{"doi":"10.1101/2024.03.01.582935","title":"Astrocytic thrombospondins 1 and 2 are required for cortical synapse development controlling instrumental performance","abstract":"Abstract During development, controlled synaptogenesis is required to form functioning neural circuits that underlie cognition and behavior. Astrocytes, a major glial-cell type in the central nervous system (CNS), promote synapse formation by secreting synaptogenic proteins. Thrombospondins 1 and 2 (TSP1/2), which act through their neuronal receptor α2δ-1, are required for proper intracortical excitatory synaptogenesis. In the adult brain, the loss of α2δ-1 impairs training-induced excitatory synaptogenesis in the anterior cingulate cortex (ACC), and this impairment leads to increased effort-exertion during high-effort tasks. Here, we tested whether TSP1 and TSP2 are required for controlling effort during operant conditioning by using a lever press for food reward training in mice. Surprisingly, we found that constitutive loss of TSP1/2 significantly reduced lever pressing performance when the effort required for a food reward was increased, a phenotype opposite of α2δ-1 loss. Loss of TSP1/2 reduced excitatory synapse number significantly in adult brains. However, in the ACC of TSP1/2 knockout mice, there was still training-induced excitatory synaptogenesis, likely through the upregulation of TSP4, a TSP isoform that is also synaptogenic. Unexpectedly, we also found a significant increase in inhibitory synapse number and function in the ACC of TSP1/2 knockout mice, which was eliminated after training. Finally, we found that astrocyte-specific ablation of TSP1/2 in developing but not adult astrocytes is sufficient to reduce performance during high-effort tasks. Taken together, our study highlights the importance of developmental astrocyte-derived synaptogenic cues TSP1 and 2 in establishing excitatory and inhibitory circuits that control effort during operant conditioning in adults.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":490211,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9535,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":813471,"name":"Francesco Paolo Ulloa Severino","orcid":"0000-0003-3725-9713","position":1,"is_corresponding":false},{"id":825714,"name":"Shiyi Wang","orcid":"0000-0003-3433-3025","position":2,"is_corresponding":false},{"id":1021813,"name":"Dhanesh Sivadasan Bindu","orcid":null,"position":3,"is_corresponding":false},{"id":562099,"name":"Kristina Sakers","orcid":"0000-0001-8853-053X","position":4,"is_corresponding":false},{"id":825715,"name":"Sarah A. Johnson","orcid":"0000-0003-3392-0535","position":5,"is_corresponding":false},{"id":351424,"name":"Henry H. Yin","orcid":"0000-0003-1546-6850","position":6,"is_corresponding":false},{"id":247144,"name":"Çağla Eroğlu","orcid":"0000-0002-7204-0218","position":7,"is_corresponding":false},{"id":825713,"name":"Oluwadamilola O. Lawal","orcid":"0000-0001-5921-4693","position":0,"is_corresponding":true}],"reference_count":112,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:08:32.775003Z","pmid":null,"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":[]}