The M-current works in tandem with the persistent sodium current to set the speed of locomotion

Verneuil, Jérémy; Brocard, Cécile; Trouplin, Virginie; Villard, Laurent; Peyronnet, Julie; Brocard, Frédéric

doi:10.1371/journal.pbio.3000738

Cited by 31 publications

(37 citation statements)

References 100 publications

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“…In our interpretation of the genotype-phenotype relationship through the prism of KCNQ2/3 heteromers, one caveat is that our current knowledge on KCNQ2 and KCNQ3 mRNA and protein colocalization stems from work primarily performed in sympathetic neurons and in neurons in the neocortex and hippocampus, with only limited information on subcortical regions (see e.g., [64][65][66]), spinal cord [67,68], and the peripheral nervous system [45]. In the hippocampus and cortex, KCNQ2 and KCNQ3 colocalization in excitatory and inhibitory cells is highly prevalent, with very few exceptions.…”

Section: Beyond the Forebrainmentioning

confidence: 99%

“…Most notably, KCNQ3 channels were highly enriched in polymodal nodose ganglion cells, whereas KCNQ2 was enriched in Piezo2-expressing nodose neurons, which are important for sensing pulmonary volume and stretching (https://ernforsgroup.shinyapps.io/vagalsensoryneurons/). Additionally, a recent report showed that KCNQ2 channels are enriched in neurons important for locomotion in the spinal cord [68], a finding similar to a previous work that found robust expression of KCNQ2 but of KCNQ3 in spinal cord neurons [67, 68]. The differential enrichment of KCNQ2 channels over KCNQ3 channels in the brainstem and some vagus neurons may also contribute to the very different symptoms exhibited by patients carrying Kcnq2 and Kcnq3 gain-of-function mutations [7].…”

Section: Introductionmentioning

confidence: 99%

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Flexible Stoichiometry: Implications for KCNQ2- and KCNQ3-Associated Neurodevelopmental Disorders

Springer

Varghese

Tzingounis³

2021

Dev Neurosci

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KCNQ2 and KCNQ3 pathogenic channel variants have been associated with a spectrum of developmentally regulated diseases that vary in age of onset, severity, and whether it is transient (i.e., benign familial neonatal seizures) or long-lasting (i.e., developmental and epileptic encephalopathy). KCNQ2 and KCNQ3 channels have also emerged as a target for novel antiepileptic drugs as their activation could reduce epileptic activity. Consequently, a great effort has taken place over the last 2 decades to understand the mechanisms that control the assembly, gating, and modulation of KCNQ2 and KCNQ3 channels. The current view that KCNQ2 and KCNQ3 channels assemble as heteromeric channels (KCNQ2/3) forms the basis of our understanding of KCNQ2 and KCNQ3 channelopathies and drug design. Here, we review the evidence that supports the formation of KCNQ2/3 heteromers in neurons. We also highlight functional and transcriptomic studies that suggest channel composition might not be necessarily fixed in the nervous system, but rather is dynamic and flexible, allowing some neurons to express KCNQ2 and KCNQ3 homomers. We propose that to fully understand KCNQ2 and KCNQ3 channelopathies, we need to adopt a more flexible view of KCNQ2 and KCNQ3 channel stoichiometry, which might differ across development, brain regions, cell types, and disease states.

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Section: Beyond the Forebrainmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Flexible Stoichiometry: Implications for KCNQ2- and KCNQ3-Associated Neurodevelopmental Disorders

Springer

Varghese

Tzingounis³

2021

Dev Neurosci

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“…PICs were measured in voltage clamp by injecting a slow depolarizing voltage ramp (10 mV/s from -90 to -10 mV) over 8 seconds 20,118,121 . PIC onset voltage, voltage at which the peak current occurs (voltage peak), peak current amplitude, and peak current density were measured from post-hoc leaksubtracted traces as in 20,118,122 .…”

Section: Data Acquisition and Analysismentioning

confidence: 99%

Maturation of persistent and hyperpolarization-activated inward currents shapes the differential activation of motoneuron subtypes during postnatal development

