Abstract
The pedunculopontine nucleus (PPN), a structure known as a cholinergic member of the reticular activating system (RAS), is source and target of cholinergic neuromodulation and contributes to the regulation of the sleep–wakefulness cycle. The M-current is a voltage-gated potassium current modulated mainly by cholinergic signaling. KCNQ subunits ensemble into ion channels responsible for the M-current. In the central nervous system, KCNQ4 expression is restricted to certain brainstem structures such as the RAS nuclei. Here, we investigated the presence and functional significance of KCNQ4 in the PPN by behavioral studies and the gene and protein expressions and slice electrophysiology using a mouse model lacking KCNQ4 expression. We found that this mouse has alterations in the adaptation to changes in light–darkness cycles, representing the potential role of KCNQ4 in the regulation of the sleep–wakefulness cycle. As cholinergic neurons from the PPN participate in the regulation of this cycle, we investigated whether the cholinergic PPN might also possess functional KCNQ4 subunits. Although the M-current is an electrophysiological hallmark of cholinergic neurons, only a subpopulation of them had KCNQ4-dependent M-current. Interestingly, the absence of the KCNQ4 subunit altered the expression patterns of the other KCNQ subunits in the PPN. We also determined that, in wild-type animals, the cholinergic inputs of the PPN modulated the M-current, and these in turn can modulate the level of synchronization between neighboring PPN neurons. Taken together, the KCNQ4 subunit is present in a subpopulation of PPN cholinergic neurons, and it may contribute to the regulation of the sleep–wakefulness cycle.
Highlights
The neuronal M-current is a voltage-gated non-inactivating potassium current that sets resting membrane potential, regulates excitability, and shapes action potential firing (Delmas and Brown, 2005; Brown and Passmore, 2009)
We aimed to demonstrate the physiological significance of the M-current in the pedunculopontine nucleus (PPN) and the contribution of KCNQ4 to its activity
We aimed to investigate whether KCNQ4 contributes to the regulation of the sleep–wakefulness cycle
Summary
The neuronal M-current is a voltage-gated non-inactivating potassium current that sets resting membrane potential, regulates excitability, and shapes action potential firing (Delmas and Brown, 2005; Brown and Passmore, 2009). It controls synaptic vesicle release (Huang and Trussell, 2011). It is under the regulation of several neuromodulatory actions; probably the best-known pathway is the cholinergic inhibition through muscarinic acetylcholine receptors (Brown and Adams, 1980; Marrion, 1997; Hernandez et al, 2008). The KCNQ2 to KCNQ5 (Kv7.2-5) channel subunits are responsible for the M-current They belong to the superfamily of voltage-gated potassium channels and can form homo- or heterotetrameric channels (Brown and Passmore, 2009). Other areas of the brainstem that express KCNQ4 are the principal and spinal trigeminal nuclei and members of the reticular activating system (RAS) such as the raphe nuclei and the ventral tegmental area (VTA) (Kharkovets et al, 2000; Koyama and Appel, 2006; Hansen et al, 2008)
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