Cholinergic modulation shifts the response of CA1 pyramidal cells to depolarizing ramps via TRPM4 channels with potential implications for place field firing

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.

Roles of TRPM channels in glioma

“… 73 In addition, calmodulin (CAM) binding sites and ATP binding sites were also found at the TRPM4 and TRPM5 channels, and these channels could affect the channel’s Ca2+ sensitivity. 74 …”

Persistent Interruption in Parvalbumin Positive Inhibitory Interneurons: Biophysical and Mathematical Mechanisms

“…Another putative substrate for persistent activity relies on the intrinsic bistable dynamic of individual neurons (Zylberberg and Strowbridge 2017). On the single cell level, persistent Na + current (Yamada-Hanff and Bean 2013) in CA1 pyramidal cells, Ca 2+ activated Ca 2+ currents in entorhinal cortical pyramidal cells (Egorov et al 2002) and CA1 pyramidal cells (Combe et al 2023), and low threshold Ca 2+ currents in other cells (Otsuka et al 2001; Perrier et al 2002) have been shown to contribute to regenerative firing, by making the neuron bistable or even multi-stable, and thus more likely to continue firing after excitation is terminated.…”

Persistent Interruption in Parvalbumin-Positive Inhibitory Interneurons: Biophysical and Mathematical Mechanisms

“…Another putative substrate for persistent activity relies on the intrinsic bistable dynamic of individual neurons ( Zylberberg and Strowbridge, 2017 ). On the single-cell level, persistent Na + current ( Yamada-Hanff and Bean, 2013 ) in CA1 pyramidal cells (PYRs), Ca 2+ -activated Ca 2+ currents in entorhinal cortical PYRs ( Egorov et al, 2002 ) and CA1 PYRs ( Combe et al, 2023 ), and L-type Ca 2+ currents in other cells ( Otsuka et al, 2001 ; Perrier et al, 2002 ) have been shown to contribute to regenerative firing, by making the neuron bistable or even multistable, and thus more likely to continue firing after excitation is terminated.…”