{"doi":"10.1093/neuonc/noae054","title":"<i>NF1</i> mutation-driven neuronal hyperexcitability sets a threshold for tumorigenesis and therapeutic targeting of murine optic glioma","abstract":"BACKGROUND: With the recognition that noncancerous cells function as critical regulators of brain tumor growth, we recently demonstrated that neurons drive low-grade glioma initiation and progression. Using mouse models of neurofibromatosis type 1 (NF1)-associated optic pathway glioma (OPG), we showed that Nf1 mutation induces neuronal hyperexcitability and midkine expression, which activates an immune axis to support tumor growth, such that high-dose lamotrigine treatment reduces Nf1-OPG proliferation. Herein, we execute a series of complementary experiments to address several key knowledge gaps relevant to future clinical translation. METHODS: We leverage a collection of Nf1-mutant mice that spontaneously develop OPGs to alter both germline and retinal neuron-specific midkine expression. Nf1-mutant mice harboring several different NF1 patient-derived germline mutations were employed to evaluate neuronal excitability and midkine expression. Two distinct Nf1-OPG preclinical mouse models were used to assess lamotrigine effects on tumor progression and growth in vivo. RESULTS: We establish that neuronal midkine is both necessary and sufficient for Nf1-OPG growth, demonstrating an obligate relationship between germline Nf1 mutation, neuronal excitability, midkine production, and Nf1-OPG proliferation. We show anti-epileptic drug (lamotrigine) specificity in suppressing neuronal midkine production. Relevant to clinical translation, lamotrigine prevents Nf1-OPG progression and suppresses the growth of existing tumors for months following drug cessation. Importantly, lamotrigine abrogates tumor growth in two Nf1-OPG strains using pediatric epilepsy clinical dosing. CONCLUSIONS: Together, these findings establish midkine and neuronal hyperexcitability as targetable drivers of Nf1-OPG growth and support the use of lamotrigine as a potential chemoprevention or chemotherapy agent for children with NF1-OPG.","journal":"Neuro-Oncology","year":2024,"id":425955,"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":18,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.956,"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":663297,"name":"Jit Chatterjee","orcid":"0000-0002-2444-9748","position":1,"is_corresponding":false},{"id":1190390,"name":"Joshua P. Koleske","orcid":"0009-0004-8133-1801","position":2,"is_corresponding":false},{"id":1060236,"name":"Yunqing Gao","orcid":null,"position":3,"is_corresponding":false},{"id":414884,"name":"Stephanie L Bozeman","orcid":null,"position":4,"is_corresponding":false},{"id":1224773,"name":"Chloe M Kernan","orcid":null,"position":5,"is_corresponding":false},{"id":1224774,"name":"Lara Isabel Marco Y Marquez","orcid":null,"position":6,"is_corresponding":false},{"id":851358,"name":"Ji‐Kang Chen","orcid":"0000-0001-7762-3888","position":7,"is_corresponding":false},{"id":1224775,"name":"Caitlin E Kelly","orcid":null,"position":8,"is_corresponding":false},{"id":1224776,"name":"Connor J Blair","orcid":null,"position":9,"is_corresponding":false},{"id":360759,"name":"Dennis J. Dietzen","orcid":"0000-0001-7593-4092","position":10,"is_corresponding":false},{"id":378389,"name":"Robert A. Kesterson","orcid":"0000-0003-1331-0780","position":11,"is_corresponding":false},{"id":295596,"name":"David H. Gutmann","orcid":"0000-0002-3127-5045","position":12,"is_corresponding":false},{"id":305781,"name":"Corina Anastasaki","orcid":"0000-0002-9928-6488","position":0,"is_corresponding":true}],"reference_count":64,"raw_metadata":null,"created_at":"2026-07-19T01:58:32.160975Z","pmid":"38607967","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":[]}