{"corpus_id":14886763,"paper_sha":"d2ea94ee019d347f9577910106479c7df5d75b09","doi":"10.1523/JNEUROSCI.2069-14.2014","arxiv_id":null,"pmid":25274828,"pmcid":"PMC6608319","mag_id":1982504898,"dblp_id":null,"acl_id":null,"title":"Pro-Brain-Derived Neurotrophic Factor Inhibits GABAergic Neurotransmission by Activating Endocytosis and Repression of GABAA Receptors","year":2014,"publication_date":"2014-10-01","venue":"Journal of Neuroscience","journal":{"name":"The Journal of Neuroscience","pages":"13516 - 13534","volume":"34"},"journal_issn":null,"journal_title":null,"publication_types":["JournalArticle"],"pubmed_pub_types":["Journal Article","Research Support, Non-U.S. Gov't"],"s2_fields_of_study":["Biology","Medicine"],"reference_count":77,"citation_count":46,"influential_citation_count":3,"is_open_access":true,"arxiv_categories":null,"arxiv_license":null,"arxiv_journal_ref":null,"mesh_headings":[{"d":"Animals","mj":false,"ui":"D000818"},{"d":"Animals, Newborn","mj":false,"ui":"D000831"},{"d":"Brain-Derived Neurotrophic Factor","mj":false,"qs":[{"q":"metabolism","mj":false,"ui":"Q000378"},{"q":"pharmacology","mj":true,"ui":"Q000494"}],"ui":"D019208"},{"d":"Endocytosis","mj":false,"qs":[{"q":"drug effects","mj":true,"ui":"Q000187"},{"q":"physiology","mj":false,"ui":"Q000502"}],"ui":"D004705"},{"d":"Enzyme Inhibitors","mj":false,"qs":[{"q":"pharmacology","mj":false,"ui":"Q000494"}],"ui":"D004791"},{"d":"Excitatory Amino Acid Antagonists","mj":false,"qs":[{"q":"pharmacology","mj":false,"ui":"Q000494"}],"ui":"D018691"},{"d":"Gene Expression Regulation","mj":false,"qs":[{"q":"drug effects","mj":false,"ui":"Q000187"}],"ui":"D005786"},{"d":"Hippocampus","mj":false,"qs":[{"q":"cytology","mj":false,"ui":"Q000166"}],"ui":"D006624"},{"d":"Inhibitory Postsynaptic Potentials","mj":false,"qs":[{"q":"drug effects","mj":false,"ui":"Q000187"}],"ui":"D053444"},{"d":"Nerve Tissue Proteins","mj":false,"qs":[{"q":"metabolism","mj":false,"ui":"Q000378"}],"ui":"D009419"},{"d":"Neuronal Plasticity","mj":false,"qs":[{"q":"drug effects","mj":false,"ui":"Q000187"}],"ui":"D009473"},{"d":"Neurons","mj":false,"qs":[{"q":"drug effects","mj":true,"ui":"Q000187"}],"ui":"D009474"},{"d":"Quinoxalines","mj":false,"qs":[{"q":"pharmacology","mj":false,"ui":"Q000494"}],"ui":"D011810"},{"d":"Rats","mj":false,"ui":"D051381"},{"d":"Rats, Wistar","mj":false,"ui":"D017208"},{"d":"Receptors, GABA","mj":false,"qs":[{"q":"metabolism","mj":true,"ui":"Q000378"}],"ui":"D018079"},{"d":"Sodium Channel Blockers","mj":false,"qs":[{"q":"pharmacology","mj":false,"ui":"Q000494"}],"ui":"D026941"},{"d":"Synaptic Transmission","mj":false,"qs":[{"q":"drug effects","mj":true,"ui":"Q000187"},{"q":"physiology","mj":false,"ui":"Q000502"}],"ui":"D009435"},{"d":"Tetrodotoxin","mj":false,"qs":[{"q":"pharmacology","mj":false,"ui":"Q000494"}],"ui":"D013779"},{"d":"Valine","mj":false,"qs":[{"q":"analogs & derivatives","mj":false,"ui":"Q000031"},{"q":"pharmacology","mj":false,"ui":"Q000494"}],"ui":"D014633"},{"d":"gamma-Aminobutyric Acid","mj":false,"qs":[{"q":"metabolism","mj":true,"ui":"Q000378"}],"ui":"D005680"}],"chemicals":[{"n":"Brain-Derived Neurotrophic Factor","ui":"D019208","reg":"0"},{"n":"Enzyme Inhibitors","ui":"D004791","reg":"0"},{"n":"Excitatory Amino Acid Antagonists","ui":"D018691","reg":"0"},{"n":"Nerve Tissue Proteins","ui":"D009419","reg":"0"},{"n":"Quinoxalines","ui":"D011810","reg":"0"},{"n":"Receptors, GABA","ui":"D018079","reg":"0"},{"n":"Sodium Channel Blockers","ui":"D026941","reg":"0"},{"n":"2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline","ui":"C062865","reg":"118876-58-7"},{"n":"Tetrodotoxin","ui":"D013779","reg":"4368-28-9"},{"n":"gamma-Aminobutyric Acid","ui":"D005680","reg":"56-12-2"},{"n":"2-amino-5-phosphopentanoic