Abstract
An important organizing feature of the CNS is that individual neurons receive input from many different sources. Independent regulation of synaptic input is critical for the function and adaptive responses of the nervous system, but the underlying molecular mechanisms are not well understood. We identify the leucine-rich repeat (LRR)-containing protein NGL-2 (Lrrc4) as a key regulator of input-specific synapse development in the hippocampus. Using genetic deletion and shRNA-mediated knockdown, we demonstrate a role for NGL-2 in regulating the strength of synaptic transmission and spine density specifically at Schaffer collateral synapses in the stratum radiatum (SR) in CA1. NGL-2 protein is restricted to SR and spine regulation requires NGL-2's LRR and PDZ-binding domains. Finally, loss of NGL-2 disrupts cooperative interactions between distal and proximal synapses in CA1 pyramidal cells. These results demonstrate that NGL-2 is critical for pathway-specific synapse development and functional integration of distinct inputs.
Copyright © 2012 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Age Factors
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Animals
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Animals, Newborn
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Axons / physiology
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CA1 Region, Hippocampal / cytology*
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Cell Line, Transformed
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Cells, Cultured
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Electric Stimulation
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Electroporation / methods
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Excitatory Amino Acid Agonists / pharmacology
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Excitatory Postsynaptic Potentials / drug effects
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Excitatory Postsynaptic Potentials / genetics
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Gene Expression Regulation, Developmental / genetics
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Gene Expression Regulation, Developmental / physiology*
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Green Fluorescent Proteins / genetics
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In Vitro Techniques
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Lentivirus / genetics
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Mutation / genetics
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N-Methylaspartate / pharmacology
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Nerve Growth Factors / genetics
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Nerve Growth Factors / metabolism
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Nerve Tissue Proteins / deficiency
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Nerve Tissue Proteins / metabolism*
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Netrin-1
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Organic Chemicals / metabolism
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Patch-Clamp Techniques
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Pyramidal Cells / cytology*
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Pyramidal Cells / physiology*
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RNA, Small Interfering / metabolism
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Rats
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Rats, Long-Evans
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Receptors, Cell Surface / metabolism
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Synapses / genetics
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Synapses / physiology*
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Transfection
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism
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alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / pharmacology
Substances
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Alexa594
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Excitatory Amino Acid Agonists
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LRRC4 protein, mouse
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LRRC4C protein, human
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Nerve Growth Factors
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Nerve Tissue Proteins
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Organic Chemicals
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RNA, Small Interfering
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Receptors, Cell Surface
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Tumor Suppressor Proteins
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enhanced green fluorescent protein
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Green Fluorescent Proteins
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Netrin-1
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N-Methylaspartate
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alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid