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.
Highlights
Cholinergic receptor activation is important for various memory processes (Spencer et al, 1985; Granon et al, 1995; Hasselmo, 1999; Anagnostaras et al, 2003) and has profound effects on the excitability and intrinsic firing patterns of neurons (Krnjevic, 1993)
Persistent firing is thought to depend on the action of muscarinic agonists to promote the appearance of an excitatory slow afterdepolarization following a brief burst of action potentials, in contrast to the brief afterhyperpolarization (AHP) that normally follows a burst of spikes in the absence of cholingergic stimulation (Haj-Dahmane and Andrade, 1998)
By examining animals in which TRPM4 and transient receptor potential melastatin 5 channel (TRPM5) were deleted, either alone or in combination, we found that TRPM5 makes an important contribution to the slow afterdepolarization (sADP) whereas we could not detect a contribution from TRPM4
Summary
Cholinergic receptor activation is important for various memory processes (Spencer et al, 1985; Granon et al, 1995; Hasselmo, 1999; Anagnostaras et al, 2003) and has profound effects on the excitability and intrinsic firing patterns of neurons (Krnjevic, 1993). One of the most intriguing examples of cholinergic regulation involves the generation of intrinsic persistent firing (Egorov et al, 2002; Fransén et al, 2006; Tahvildari et al, 2008). Persistent firing is thought to depend on the action of muscarinic agonists to promote the appearance of an excitatory slow afterdepolarization (sADP) following a brief burst of action potentials, in contrast to the brief afterhyperpolarization (AHP) that normally follows a burst of spikes in the absence of cholingergic stimulation (Haj-Dahmane and Andrade, 1998). In addition to the importance of muscarinic receptor stimulation for sADPs in many cells
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