Cholinergic modulation shifts the response of CA1 pyramidal cells to depolarizing ramps via TRPM4 channels with potential implications for place field firing
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 trav...
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2023-07-01
|
| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/84387 |
| _version_ | 1827894373797330944 |
|---|---|
| author | Crescent L Combe Carol M Upchurch Carmen C Canavier Sonia Gasparini |
| author_facet | Crescent L Combe Carol M Upchurch Carmen C Canavier Sonia Gasparini |
| author_sort | Crescent L Combe |
| collection | DOAJ |
| description | 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 NaV 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 Ca2+-activated nonspecific cation current, ICAN, carried by TRPM4 channels. The cholinergic shift of the center of mass of firing is prevented by strong intracellular Ca2+ buffering but not by antagonists for IP3 and ryanodine receptors, ruling out a role for known mechanisms of release from intracellular Ca2+ stores. Pharmacology combined with modeling suggest that [Ca2+] in a nanodomain near the TRPM4 channel is elevated through an unknown source that requires both muscarinic receptor activation and depolarization-induced Ca2+ 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. |
| first_indexed | 2024-03-12T22:05:42Z |
| format | Article |
| id | doaj.art-fcb88f640af74fb18a8c3894c8eee646 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-03-12T22:05:42Z |
| publishDate | 2023-07-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-fcb88f640af74fb18a8c3894c8eee6462023-07-24T16:11:14ZengeLife Sciences Publications LtdeLife2050-084X2023-07-011210.7554/eLife.84387Cholinergic modulation shifts the response of CA1 pyramidal cells to depolarizing ramps via TRPM4 channels with potential implications for place field firingCrescent L Combe0https://orcid.org/0000-0003-1181-6569Carol M Upchurch1Carmen C Canavier2Sonia Gasparini3https://orcid.org/0000-0001-5847-9315Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, United StatesDepartment of Cell Biology and Anatomy, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, United StatesDepartment of Cell Biology and Anatomy, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, United StatesNeuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, United States; Department of Cell Biology and Anatomy, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, United StatesA 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 NaV 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 Ca2+-activated nonspecific cation current, ICAN, carried by TRPM4 channels. The cholinergic shift of the center of mass of firing is prevented by strong intracellular Ca2+ buffering but not by antagonists for IP3 and ryanodine receptors, ruling out a role for known mechanisms of release from intracellular Ca2+ stores. Pharmacology combined with modeling suggest that [Ca2+] in a nanodomain near the TRPM4 channel is elevated through an unknown source that requires both muscarinic receptor activation and depolarization-induced Ca2+ 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.https://elifesciences.org/articles/84387hippocampusmulticompartmental modelingpatch clampnanodomainnonspecific cation currentneuromodulation |
| spellingShingle | Crescent L Combe Carol M Upchurch Carmen C Canavier Sonia Gasparini Cholinergic modulation shifts the response of CA1 pyramidal cells to depolarizing ramps via TRPM4 channels with potential implications for place field firing eLife hippocampus multicompartmental modeling patch clamp nanodomain nonspecific cation current neuromodulation |
| title | Cholinergic modulation shifts the response of CA1 pyramidal cells to depolarizing ramps via TRPM4 channels with potential implications for place field firing |
| title_full | Cholinergic modulation shifts the response of CA1 pyramidal cells to depolarizing ramps via TRPM4 channels with potential implications for place field firing |
| title_fullStr | Cholinergic modulation shifts the response of CA1 pyramidal cells to depolarizing ramps via TRPM4 channels with potential implications for place field firing |
| title_full_unstemmed | Cholinergic modulation shifts the response of CA1 pyramidal cells to depolarizing ramps via TRPM4 channels with potential implications for place field firing |
| title_short | Cholinergic modulation shifts the response of CA1 pyramidal cells to depolarizing ramps via TRPM4 channels with potential implications for place field firing |
| title_sort | cholinergic modulation shifts the response of ca1 pyramidal cells to depolarizing ramps via trpm4 channels with potential implications for place field firing |
| topic | hippocampus multicompartmental modeling patch clamp nanodomain nonspecific cation current neuromodulation |
| url | https://elifesciences.org/articles/84387 |
| work_keys_str_mv | AT crescentlcombe cholinergicmodulationshiftstheresponseofca1pyramidalcellstodepolarizingrampsviatrpm4channelswithpotentialimplicationsforplacefieldfiring AT carolmupchurch cholinergicmodulationshiftstheresponseofca1pyramidalcellstodepolarizingrampsviatrpm4channelswithpotentialimplicationsforplacefieldfiring AT carmenccanavier cholinergicmodulationshiftstheresponseofca1pyramidalcellstodepolarizingrampsviatrpm4channelswithpotentialimplicationsforplacefieldfiring AT soniagasparini cholinergicmodulationshiftstheresponseofca1pyramidalcellstodepolarizingrampsviatrpm4channelswithpotentialimplicationsforplacefieldfiring |