{"doi":"10.1093/cercor/bhaa413","title":"Hyperactive MEK1 Signaling in Cortical GABAergic Neurons Promotes Embryonic Parvalbumin Neuron Loss and Defects in Behavioral Inhibition","abstract":"Many developmental syndromes have been linked to genetic mutations that cause abnormal ERK/MAPK activity; however, the neuropathological effects of hyperactive signaling are not fully understood. Here, we examined whether hyperactivation of MEK1 modifies the development of GABAergic cortical interneurons (CINs), a heterogeneous population of inhibitory neurons necessary for cortical function. We show that GABAergic-neuron specific MEK1 hyperactivation in vivo leads to increased cleaved caspase-3 labeling in a subpopulation of immature neurons in the embryonic subpallial mantle zone. Adult mutants displayed a significant loss of parvalbumin (PV), but not somatostatin, expressing CINs and a reduction in perisomatic inhibitory synapses on excitatory neurons. Surviving mutant PV-CINs maintained a typical fast-spiking phenotype but showed signs of decreased intrinsic excitability that coincided with an increased risk of seizure-like phenotypes. In contrast to other mouse models of PV-CIN loss, we discovered a robust increase in the accumulation of perineuronal nets, an extracellular structure thought to restrict plasticity. Indeed, we found that mutants exhibited a significant impairment in the acquisition of behavioral response inhibition capacity. Overall, our data suggest PV-CIN development is particularly sensitive to hyperactive MEK1 signaling, which may underlie certain neurological deficits frequently observed in ERK/MAPK-linked syndromes.","journal":"Cerebral Cortex","year":2020,"id":75831,"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":23,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9571,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":395691,"name":"Lauren T. Hewitt","orcid":"0000-0001-7270-7679","position":1,"is_corresponding":false},{"id":395692,"name":"Kenji Nishimura","orcid":"0000-0002-2955-5195","position":2,"is_corresponding":false},{"id":395693,"name":"Sara Knowles","orcid":"0000-0003-3906-8195","position":3,"is_corresponding":false},{"id":395694,"name":"George R. Bjorklund","orcid":"0000-0002-8113-2739","position":4,"is_corresponding":false},{"id":246668,"name":"Shiv Shah","orcid":"0000-0001-6605-0877","position":5,"is_corresponding":false},{"id":396546,"name":"Noah Fry","orcid":null,"position":6,"is_corresponding":false},{"id":395695,"name":"Katherina P. Rees","orcid":"0000-0003-4663-6672","position":7,"is_corresponding":false},{"id":395696,"name":"Tanya Gupta","orcid":"0000-0002-4938-4637","position":8,"is_corresponding":false},{"id":395697,"name":"Carter W. Daniels","orcid":"0000-0002-9043-8000","position":9,"is_corresponding":false},{"id":395698,"name":"Guohui Li","orcid":"0000-0003-0033-3895","position":10,"is_corresponding":false},{"id":396547,"name":"Steven T. Marsh","orcid":null,"position":11,"is_corresponding":false},{"id":395699,"name":"David M. Treiman","orcid":"0000-0001-5028-4097","position":12,"is_corresponding":false},{"id":395700,"name":"M. Foster Olive","orcid":"0000-0002-2517-0351","position":13,"is_corresponding":false},{"id":395701,"name":"Trent Anderson","orcid":"0000-0002-3541-7741","position":14,"is_corresponding":false},{"id":395702,"name":"Federico Sanabria","orcid":"0000-0003-0719-6766","position":15,"is_corresponding":false},{"id":393820,"name":"William D. Snider","orcid":null,"position":16,"is_corresponding":false},{"id":395703,"name":"Jason M. Newbern","orcid":"0000-0003-2865-0112","position":17,"is_corresponding":false},{"id":396545,"name":"Michael Holter","orcid":null,"position":0,"is_corresponding":true}],"reference_count":112,"raw_metadata":null,"created_at":"2026-07-18T21:46:55.856612Z","pmid":"33570093","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":[]}