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Transsynaptic cerebellin 4–neogenin 1 signaling mediates LTP in the mouse dentate gyrus

Five decades ago, long-term potentiation (LTP) of synaptic transmission was discovered at entorhinal cortex→dentate gyrus (EC→DG) synapses, but the molecular determinants of EC→DG LTP remain largely unknown. Here, we show that the presynaptic neurexin–ligand cerebellin-4 (Cbln4) is highly expressed...

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Autores principales: Liakath-Ali, Kif, Polepalli, Jai S., Lee, Sung-Jin, Cloutier, Jean-Francois, Südhof, Thomas C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9171784/
https://www.ncbi.nlm.nih.gov/pubmed/35544694
http://dx.doi.org/10.1073/pnas.2123421119
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author Liakath-Ali, Kif
Polepalli, Jai S.
Lee, Sung-Jin
Cloutier, Jean-Francois
Südhof, Thomas C.
author_facet Liakath-Ali, Kif
Polepalli, Jai S.
Lee, Sung-Jin
Cloutier, Jean-Francois
Südhof, Thomas C.
author_sort Liakath-Ali, Kif
collection PubMed
description Five decades ago, long-term potentiation (LTP) of synaptic transmission was discovered at entorhinal cortex→dentate gyrus (EC→DG) synapses, but the molecular determinants of EC→DG LTP remain largely unknown. Here, we show that the presynaptic neurexin–ligand cerebellin-4 (Cbln4) is highly expressed in the entorhinal cortex and essential for LTP at EC→DG synapses, but dispensable for basal synaptic transmission at these synapses. Cbln4, when bound to cell-surface neurexins, forms transcellular complexes by interacting with postsynaptic DCC (deleted in colorectal cancer) or neogenin-1. DCC and neogenin-1 act as netrin and repulsive guidance molecule-a (RGMa) receptors that mediate axon guidance in the developing brain, but their binding to Cbln4 raised the possibility that they might additionally function in the mature brain as postsynaptic receptors for presynaptic neurexin/Cbln4 complexes, and that as such receptors, DCC or neogenin-1 might mediate EC→DG LTP that depends on Cbln4. Indeed, we observed that neogenin-1, but not DCC, is abundantly expressed in dentate gyrus granule cells, and that postsynaptic neogenin-1 deletions in dentate granule cells blocked EC→DG LTP, but again did not affect basal synaptic transmission similar to the presynaptic Cbln4 deletions. Thus, binding of presynaptic Cbln4 to postsynaptic neogenin-1 renders EC→DG synapses competent for LTP, but is not required for establishing these synapses or for otherwise enabling their function.
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spelling pubmed-91717842022-11-15 Transsynaptic cerebellin 4–neogenin 1 signaling mediates LTP in the mouse dentate gyrus Liakath-Ali, Kif Polepalli, Jai S. Lee, Sung-Jin Cloutier, Jean-Francois Südhof, Thomas C. Proc Natl Acad Sci U S A Biological Sciences Five decades ago, long-term potentiation (LTP) of synaptic transmission was discovered at entorhinal cortex→dentate gyrus (EC→DG) synapses, but the molecular determinants of EC→DG LTP remain largely unknown. Here, we show that the presynaptic neurexin–ligand cerebellin-4 (Cbln4) is highly expressed in the entorhinal cortex and essential for LTP at EC→DG synapses, but dispensable for basal synaptic transmission at these synapses. Cbln4, when bound to cell-surface neurexins, forms transcellular complexes by interacting with postsynaptic DCC (deleted in colorectal cancer) or neogenin-1. DCC and neogenin-1 act as netrin and repulsive guidance molecule-a (RGMa) receptors that mediate axon guidance in the developing brain, but their binding to Cbln4 raised the possibility that they might additionally function in the mature brain as postsynaptic receptors for presynaptic neurexin/Cbln4 complexes, and that as such receptors, DCC or neogenin-1 might mediate EC→DG LTP that depends on Cbln4. Indeed, we observed that neogenin-1, but not DCC, is abundantly expressed in dentate gyrus granule cells, and that postsynaptic neogenin-1 deletions in dentate granule cells blocked EC→DG LTP, but again did not affect basal synaptic transmission similar to the presynaptic Cbln4 deletions. Thus, binding of presynaptic Cbln4 to postsynaptic neogenin-1 renders EC→DG synapses competent for LTP, but is not required for establishing these synapses or for otherwise enabling their function. National Academy of Sciences 2022-05-11 2022-05-17 /pmc/articles/PMC9171784/ /pubmed/35544694 http://dx.doi.org/10.1073/pnas.2123421119 Text en Copyright © 2022 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Biological Sciences
Liakath-Ali, Kif
Polepalli, Jai S.
Lee, Sung-Jin
Cloutier, Jean-Francois
Südhof, Thomas C.
Transsynaptic cerebellin 4–neogenin 1 signaling mediates LTP in the mouse dentate gyrus
title Transsynaptic cerebellin 4–neogenin 1 signaling mediates LTP in the mouse dentate gyrus
title_full Transsynaptic cerebellin 4–neogenin 1 signaling mediates LTP in the mouse dentate gyrus
title_fullStr Transsynaptic cerebellin 4–neogenin 1 signaling mediates LTP in the mouse dentate gyrus
title_full_unstemmed Transsynaptic cerebellin 4–neogenin 1 signaling mediates LTP in the mouse dentate gyrus
title_short Transsynaptic cerebellin 4–neogenin 1 signaling mediates LTP in the mouse dentate gyrus
title_sort transsynaptic cerebellin 4–neogenin 1 signaling mediates ltp in the mouse dentate gyrus
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9171784/
https://www.ncbi.nlm.nih.gov/pubmed/35544694
http://dx.doi.org/10.1073/pnas.2123421119
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