{"doi":"10.1016/j.neuron.2025.04.013","title":"Presynaptic α2δs specify synaptic gain, not synaptogenesis, in the mammalian brain","abstract":"The α 2 δs are a family of extracellular synaptic molecules that are auxiliary subunits of voltage-gated Ca 2+ channel (Ca V ) complexes. They are linked to brain disorders and are drug targets. The α 2 δs are implicated in controlling synapse development and function through distinct Ca V -dependent and Ca V -independent pathways. However, the mechanisms of action remain enigmatic since synapses contain mixtures of α 2 δ isoforms in the pre- and postsynaptic compartments. We developed a triple conditional knockout mouse model and demonstrated the combined selective presynaptic ablation of α 2 δs in vivo in a developing mammalian glutamatergic synapse. We identified presynaptic α 2 δs as positive regulators of Munc13-1 levels, an essential neurotransmitter release protein. We found that mammalian synapse development, presynaptic Ca V 2.1 organization, and the transsynaptic alignment of presynaptic release sites and postsynaptic glutamate receptors are independent of presynaptic α 2 δs. Therefore, our results define presynaptic α 2 δ regulatory roles and suggest a new α 2 δ role in controlling synaptic strength and plasticity.","journal":"Neuron","year":2025,"id":523349,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9478,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1395780,"name":"Jianing Li","orcid":"0000-0001-5384-773X","position":1,"is_corresponding":false},{"id":495705,"name":"Connon I. Thomas","orcid":"0000-0003-0995-9667","position":2,"is_corresponding":false},{"id":1395781,"name":"Mohammed Al-Yaari","orcid":"0000-0003-3196-266X","position":3,"is_corresponding":false},{"id":364083,"name":"Debbie Guerrero‐Given","orcid":"0009-0006-5898-6919","position":4,"is_corresponding":false},{"id":364082,"name":"Naomi Kamasawa","orcid":"0000-0002-8926-5309","position":5,"is_corresponding":false},{"id":471426,"name":"Samuel Young","orcid":"0000-0002-7589-7612","position":6,"is_corresponding":false},{"id":1396267,"name":"William Milanick","orcid":null,"position":0,"is_corresponding":true}],"reference_count":91,"raw_metadata":null,"created_at":"2026-07-19T02:50:03.004175Z","pmid":"40367942","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}