{"doi":"10.1101/2022.10.24.513511","title":"Cholinergic Modulation Shifts the Response of CA1 Pyramidal Cells to Depolarizing Ramps via TRPM4 Channels with Potential Implications for Place Field Firing","abstract":"Abstract A synergistic combination of in vitro electrophysiology and multicompartmental modeling of rat CA1 pyramidal neurons identified TRPM4 channels as major drivers of cholinergic modulation of the firing rate during a triangular current ramp, which emulates the bump in synaptic input received while traversing the place field. In control, fewer spikes at lower frequencies are elicited on the down-ramp compared to the up-ramp due to long-term inactivation of the Na V channel. The cholinergic agonist carbachol (CCh) removes or even reverses this spike rate adaptation, causing more spikes to be elicited on the down-ramp than the up-ramp. CCh application during Schaffer collateral stimulation designed to simulate a ramp produces similar shifts in the center of mass of firing to later in the ramp. The non-specific TRP antagonist flufenamic acid and the TRPM4-specific blockers CBA and 9-phenanthrol, but not the TRPC-specific antagonist SKF96365, reverse the effect of CCh; this implicates the Ca 2+ -activated nonspecific cation current, I CAN , carried by TRPM4 channels. The cholinergic shift of the center of mass of firing is prevented by strong intracellular Ca 2+ buffering but not by antagonists for IP 3 and ryanodine receptors, ruling out a role for known mechanisms of release from intracellular Ca 2+ stores. Pharmacology combined with modeling suggest that [Ca 2+ ] in a nanodomain near the TRPM4 channel is elevated through an unknown source that requires both muscarinic receptor activation and depolarization-induced Ca 2+ influx during the ramp. Activation of the regenerative inward TRPM4 current in the model qualitatively replicates and provides putative underlying mechanisms for the experimental observations.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":312666,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9534,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":831220,"name":"Carol Upchurch","orcid":"0000-0002-8693-436X","position":1,"is_corresponding":false},{"id":426000,"name":"Carmen C. Canavier","orcid":"0000-0003-4368-6906","position":2,"is_corresponding":false},{"id":636197,"name":"Sonia Gasparini","orcid":"0000-0001-5847-9315","position":3,"is_corresponding":false},{"id":636196,"name":"Crescent L. Combe","orcid":"0000-0003-1181-6569","position":0,"is_corresponding":true}],"reference_count":131,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T00:33:40.460845Z","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":[]}