Biology subjects

Vandenbempt, J.

Publications and source records attributed to Vandenbempt, J..

7 recordsLinked to original sources

bioRxiv2026

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.

neuroscience↗

bioRxiv2026

Multimodal profiling and intersectional genetics reveal CA1 border inhibitory neuron diversity and postnatal emergence of retrosplenial connectivity

Inhibitory neurons (INs) at the stratum radiatum/stratum lacunosum-moleculare border of hippocampal CA1 comprise diverse populations, including long-range-projecting neurons that innervate the retrosplenial cortex (RSCtx). However, their molecular organization and developmental connectivity remain poorly understood. Here, we combine multimodal transcriptomic profiling, intersectional genetics, and retrograde tracing to characterize CA1 border INs. We identified two major caudal ganglionic eminence-derived, Cxcl14-enriched populations distinguished by Syt6/Cck-related and Ntng1-expressing transcriptional profiles. We then generated a Cxcl14-Cre mouse line that, when combined with an IN-specific viral enhancer, provides genetic access to CA1 border INs. Retrograde labeling established that CA1 INs projecting to the RSCtx belong to the Ntng1-expressing population, and that this long-range projection emerges during postnatal mouse development, between postnatal days 3 and 5. Finally, analysis of genes encoding cell-surface proteins, key regulators of connectivity, revealed distinct expression profiles in RSCtx-projecting and SYT6-positive INs. Together, these findings establish a molecular and developmental framework for CA1 border IN diversity and provide a genetic strategy for investigating the assembly and function of these inhibitory circuits.

neuroscience↗

bioRxiv2026

A systematic cross-modal approach identifies astrocytic VCAM1 as a regulator of hippocampal synapse development

Astrocyte-mediated cell-cell interactions at synapses are essential for circuit formation, yet the molecular mechanisms underlying astrocyte-mediated regulation of hippocampal synapse development remain incompletely characterized. Here, we take a systematic cross-modal approach to identify novel astrocytic cell surface proteins (CSPs) at the tripartite synapse. By using single-cell spatial transcriptomics (scST) targeting CSPs identified in a previous hippocampal synaptic dataset, we find 10 potential candidate astrocytic CSPs. Subsequent systematic protein-level profiling using multiple antibody-based assays establishes GPR37L1, HepaCAM, and VCAM1 as astrocytic peri-synaptic CSPs. To gain insight into the molecular context in which these proteins operate at synapses, we map their synaptic interaction partners using affinity purification-mass spectrometry (AP-MS), revealing distinct hippocampal synaptic interactomes for GPR37L1 and VCAM1. We then develop a custom multi-metric image-based synapse analysis pipeline to assess the roles of GPR37L1 and VCAM1 in synaptic development, using CRISPR/Cas9-mediated gene knockout (KO) in the mouse hippocampus. While loss of GPR37L1 does not substantially affect excitatory and inhibitory synapses, VCAM1 loss impairs excitatory hippocampal synapse development. Conversely, addition of recombinant VCAM1 to cultured hippocampal neurons increases the density of excitatory synapses. Together, these results identify astrocytic VCAM1 as a regulator of hippocampal synapse development.

neuroscience↗

bioRxiv2026

Extracellular neuroligin-ICAM5 coupling drives dendritic growth via actin remodeling

Neuroligins (NLGNs) organize neuronal connectivity by engaging a diverse set of interaction partners, yet how extracellular recognition couples to intracellular growth programs remains unclear. Using affinity proteomics, we identify intercellular adhesion molecule-5 (ICAM5), a cell-surface protein localized to dendritic filopodia, as a novel neuroligin interactor. Surface plasmon resonance and cell-based assays demonstrate direct binding between the ICAM5 and NLGN3 extracellular domains and reveal that ICAM5 engages all neuroligin isoforms. ICAM5 is required for NLGN-induced dendritic outgrowth, but the NLGN3-ICAM5 complex does not contribute to synaptogenesis. Mechanistically, ICAM5 sustains PAK-Cofilin signaling and F-actin organization in growth cones, positioning it as a downstream effector that links neuroligin engagement to actin remodeling. Together, these findings define a neuroligin-ICAM5 axis that couples extracellular recognition to intracellular actin remodeling to control neuronal structural development.

neuroscience↗

bioRxiv2025

A dynamic gene regulatory code drives synaptic development of hippocampal granule cells

Connecting neurons into functional circuits requires the formation, maturation, and plasticity of synapses. While advances have been made in identifying individual genes regulating synapse development, the molecular programs orchestrating their action during circuit integration of neurons remain poorly understood. Here, we take a multiomic approach to reconstruct gene regulatory networks (GRNs), comprising transcription factors (TFs), regulatory regions, and predicted target genes, in hippocampal granule cells (GCs). We find a dynamic gene regulatory code, with early and late postnatal GRNs regulating cell morphogenesis and synapse organization and plasticity, respectively. Our results predict sequential regulations, with early-active TFs delaying the activation of later GRNs and their putative synaptic targets. Using a loss-of-function approach, we identify Bcl6 as a regulator of pre- and postsynaptic structural maturation, and Smad3 as a modulator of inhibitory synaptic transmission, in GCs. Together, these findings highlight the networks of key TFs and target genes orchestrating GC synapse development.

neuroscience↗

bioRxiv2024

Cell-surface receptor-mediated regulation of synaptic organelle distribution controls dendritic spine maturation

The spine apparatus (SA), an endoplasmic reticulum-related organelle present in a subset of mature dendritic spines, plays a key role in postsynaptic development and has been implicated in various neurological disorders. However, the molecular mechanisms that dictate SA localization at selected synapses remain elusive. Here, we identify a postsynaptic signaling complex comprising the GPCR-like receptor GPR158 and a largely uncharacterized phospholipase C (PLC), PLCXD2, that controls SA abundance. Sparse genetic manipulations in vivo demonstrate that in the absence of GPR158, unrestrained PLCXD2 activity impedes postsynaptic SA incorporation and hampers dendritic spine maturation. Finally, we show that extracellular heparan sulfate proteoglycan (HSPG) binding modulates the GPR158-PLCXD2 interaction. Together, our findings reveal how a postsynaptic receptor signaling complex regulates the local lipid microenvironment to control SA abundance required for the proper maturation of dendritic spines.

neuroscience↗

bioRxiv2021

Melanin Concentrating Hormone- and sleep-dependent synaptic downscaling is impaired in Alzheimer's Disease

In Alzheimers disease (AD), pathophysiological changes in the hippocampus cause deficits in episodic memory formation, leading to cognitive impairment 1,2. Neuronal hyperactivity is observed early in AD 3,4. Here, we find that homeostatic mechanisms transiently counteract increased neuronal activity in the hippocampal CA1 region of the AppNL-G-F humanized knock-in mouse model for AD 5, but ultimately fail to maintain neuronal activity at set-point. Spatial transcriptomic analysis in CA1 during the homeostatic response identifies the Melanin-Concentrating Hormone (MCH)-encoding gene. MCH is expressed in sleep-active lateral hypothalamic neurons that project to CA1 and modulate memory 6. We show that MCH regulates synaptic plasticity genes and synaptic downscaling in hippocampal neurons. Furthermore, MCH-neuron activity is impaired in AppNL-G-F mice, disrupting sleep-dependent homeostatic plasticity and stability of neuronal activity in CA1. Finally, we find perturbed MCH-axon morphology in CA1 early in AppNL-G-F mice and in AD patients. Our work identifies dysregulation of the MCH-system as a key player in aberrant neuronal activity in the early stages of AD.

neuroscience↗