Cholinergic modulation shifts the response of CA1 pyramidal cells to depolarizing ramps via TRPM4 Channels with potential implications for place field firing
- Louisiana State University Health Sciences Center New Orleans, United States
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 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.
Data availability
All data generated during this study are included in the manuscript; Source Data files have been provided for all experimental figures (1,2,3,4,5,6,10)Model code is freely available and can be downloaded from ModelDB at: http://modeldb.yale.edu/267599,access code: cholinergicshift.
Article and author information
Author details
Funding
National Institute of Mental Health (R01MH115832)
- Carmen C Canavier
National Institute of Mental Health (R01MH115832)
- Sonia Gasparini
National Science Foundation (2018936)
- Carmen C Canavier
Louisiana State University Health Sciences Center School of Medicine (Research Enhancement Program)
- Sonia Gasparini
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All the procedures described below were conducted according to protocols developed by following guidelines on the responsible use of laboratory animals in research from the National Institutes of Health and approved by the Louisiana State University Health Sciences Center-New Orleans Institutional Animal Care and Use Committee (IACUC, protocol numbers 3583 and 3851).Rats were deeply anesthetized via intraperitoneal injection of ketamine and xylazine (90 and 10 mg/kg, respectively), until the disappearance of the toe-pinch and palpebral reflexes.
Copyright
© 2023, Combe et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Cholinergic modulation shifts the response of CA1 pyramidal cells to depolarizing ramps via TRPM4 Channels with potential implications for place field firing
eLife 12:e84387.
https://doi.org/10.7554/eLife.84387