acid","ui":"C056639","reg":"76326-31-3"},{"n":"Valine","ui":"D014633","reg":"HG18B9YRS7"}],"comments_corrections":null,"source_flags":5,"s2_open_access_pdf_url":"https://www.jneurosci.org/content/jneuro/34/40/13516.full.pdf","s2_open_access_landing_url":"https://www.semanticscholar.org/paper/d2ea94ee019d347f9577910106479c7df5d75b09","s2_open_access_license":"CCBYNCSA","s2_open_access_status":"HYBRID","pmc_open_access_pdf_url":null,"pmc_open_access_landing_url":null,"pmc_open_access_license":null,"pmc_open_access_status":null,"unpaywall_open_access_pdf_url":null,"unpaywall_open_access_landing_url":null,"unpaywall_open_access_license":null,"unpaywall_open_access_status":null,"abstract":"GABA is the canonical inhibitory neurotransmitter in the CNS. This inhibitory action is largely mediated by GABA type A receptors (GABAARs). Among the many factors controlling GABAergic transmission, brain-derived neurotrophic factor (BDNF) appears to play a major role in regulating synaptic inhibition. Recent findings have demonstrated that BDNF can be released as a precursor (proBDNF). Although the role of mature BDNF on GABAergic synaptogenesis and maintenance has been well studied, an important question still unanswered is whether secreted proBDNF might affect GABAergic neurotransmission. Here, we have used 14 d in vitro primary culture of hippocampal neurons and ex vivo preparations from rats to study the function of proBDNF in regulation of GABAAR trafficking and activity. We demonstrate that proBDNF impairs GABAergic transmission by the activation of two distinct pathways: (1) a RhoA-Rock-PTEN pathway that decreases the phosphorylation levels of GABAAR, thus affecting receptor function and triggering endocytosis and degradation of internalized receptors, and (2) a JAK-STAT-ICER pathway leading to the repression of GABAARs synthesis. These effects lead to the diminution of GABAergic synapses and are correlated with a decrease in GABAergic synaptic currents. These results revealed new functions for proBDNF-p75 neurotrophin receptor signaling pathway in the control of the efficacy of GABAergic synaptic activity by regulating the trafficking and synthesis of GABAARs at inhibitory synapses.","claims":[{"public_id":"cl_90224cd6d65d9ae738c557d7f8ed1973","status":"active","text":"Secreted proBDNF impairs GABAergic transmission in hippocampal neurons and ex vivo rat preparations.","confidence":0.98,"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/claims/cl_90224cd6d65d9ae738c557d7f8ed1973"},{"public_id":"cl_66671f1b7922d478578ea2ab9de231c9","status":"active","text":"These mechanisms diminish GABAergic synapses and are associated with reduced GABAergic synaptic currents.","confidence":0.95,"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/claims/cl_66671f1b7922d478578ea2ab9de231c9"},{"public_id":"cl_7e2b9fd36576b64304194cb9604b003f","status":"active","text":"proBDNF activates a JAK-STAT-ICER pathway that represses GABAA receptor synthesis.","confidence":0.96,"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/claims/cl_7e2b9fd36576b64304194cb9604b003f"},{"public_id":"cl_3914fd60921f383aa20fd87000248709","status":"active","text":"proBDNF activates a RhoA-Rock-PTEN pathway that reduces GABAA receptor phosphorylation, promotes receptor endocytosis and degradation, and weakens receptor function.","confidence":0.97,"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/claims/cl_3914fd60921f383aa20fd87000248709"}],"concepts":[{"public_id":"co_258d8c99beb5cde7072aebcc1659a80c","status":"active","name":"proBDNF","description":"The precursor form of brain-derived neurotrophic factor that is secreted and studied here as a regulator of inhibitory synaptic function.","types":["protein"],"aliases":["pro-brain-derived neurotrophic factor"],"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/concepts/co_258d8c99beb5cde7072aebcc1659a80c"},{"public_id":"co_330dba1de16e139eeeae6610dc5c39de","status":"active","name":"ex vivo preparations from rats","description":"Tissue preparations from rats used outside the organism to assess neuronal signaling.","types":["experimental preparation"],"aliases":["rat ex vivo preparations"],"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/concepts/co_330dba1de16e139eeeae6610dc5c39de"},{"public_id":"co_5b5dc1a8f4ca40e202c5c48ececd73ec","status":"active","name":"GABAergic