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bioRxiv · 10.1101/2022.10.24.513511

Cholinergic Modulation Shifts the Response of CA1 Pyramidal Cells to Depolarizing Ramps via TRPM4 Channels with Implications for Place Field Firing

Combe, C. L.·Upchurch, C. M.·Canavier, C. C.·Gasparini, S.
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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.

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Combe, C. L., Upchurch, C. M., Canavier, C. C., Gasparini, S.. 2022-10-25. Cholinergic Modulation Shifts the Response of CA1 Pyramidal Cells to Depolarizing Ramps via TRPM4 Channels with Implications for Place Field Firing. https://doi.org/10.1101/2022.10.24.513511

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