Abstract
Balanced development of excitatory and inhibitory synapses is required for normal brain function, and an imbalance in this development may underlie the pathogenesis of many neuropsychiatric disorders. Compared with the many identified trans-synaptic adhesion complexes that organize excitatory synapses, little is known about the organizers that are specific for inhibitory synapses. We found that Slit and NTRK-like family member 3 (Slitrk3) actS as a postsynaptic adhesion molecule that selectively regulates inhibitory synapse development via trans-interaction with axonal tyrosine phosphatase receptor PTPδ. When expressed in fibroblasts, Slitrk3 triggered only inhibitory presynaptic differentiation in contacting axons of co-cultured rat hippocampal neurons. Recombinant Slitrk3 preferentially localized to inhibitory postsynaptic sites. Slitrk3-deficient mice exhibited decreases in inhibitory, but not excitatory, synapse number and function in hippocampal CA1 neurons and exhibited increased seizure susceptibility and spontaneous epileptiform activity. Slitrk3 required trans-interaction with axonal PTPδ to induce inhibitory presynaptic differentiation. These results identify Slitrk3-PTPδ as an inhibitory-specific trans-synaptic organizing complex that is required for normal functional GABAergic synapse development.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Animals, Newborn
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Brain / cytology
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Cell Adhesion Molecules / metabolism
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Cell Differentiation / genetics
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Cells, Cultured
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Chlorocebus aethiops
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Coculture Techniques
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Disease Models, Animal
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Electroencephalography
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Epilepsy / genetics
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Female
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Gene Expression Regulation / genetics
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Glutamate Decarboxylase / metabolism
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Humans
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Inhibitory Postsynaptic Potentials / genetics
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Inhibitory Postsynaptic Potentials / physiology*
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Luminescent Proteins / genetics
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Luminescent Proteins / metabolism
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Male
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Membrane Proteins / deficiency
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Membrane Proteins / metabolism*
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Nerve Tissue Proteins / deficiency
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Nerve Tissue Proteins / metabolism*
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Neural Inhibition / genetics
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Neural Inhibition / physiology*
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Presynaptic Terminals
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Protein Binding
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Rats
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Receptor-Like Protein Tyrosine Phosphatases, Class 2 / genetics
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Receptor-Like Protein Tyrosine Phosphatases, Class 2 / metabolism*
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Synapses / genetics
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Synapses / physiology*
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Synaptic Transmission / genetics
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Synaptic Transmission / physiology*
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Transfection
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Vesicular Glutamate Transport Protein 1 / metabolism
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Vesicular Inhibitory Amino Acid Transport Proteins / metabolism
Substances
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Cell Adhesion Molecules
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Luminescent Proteins
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Membrane Proteins
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Nerve Tissue Proteins
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RNA, Small Interfering
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Slc17a7 protein, mouse
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Slitrk protein, mouse
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Vesicular Glutamate Transport Protein 1
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Vesicular Inhibitory Amino Acid Transport Proteins
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Viaat protein, mouse
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Receptor-Like Protein Tyrosine Phosphatases, Class 2
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Glutamate Decarboxylase