{"doi":"10.64898/2025.12.30.697121","title":"Rescuing Neurodevelopmental Deficits in AMPA Receptor Gain-of-Function Mutant","abstract":"Abstract AMPA receptors (AMPARs) mediate fast excitatory synaptic transmission and are essential for neuronal development and brain function. We investigated the role of a recurrent variant in the AMPAR GluA1 subunit (GRIA1 p.A636T) identified in individuals with autism spectrum disorder (ASD) and intellectual disability (ID). To test causality and mechanism, we generated a Gria1 -A636T knock-in mouse model. Mutant mice exhibited core ASD/ID-like behaviors and a selective hippocampal vulnerability characterized by progressive dendritic atrophy and neuronal loss. Despite reduced GluA1-containing complexes, AMPARs displayed synaptic hyperexcitability and failed to undergo the normal postnatal transition to calcium-impermeable AMPARs, resulting in persistent excitotoxicity. To explore therapeutic intervention, we designed an allele-specific antisense oligonucleotide to specifically silence the mutant transcript. A single neonatal administration of the antisense oligonucleotide entirely prevented hippocampal pathology and ameliorated behavioral deficits. These findings establish GRIA1 -A636T as a gain-of-function mutation that drives developmental excitotoxicity and highlight the potential of RNA-targeted precision medicine for neurodevelopmental disorders.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":559763,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9554,"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":1461966,"name":"Yu-Min Huang","orcid":null,"position":1,"is_corresponding":false},{"id":1461579,"name":"Chih‐Ching Chung","orcid":"0000-0002-7843-4154","position":2,"is_corresponding":false},{"id":1461967,"name":"R T Johnson","orcid":null,"position":3,"is_corresponding":false},{"id":1461968,"name":"Cheng-Ya Tsai","orcid":null,"position":4,"is_corresponding":false},{"id":1461580,"name":"Yuhan Chen","orcid":"0009-0004-8540-2435","position":5,"is_corresponding":false},{"id":644086,"name":"Han L. Tan","orcid":"0000-0001-5163-7720","position":6,"is_corresponding":false},{"id":1461969,"name":"Fu-Yun Hsiao","orcid":null,"position":7,"is_corresponding":false},{"id":275418,"name":"Richard L. Huganir","orcid":"0000-0001-9783-5183","position":8,"is_corresponding":false},{"id":1461970,"name":"Shu-Ling Chiu","orcid":null,"position":9,"is_corresponding":false},{"id":1461578,"name":"Chih-Ming Chen","orcid":"0000-0002-0290-4279","position":0,"is_corresponding":true}],"reference_count":42,"raw_metadata":null,"created_at":"2026-07-19T02:55:39.010633Z","pmid":"41509361","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":[]}