Stein Aerts (ORCID: https://orcid.org/0000-0002-8006-0315)
- Pedro Magalhães (ORCID: https://orcid.org/0000-0001-8654-8752)
- Kristofer Davie (ORCID: https://orcid.org/0000-0003-2182-1249)
- Danie Daaboul (ORCID: https://orcid.org/0000-0001-8542-650X)
- Ine Vlaeminck (ORCID: https://orcid.org/0000-0001-8934-6179)
- Joris Vandenbempt (ORCID: https://orcid.org/0009-0004-9012-4775)
- Marta Wojno (ORCID: https://orcid.org/0000-0003-2711-1264)
- Joris de Wit (ORCID: https://orcid.org/0000-0003-1120-1089)
- Dan Dascenco (ORCID: https://orcid.org/0000-0002-4629-8266)
- Suresh Kumar Poovathingal (ORCID: https://orcid.org/0000-0002-3236-2255)
- Gabriela Michel (ORCID: https://orcid.org/0000-0002-6676-2863)
- Nelson Spruston (ORCID: https://orcid.org/0000-0003-3118-1636)
- Nicolás Alcaraz (ORCID: https://orcid.org/0000-0003-0839-8423)
- Keimpe D. B. Wierda (ORCID: https://orcid.org/0000-0002-8784-9490)
- Blanca Lorente-Echeverría (ORCID: https://orcid.org/0000-0003-4739-0926)
- Niklas Kempynck (ORCID: https://orcid.org/0000-0002-0104-4844)
- Elke Leysen (ORCID: https://orcid.org/0000-0002-5606-6725)
- Jeroen Vandensteen (ORCID: https://orcid.org/0009-0004-5084-7696)
- Lise Vervloessem
- Malou Reverendo (ORCID: https://orcid.org/0009-0008-8412-6757)
Institutions
- Howard Hughes Medical Institute (US)
- Janelia Research Campus (US)
- Center for Neurosciences (US)
- VIB-KU Leuven Center for Brain & Disease Research (BE)
- KU Leuven (BE)
Publication Details
- Journal
- bioRxiv (Cold Spring Harbor Laboratory)
- Published
- 2026-11-04
- DOI
- https://doi.org/10.64898/2026.11.03.763963
- Primary Topic
- Neurogenesis and neuroplasticity mechanisms
- Type
- preprint