KCNQ Current Contributes to Inspiratory Burst Termination in the Pre-Bötzinger Complex of Neonatal Rats in vitro

Abstract

The pre-Bötzinger complex (preBötC) of the ventral medulla generates the mammalian inspiratory breathing rhythm. When isolated in explants and deprived of synaptic inhibition, the preBötC continues to generate inspiratory-related rhythm. Mechanisms underlying burst generation have been investigated for decades, but cellular and synaptic mechanisms responsible for burst termination have received less attention. KCNQ-mediated K+ currents contribute to burst termination in other systems, and their transcripts are expressed in preBötC neurons. Therefore, we tested the hypothesis that KCNQ channels also contribute to burst termination in the preBötC. We recorded KCNQ-like currents in preBötC inspiratory neurons in neonatal rat slices that retain respiratory rhythmicity. Blocking KCNQ channels with XE991 or linopirdine (applied via superfusion or locally) increased inspiratory burst duration by 2- to 3-fold. By contrast, activation of KCNQ with retigabine decreased inspiratory burst duration by ~35%. These data from reduced preparations suggest that the KCNQ current in preBötC neurons contributes to inspiratory burst termination.

Putting the theory into ‘burstlet theory’ with a biophysical model of burstlets and bursts in the respiratory preBötzinger complex

“…Although our model incorporates various key biological features, it does not include some of the biophysical mechanisms that are known to shape preBötC patterned output or that are hypothesized to contribute to the properties described by burstlet theory. For example, the M-current associated with KCNQ potassium channels has been shown to impact burst duration by contributing to burst termination ( Revill et al, 2021 ). Additionally, intrinsic conductances associated with a hyperpolarization-activated mixed cation current ( ) and a transient potassium current ( ) are hypothesized to be selectively expressed in the pattern- and rhythm-generating preBötC subpopulations ( Picardo et al, 2013 ; Phillips et al, 2018 ).…”

Predictions and experimental tests of a new biophysical model of the mammalian respiratory oscillator

“…Our recent biophysical characterization of INaP for these neurons has confirmed that this current is slowly inactivating (Yamanishi et al, 2018), which is a basic assumption of the present and previous models , although the details of the voltage-dependent kinetic properties are more complex than represented by the first-order kinetics in the present and previous models. Moreover, some additional currents or dynamical processes (e.g., inhibitory currents from local circuit connections, synaptic depression) (Thoby- Hayes et al, 2008;Andrew and Del Negro, 2015;Phillips et al, 2018;Baertsch et al, 2018;Juárez-Vidales, et al, 2021;Abdulla et al, 2021;Revill et al, 2021), which are not considered in the model, may play a role in augmenting/shaping inspiratory bursting.…”

Evidence for Dual Activation of IK(M) and IK(Ca) Caused by QO-58 (5-(2,6-Dichloro-5-fluoropyridin-3-yl)-3-phenyl-2-(trifluoromethyl)-1H-pyrazolol[1,5-a]pyrimidin-7-one)

“…However, how QO-58induced changes in I K(M) 's V hys are linked to the behavior of these cells occurring in vivo remains unclear. Of importance, the main point raised is that the adjustments by QO-58 of I K(M) 's V hys residing in excitable cells are anticipated to be responsible for altering the bursting pattern of action potentials in excitable cells [13][14][15][16][17]19,20,30,60].…”

“…Earlier reports have shown the capability of I K(M) strength to modulate the patterns of bursting firing in central neurons [13,[15][16][17]20]. Therefore, we continued to evaluate how the presence of QO-58 could have any perturbations on I K(M) responding to upright triangular V ramp with varying durations.…”

“…The enhanced activity of this family of voltagegated K + channels (KCNQx, K V 7x, or K M [M-type K + ] channels) can generate macroscopic M-type K + current (I K(M) ), which is biophysically characterized by current activation upon low-threshold voltage [10,11]. Once being evoked during membrane depolarization, this type of K + currents, which is susceptible to block by linopirdine, has been disclosed to exhibit a slowly activating and deactivating property as well to affect the bursting patterns in different types of neurons, and endocrine or neuroendocrine cells [12][13][14][15][16][17][18][19][20]. Moreover, targeting I K(M) has been growingly thought to be an adjunctive regimen for the management of varying neurological, smooth muscle, or endocrine disorders which are closely linked to membrane hyperexcitability.…”