Slit-Robo signaling links synapse specificity with functional circuit wiring

Abstrat: The thousands of connections made by each of neuron in our brain underlie our ability to perceive and interact with our environment. Neural circuits are wired up during development by virtue of a molecular code that allows individual neurons to find their correct connection partners. Given their functional significance, even subtle defects in the developmental mechanisms establishing synaptic connections are thought to underlie many neurodevelopmental disorders including autism spectrum disorders, Tourette syndrome, schizophrenia and epilepsy. Therefore, investigating the molecular mechanisms underlying the assembly of the connectome of functional neural circuits is highly significant. I will report results identifying a new function for the well-studied axon guidance proteins Robo receptors and its ligand, the leucine-rich repeat (LRR) domaincontaining Slit, as synaptogenic molecules underlying the formation of excitatory synapses in hippocampal circuits important for learning and memory.

Using an in vitro hemisynapse assay, we found that Robo1/2 are able to induce excitatory (but not inhibitory) synapse formation in a Slit-dependent manner. We provide in vitro and in vivo evidence that Robo receptors are required postsynaptically, but not in presynaptic axons, to induce synaptogenesis in a Slit-dependent manner. We also obtained preliminary results strongly suggesting that presynaptic Neurexins are functional presynaptic receptors mediating the postsynaptic function of Robo/Slit-dependent synaptogenesis. Developmental, cell-autonomous conditional deletion of Robo2 from hippocampal CA1 PNs leads to a drastic reduction (~50%) of excitatory synapse number in the apical oblique and basal (but not in apical tuft) of these neurons. We are currently testing the biochemical nature of this novel, potentially tripartite Robo/Slit/Neurexin transsynaptic adhesion complex and use this molecular effectors of synaptic specificity to test the functional consequences of its disruption on CA1PNs spatial tuning properties.

Finally, we employed chronic in vivo 2P Ca2+ imaging at cellular resolution to monitor functional properties of spatial information encoding following developmental Robo2 conditional deletion. Our results demonstrate that the reduction in structural connectivity of CA2/3 -> CA1 PNs significantly alters their spatial tuning properties and most significantly the stability of place cells over longitudinal (5 days) imaging. We are complementing this approach with comprehensive behavioral assessment of Robo2 CA1-specific conditional deletion with a focus on hippocampus-dependent spatial learning behaviors.

Taken together, our results provide a direct link between effectors of synaptic specificity and their role in the emergence of the functional properties characterizing neural circuits in vivo.

 

Franck Polleux

Columbia University – Mortimer Zuckerman Mind Brain Behavior Institute

New York – USA

 

Invited by : Rosa Cossart

Inmed meeting room, Monday September 23rd, 11 am

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