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

Abstract

AbstractA synergistic combination ofin vitroelectrophysiology 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. The cholinergic agonist carbachol (CCh) reverses this spike rate adaptation, causing more spikes to be elicited on the down-ramp than the up-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. Modeling suggests that the IP3receptor is the locus that requires both CCh and sustained depolarization to produce the rightward shift in firing rate along the ramp. In the model, a step change in IP3, representing the activation of muscarinic receptors by CCh, coupled with an increase in bulk [Ca2+] due to voltage-gated Ca2+influx during the ramp, activates Ca2+-induced Ca2+release (CICR). CICR in turn activates TRPM4, via a nanodomain required by the presumed micromolar half-activation for TRPM4.