Sharples

Miles

2021

Preprint

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The fine control of movement is a prerequisite for complex behaviour and is mediated by the orderly recruitment of motor units composed of slow and fast twitch muscle fibres. The size principle was initially proposed to account for orderly recruitment; however, motoneuron size is a poor predictor of recruitment amongst functionally defined motor unit subtypes. While intrinsic properties of motoneurons are key regulators of motoneuron recruitment, the underlying currents involved are not well defined. Whole-cell patch-clamp electrophysiology was deployed to study intrinsic properties, and the underlying currents, that contribute to the differential recruitment of fast and slow motoneurons. Motoneurons were studied during the first three postnatal weeks in mice to identify key properties that establish orderly recruitment and contribute to the emergence of fine motor control. We find that fast and slow motoneurons are functionally homogeneous during the first postnatal week and are recruited based on size, irrespective of motoneuron subtype. The recruitment of fast and slow motoneurons becomes staggered during the second postnatal week due to the differential maturation of passive and active properties, particularly persistent inward currents (PICs). The current required to recruit fast motoneurons increases further in the third postnatal week, despite no additional changes in passive properties or PICs. This further staggering of recruitment currents reflects development of a hyperpolarization-activated inward current during week 3. Our results suggest that motoneuron recruitment is multifactorial, with recruitment order established during postnatal development through the differential maturation of passive properties and sequential integration of persistent and hyperpolarization-activated inward currents.

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“…Indeed, Kcnq2 deletion or expression of KCNQ2 pathogenic variants in neurons leads to elevated excitability, typically manifested as a higher number of action potentials and reduced spike frequency adaptation. Such changes in excitability occur in multiple brain regions, including the hippocampus and neocortex, and across multiple cell types ( Peters et al, 2005 ; Singh et al, 2008 ; Soh et al, 2014 , 2018 ; Verneuil et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Loss of KCNQ2 or KCNQ3 Leads to Multifocal Time-Varying Activity in the Neonatal ForebrainEx Vivo

Hou¹,

Varghese²,

Soh³

et al. 2021

eNeuro

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Epileptic encephalopathies represent a group of disorders often characterized by refractory seizures, regression in cognitive development, and typically poor prognosis. Dysfunction of KCNQ2 and KCNQ3 channels has emerged as a major cause of neonatal epilepsy. However, our understanding of the cellular mechanisms that may both explain the origins of epilepsy and inform treatment strategies for KCNQ2 and KCNQ3 dysfunction is still lacking. Here, using mesoscale calcium imaging and pharmacology, we demonstrate that in mouse neonatal brain slices, conditional loss of Kcnq2 from forebrain excitatory neurons ( Pyr:Kcnq2 mice) or constitutive deletion of Kcnq3 leads to sprawling hyperactivity across the neocortex. Surprisingly, the generation of time-varying hypersynchrony in slices from Pyr:Kcnq2 mice does not require fast synaptic transmission. This is in contrast to control littermates and constitutive Kcnq3 knock-out mice where activity is primarily driven by fast synaptic transmission in the neocortex. Unlike in the neocortex, hypersynchronous activity in the hippocampal formation from Kcnq2 conditional and Kcnq3 constitutive knock-out mice persists in the presence of synaptic transmission blockers. Thus, we propose that loss of KCNQ2 or KCNQ3 function differentially leads to network hyperactivity across the forebrain in a region-specific and macro-circuit-specific manner.

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The M-current works in tandem with the persistent sodium current to set the speed of locomotion

Cited by 31 publications

References 100 publications

Flexible Stoichiometry: Implications for KCNQ2- and KCNQ3-Associated Neurodevelopmental Disorders

Flexible Stoichiometry: Implications for KCNQ2- and KCNQ3-Associated Neurodevelopmental Disorders

Maturation of persistent and hyperpolarization-activated inward currents shapes the differential activation of motoneuron subtypes during postnatal development

Loss of KCNQ2 or KCNQ3 Leads to Multifocal Time-Varying Activity in the Neonatal ForebrainEx Vivo

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