synaptic currents","description":"Electrical currents produced by inhibitory synaptic activation of GABA receptors.","types":["electrophysiological measure"],"aliases":[],"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/concepts/co_5b5dc1a8f4ca40e202c5c48ececd73ec"},{"public_id":"co_69542b93c07ef58ff3a5659bcd7c3d0d","status":"active","name":"hippocampal neurons","description":"Primary neurons from the hippocampus used in culture to examine synaptic regulation.","types":["cell type"],"aliases":[],"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/concepts/co_69542b93c07ef58ff3a5659bcd7c3d0d"},{"public_id":"co_77d3f7996012ccc383031367521f21bb","status":"active","name":"RhoA-Rock-PTEN pathway","description":"A signaling cascade involving RhoA, ROCK, and PTEN that regulates receptor phosphorylation and trafficking.","types":["signaling pathway"],"aliases":[],"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/concepts/co_77d3f7996012ccc383031367521f21bb"},{"public_id":"co_90e96f6935aac0335a31ad852793db14","status":"active","name":"GABAergic transmission","description":"Synaptic inhibitory signaling mediated by gamma-aminobutyric acid in the central nervous system.","types":["neurotransmission"],"aliases":["GABA transmission"],"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/concepts/co_90e96f6935aac0335a31ad852793db14"},{"public_id":"co_c9843643c6727ac0e0d6bca90fb9b155","status":"active","name":"GABAergic synapses","description":"Inhibitory synaptic connections that use GABA as the neurotransmitter.","types":["synapse"],"aliases":[],"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/concepts/co_c9843643c6727ac0e0d6bca90fb9b155"},{"public_id":"co_c996f1a163d6e91131bd07257eefa311","status":"active","name":"JAK-STAT-ICER pathway","description":"A signaling cascade involving JAK, STAT, and ICER that regulates gene repression.","types":["signaling pathway"],"aliases":["JAK-STAT-ICER"],"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/concepts/co_c996f1a163d6e91131bd07257eefa311"},{"public_id":"co_da8d69700c611d45c00b837dc767f82b","status":"active","name":"GABAA receptors","description":"Ionotropic GABA receptors that mediate most fast inhibitory neurotransmission.","types":["receptor"],"aliases":["GABA type A receptors","GABAARs"],"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/concepts/co_da8d69700c611d45c00b837dc767f82b"}],"external_ids":{"DOI":"10.1523/JNEUROSCI.2069-14.2014","ArXiv":null,"PubMed":25274828,"PubMedCentral":"PMC6608319","MAG":1982504898,"DBLP":null,"ACL":null},"open_access":{"is_open_access":true,"pdf_url":"https://www.jneurosci.org/content/jneuro/34/40/13516.full.pdf","landing_url":"https://www.semanticscholar.org/paper/d2ea94ee019d347f9577910106479c7df5d75b09","source":"semantic_scholar","pdf_url_source":"semantic_scholar_open_access_pdf","license":"CCBYNCSA","status":"HYBRID","reason":null},"reference_availability":{"status":"available","references_indexed":true,"full_text_available":false,"full_text_source":null,"count_basis":"semantic_scholar_metadata","extraction_status":"not_applicable","reason":null},"source":{"provider":"episteme2","base_corpus":"semantic_scholar_dump","freshness_mode":"unknown","basis":["semantic_scholar_metadata","postgres_metadata"],"limits":["paper metadata is based on indexed upstream scholarly datasets","claims and concepts are available only for extracted papers","absence of claims or concepts means no extracted graph data is available in this response"],"status":"available","degraded":false,"degraded_reasons":[],"diagnostics":{"status":"available","degraded":false,"degraded_reasons":[],"metadata_status":"available","graph_status":"available","abstract_status":"available"},"source_flags":5},"paper_id":633772,"paper_uid":"6ccdb7c1-f1da-4e40-a888-ee7efbf309ee","canonical_identity":{"paper_id":633772,"paper_uid":"6ccdb7c1-f1da-4e40-a888-ee7efbf309ee","identity_status":"available","lookup_basis":"semantic_scholar_external_id","compatibility_path":"corpus_id"},"url":"https://sah.borca.ai/papers/14886763"}