Biology subjects

Vennekens, K. M.

Publications and source records attributed to Vennekens, K. M..

3 recordsLinked to original sources

bioRxiv2019

Mapping the cell-surface proteome underlying hippocampal mossy fiber synapse identity

Synaptic diversity is a key feature of neural circuits. The structural and functional diversity of closely spaced inputs converging on the same neuron suggests that cell-surface interactions are essential in organizing input properties. Here, we analyzed the cell-surface protein (CSP) composition of hippocampal mossy fiber (MF) inputs on CA3 pyramidal neurons to identify regulators of MF-CA3 synapse properties. We uncover a rich cell-surface repertoire that includes adhesion proteins, guidance cue receptors, extracellular matrix (ECM) proteins, and uncharacterized CSPs. Interactome screening reveals multiple ligand-receptor modules and identifies ECM protein Tenascin-R (TenR) as a ligand of the uncharacterized neuronal receptor IgSF8. Presynaptic Igsf8 deletion impairs MF-CA3 synaptic architecture and robustly decreases the density of bouton filopodia that provide feedforward inhibition of CA3 neurons. Consequently, loss of IgSF8 increases CA3 neuron excitability. Our findings identify IgSF8 as a regulator of CA3 microcircuit development and suggest that combinations of CSP modules define input identity.

neuroscience↗

bioRxiv2019

Synaptogenic activity of the axon guidance molecule Robo2 is critical for hippocampal circuit function

The developmental transition between axon guidance and synapse formation is critical for circuit assembly but still poorly understood at the molecular level. We hypothesized that this key transition could be regulated by axon guidance cues switching their function to regulate synaptogenesis with subcellular specificity. Here, we report evidence for such a functional switch, describing a novel role for the axon guidance molecule Robo2 in excitatory synapse formation onto dendrites of CA1 pyramidal neurons (PNs) in the mouse hippocampus. Cell-autonomous deletion of Robo2 from CA1 PNs leads to a drastic reduction of the number of excitatory synapses specifically in proximal dendritic compartments. At the molecular level, we show that this novel postsynaptic function of Robo2 depends on both its canonical ligand Slit and a novel interaction with presynaptic Neurexins. Biophysical analysis reveals that Robo2 binds directly to Neurexins via its Ig4-5 domains. In vivo 2-photon Ca2+ imaging of CA1 PNs during spatial navigation in mice shows that sparse deletion of Robo2 during development drastically reduces the likelihood of place cell emergence and alters spatial coding properties of the remaining place cells. Our results identify Robo2 as a novel molecular effector linking synaptic specificity to the acquisition of spatial coding properties characterizing hippocampal circuits.

neuroscience↗

bioRxiv2019

SorCS1-mediated Sorting of Neurexin in Dendrites Maintains Presynaptic Function

The pre- and postsynaptic membranes comprising the synaptic junction differ in protein composition. The mechanisms that maintain the polarized distribution of synaptic membrane proteins are poorly understood. The sorting receptor SorCS1 is a critical trafficking regulator of neuronal receptors, including neurexin (Nrxn), a presynaptic adhesion molecule essential for synaptic transmission. We find that SorCS1 controls a balance between axonal and dendritic Nrxn1 surface levels. Newly synthesized Nrxn1 traffics to the somatodendritic surface, followed by endocytosis. SorCS1 interacts with the Rab11 effector protein Rab11FIP5/Rip11 to facilitate the transition of internalized Nrxn1 from early to recycling endosomes and bias Nrxn1 surface polarization toward the axon. In the absence of SorCS1, Nrxn1 accumulates in early endosomes and mis-polarizes to the dendritic surface, impairing presynaptic function. The axonal/dendritic balance of Nrxn1 surface distribution is activity-dependent, indicating that SorCS1-mediated sorting in somatodendritic endosomes dynamically controls Nrxn1 axonal surface polarization required for proper presynaptic function.

neuroscience↗