Differential contribution of TRPM4 and TRPM5 nonselective cation channels to the slow afterdepolarization in mouse prefrontal cortex neurons

Abstract

In certain neurons from different brain regions, a brief burst of action potentials can activate a slow afterdepolarization (sADP) in the presence of muscarinic acetylcholine receptor agonists. The sADP, if suprathreshold, can contribute to persistent non-accommodating firing in some of these neurons. Previous studies have characterized a Ca2+-activated non-selective cation (CAN) current (ICAN) that is thought to underlie the sADP. ICAN depends on muscarinic receptor stimulation and exhibits a dependence on neuronal activity, membrane depolarization and Ca2+-influx similar to that observed for the sADP. Despite the widespread occurrence of sADPs in neurons throughout the brain, the molecular identity of the ion channels underlying these events, as well as ICAN, remains uncertain. Here we used a combination of genetic, pharmacological and electrophysiological approaches to characterize the molecular mechanisms underlying the muscarinic receptor-dependent sADP in layer 5 pyramidal neurons of mouse prefrontal cortex. First, we confirmed that in the presence of the cholinergic agonist carbachol a brief burst of action potentials triggers a prominent sADP in these neurons. Second, we confirmed that this sADP requires activation of a PLC signaling cascade and intracellular calcium signaling. Third, we obtained direct evidence that the transient receptor potential (TRP) melastatin 5 channel (TRPM5), which is thought to function as a CAN channel in non-neural cells, contributes importantly to the sADP in the layer 5 neurons. In contrast, the closely related TRPM4 channel may play only a minor role in the sADP.

Mechanisms of Persistent Activity in Cortical Circuits: Possible Neural Substrates for Working Memory

“…The primary evidence for an indirect pathway is the sensitivity of persistent firing to chelation of Ca 2+ ions (Lei et al 2014, Rahman & Berger 2011). Simple biophysical mechanisms, such as triggering regenerative inward Ca 2+ or Na + currents, are triggered directly by depolarizing stimuli and therefore should not be abolished by blockade of the intracellular signaling function of Ca 2+ ions.…”

“…Although the molecular identity of the ion channel mediating this response is unknown, it appears to be gated by Ca 2+ (or Ca 2+ ions bound to an accessory protein), is permeable to Na + and Ca 2+ , and is sensitive to flufenamic acid (FFA; Haj-Dahmane & Andrade 1999, Lei et al 2014, Rahman & Berger 2011, Tahvildari et al 2008, Zhang et al 2011), a nonsteroidal anti-inflammatory agent. Several groups have hypothesized that a subtype of transient receptor potential (TRP) channels may mediate I CAN responses, based on pharmacological studies (Lei et al 2014, Reboreda et al 2011, Petersson & Fransén 2012) and tests of peptides that interfere with TRP channel function (Yan et al 2009, Zhang et al 2011). However, thus far no direct evidence has demonstrated that persistent firing and the associated afterdepolarization response are abolished in TRP channel knockout animals [although Lei et al (2014) found partial blockade in TRPM5 knockout mice].…”

“…Several groups have hypothesized that a subtype of transient receptor potential (TRP) channels may mediate I CAN responses, based on pharmacological studies (Lei et al 2014, Reboreda et al 2011, Petersson & Fransén 2012) and tests of peptides that interfere with TRP channel function (Yan et al 2009, Zhang et al 2011). However, thus far no direct evidence has demonstrated that persistent firing and the associated afterdepolarization response are abolished in TRP channel knockout animals [although Lei et al (2014) found partial blockade in TRPM5 knockout mice]. Given the wide diversity of TRP channels (Reboreda et al 2011), fully testing this hypothesis may require generating mice that are null for many different TRP subunits.…”

Ionic mechanisms maintaining action potential conduction velocity at high firing frequencies in an unmyelinated axon

“…; Lei et al. ). Future experiments should focus on rigorously ruling out calcium currents involved in AHP shortening via highly selectively calcium channel blockers.…”

TRPC channels are not required for graded persistent activity in entorhinal cortex neurons

“…Indeed, besides TRPC, other subfamily member of TRP channels, that are expressed in the brain (Sawamura, Shirakawa, Nakagawa, Mori, & Kaneko, ), could underlie persistent activity in cortical neurons. For instance, the TRP melastatin 5 channel (TRPM5) contributes importantly to the sADP in the mouse prefrontal cortex (Lei et al, ). By examining animals in which TRPM4 and TRPM5 channels were genetically deleted either alone or in combination this study further showed that TRPM5 but not TRPM4 channels are involved in the generation of the sADP in LV neurons.…”