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Here, we examined how BDNF-TrkB signalling regulates synaptic GluN2A-containing N-methyl-D-aspartate receptors (NMDAR) and impacts network synchronization in cultured hippocampal neurons.<\/jats:p>\n                  <jats:p>BDNF increased synaptic surface expression of GluN2A-NMDAR in rat hippocampal synaptoneurosomes and cultured neurons in a time- and protein synthesis-dependent manner. Mechanistically, we identified a signalling cascade involving hnRNPK, Pyk2 and protein kinase C (PKC) as critical for this effect. Knockdown of hnRNPK or Pyk2, PKC inhibition or expression of a phosphorylation-deficient Pyk2 mutant prevented BDNF-induced GluN2A synaptic accumulation. Pyk2 phosphorylation at Y402 was required for both basal and BDNF-induced GluN2A expression. Multielectrode array recordings demonstrated that BDNF and GluN2A-NMDAR contribute to enhanced network activity following neuronal stimulation. In vivo, BDNF-TrkB signalling mediated increased synaptic GluN2A expression in the hippocampus of rats subjected to the pilocarpine model of temporal lobe epilepsy, confirming a TrkB-dependent mechanism.<\/jats:p>\n                  <jats:p>These findings reveal a BDNF\/TrkB\u2013PKC\u2013Pyk2\u2013hnRNPK pathway that regulates GluN2A synaptic expression and neuronal excitability, offering new insights into the molecular basis of synaptic plasticity and epilepsy.<\/jats:p>","DOI":"10.1093\/brain\/awag164","type":"journal-article","created":{"date-parts":[[2026,5,3]],"date-time":"2026-05-03T21:04:46Z","timestamp":1777842286000},"source":"Crossref","is-referenced-by-count":2,"title":["GluN2A-NMDA receptors mediate the effect of BDNF on network hyperexcitability in hippocampal neurons"],"prefix":"10.1093","author":[{"given":"Pasqualino","family":"De Luca","sequence":"first","affiliation":[{"name":"CNC-Center for Neuroscience and Cell Biology, University of Coimbra , 3004-504 Coimbra ,","place":["Portugal"]},{"name":"CIBB-Center for Innovation in Biomedicine and Biotechnology, University of Coimbra , 3004-504 Coimbra ,","place":["Portugal"]},{"name":"Institute for Interdisciplinary Research, University of Coimbra , 3030-789 Coimbra ,","place":["Portugal"]},{"name":"PhD Programme in Experimental Biology and Biomedicine (PDBEB), Institute for Interdisciplinary Research (IIIUC), University of Coimbra , 3030-789 Coimbra ,","place":["Portugal"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miranda","family":"Mele","sequence":"additional","affiliation":[{"name":"CNC-Center for Neuroscience and Cell Biology, University of Coimbra , 3004-504 Coimbra ,","place":["Portugal"]},{"name":"CIBB-Center for Innovation in Biomedicine and Biotechnology, University of Coimbra , 3004-504 Coimbra ,","place":["Portugal"]},{"name":"Institute for Interdisciplinary Research, University of Coimbra , 3030-789 Coimbra ,","place":["Portugal"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Napoli","sequence":"additional","affiliation":[{"name":"CNC-Center for Neuroscience and Cell Biology, University of Coimbra , 3004-504 Coimbra ,","place":["Portugal"]},{"name":"CIBB-Center for Innovation in Biomedicine and Biotechnology, University of Coimbra , 3004-504 Coimbra ,","place":["Portugal"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philemon","family":"Mshelia","sequence":"additional","affiliation":[{"name":"CNC-Center for Neuroscience and Cell Biology, University of Coimbra , 3004-504 Coimbra ,","place":["Portugal"]},{"name":"CIBB-Center for Innovation in Biomedicine and Biotechnology, University of Coimbra , 3004-504 Coimbra ,","place":["Portugal"]},{"name":"Abubakar Tafawa Balewa University Department of Human Physiology, , Bauchi 740272 ,","place":["Nigeria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui O","family":"Costa","sequence":"additional","affiliation":[{"name":"CNC-Center for Neuroscience and Cell Biology, University of Coimbra , 3004-504 Coimbra ,","place":["Portugal"]},{"name":"CIBB-Center for Innovation in Biomedicine and Biotechnology, University of Coimbra , 3004-504 Coimbra ,","place":["Portugal"]},{"name":"Institute for Interdisciplinary Research, University of Coimbra , 3030-789 Coimbra ,","place":["Portugal"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos B","family":"Duarte","sequence":"additional","affiliation":[{"name":"CNC-Center for Neuroscience and Cell Biology, University of Coimbra , 3004-504 Coimbra ,","place":["Portugal"]},{"name":"CIBB-Center for Innovation in Biomedicine and Biotechnology, University of Coimbra , 3004-504 Coimbra ,","place":["Portugal"]},{"name":"Department of Life Sciences, University of Coimbra , 3000-456 Coimbra 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