A Modular Organization of LRR Protein-Mediated Synaptic Adhesion Defines Synapse Identity

• Published in: Neuron (Cambridge, Mass.) Vol. 99; no. 2; pp. 329 - 344.e7
• Main Authors: Schroeder, Anna, Vanderlinden, Jeroen, Vints, Katlijn, Ribeiro, Luís F., Vennekens, Kristel M., Gounko, Natalia V., Wierda, Keimpe D., de Wit, Joris
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 25-07-2018; Elsevier Limited
• Subjects: Animals; Brain; CA1 pyramidal neuron; Cells, Cultured; Coculture Techniques; Excitatory Postsynaptic Potentials - physiology; Experiments; Female; Gene expression; glutamatergic transmission; Grants; HEK293 Cells; Hippocampus; Humans; Immunoglobulins; Leucine; leucine-rich repeat; Localization; Male; Mammals; Membrane Glycoproteins - analysis; Membrane Glycoproteins - physiology; Membrane Glycoproteins - ultrastructure; Membrane Proteins - analysis; Membrane Proteins - physiology; Membrane Proteins - ultrastructure; Mice; Mice, Inbred C57BL; Mice, Knockout; molecular diversity; Neural Cell Adhesion Molecules - analysis; Neural Cell Adhesion Molecules - physiology; Neural Cell Adhesion Molecules - ultrastructure; Neurons; neurotransmitter receptor; Phenotypes; Postsynaptic density; Proteins; Pyramidal cells; Rats; Rats, Wistar; Receptor density; Schaffer collateral; Structure-function relationships; Synapses - chemistry; Synapses - physiology; Synapses - ultrastructure; synaptic adhesion; synaptic specificity; Synaptic transmission; Synaptic Transmission - physiology; synaptogenesis; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors; neurotransmitter receptor; glutamatergic transmission; synaptic specificity; CA1 pyramidal neuron; hippocampus; leucine-rich repeat; Schaffer collateral; molecular diversity; synaptogenesis; synaptic adhesion
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2018.06.026

Pyramidal neurons express rich repertoires of leucine-rich repeat (LRR)-containing adhesion molecules with similar synaptogenic activity in culture. The in vivo relevance of this molecular diversity is unclear. We show that hippocampal CA1 pyramidal neurons express multiple synaptogenic LRR proteins that differentially distribute to the major excitatory inputs on their apical dendrites. At Schaffer collateral (SC) inputs, FLRT2, LRRTM1, and Slitrk1 are postsynaptically localized and differentially regulate synaptic structure and function. FLRT2 controls spine density, whereas LRRTM1 and Slitrk1 exert opposing effects on synaptic vesicle distribution at the active zone. All LRR proteins differentially affect synaptic transmission, and their combinatorial loss results in a cumulative phenotype. At temporoammonic (TA) inputs, LRRTM1 is absent; FLRT2 similarly controls functional synapse number, whereas Slitrk1 function diverges to regulate postsynaptic AMPA receptor density. Thus, LRR proteins differentially control synaptic architecture and function and act in input-specific combinations and a context-dependent manner to specify synaptic properties.
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•Single hippocampal CA1 neurons express multiple synaptic organizing LRR proteins•FLRT2 regulates dendritic spine density in CA1 neurons•LRRTM1 and Slitrk1 organize synaptic vesicle distribution in an opposing manner•Input-specific combinations of LRR proteins specify synaptic properties
Hippocampal CA1 pyramidal neurons express multiple synaptogenic leucine-rich repeat (LRR)-containing adhesion molecules. Schroeder et al. show that LRR proteins differentially control synaptic structure and function and act in input-specific combinations and a context-dependent manner to specify synaptic properties.