Pathophysiology of Dyt1 dystonia is mediated by spinal cord dysfunction

Pocratsky, Amanda M; Nascimento, Filipe; Özyurt, Mustafa Görkem; White, Ian J.; Sullivan, Roisin; Smith, Calvin C.; Surana, Sunaina; Beato, Marco; Brownstone, Robert M.

doi:10.1101/2022.05.05.490750

“…ALS can spread in a cell-to-cell "domino-like" manner, with a contiguous caudal-to-rostral spinal progression of disease pathology occurring in spinal onset patients; this is also a typical feature observed in mSOD1 mice 38 . Similar progression patterns have been observed in other motor diseases, for example, in a mouse model of dystonia, spinal circuit dysfunction was responsible for a progressive monosynaptic Ia reflex impairment from lower to upper lumbar regions 61 . Through BQA we found that an increase in the probability of release from Ia terminals to lower lumbar motoneurons is likely responsible for enhancement of the proprioceptive Ia afferent drive to motoneurons 43,62,63 .…”

Section: Discussionsupporting

confidence: 75%

Spinal microcircuits go through multiphasic homeostatic compensations in a mouse model of motoneuron degeneration

Nascimento,

Özyurt,

Halablab

et al. 2024

Preprint

Self Cite

2

0

View full text Add to dashboard Cite

SummaryIn neurological conditions affecting the brain, early-stage neural circuit adaption is key for long-term preservation of normal behaviour. We tested if motoneurons and respective microcircuits also adapt in the initial stages of disease progression in a mouse model of progressive motoneuron degeneration. Using a combination ofin vitroandin vivoelectrophysiology and super-resolution microscopy, we found that, preceding muscle denervation and motoneuron death, recurrent inhibition mediated by Renshaw cells is reduced in half due to impaired quantal size associated with decreased glycine receptor density. Additionally, higher probability of release from proprioceptive Ia terminals leads to increased monosynaptic excitation to motoneurons. Surprisingly, the initial impairment in recurrent inhibition is not a widespread feature of inhibitory spinal circuits, such as group I inhibitory afferents, and is compensated at later stages of disease progression. We reveal that in disease conditions, spinal microcircuits undergo specific multiphasic homeostatic compensations to preserve force output.

show abstract

“…Importantly, our work here suggests that the effects of KCNQ‐targeting therapies are likely to be restricted to the susceptible subsets of motoneurons in ALS. In addition, hyperexcitability leading to spasticity is a hallmark of other neurological disorders including but not limited to spinal cord injury (Elbasiouny et al., 2010; Gorassini et al., 2004), cerebral palsy (Bar‐On et al., 2015; Condliffe et al., 2016; Reedich et al., 2023; Steele et al., 2020), multiple sclerosis (Beard et al., 2003), stroke (Burke et al., 2013; Mottram et al., 2014; Nielsen et al., 2019; Udby Blicher & Nielsen, 2009) and dystonia (Pocratsky et al., 2023). Although KCNQ channels have not yet been investigated as therapeutic targets in these conditions, they represent promising avenues for future study.…”

Section: Discussionmentioning

confidence: 99%

M‐type potassium currents differentially affect activation of motoneuron subtypes and tune recruitment gain

Sharples,

Broadhead,

Gray

et al. 2023

The Journal of Physiology

1

0

View full text Add to dashboard Cite

The size principle is a key mechanism governing the orderly recruitment of motor units and is believed to be dependent on passive properties of the constituent motoneurons. However, motoneurons are endowed with voltage‐sensitive ion channels that create non‐linearities in their input–output functions. Here we describe a role for the M‐type potassium current, conducted by KCNQ channels, in the control of motoneuron recruitment in mice. Motoneurons were studied with whole‐cell patch clamp electrophysiology in transverse spinal slices and identified based on delayed (fast) and immediate (slow) onsets of repetitive firing. M‐currents were larger in delayed compared to immediate firing motoneurons, which was not reflected by variations in the presence of Kv7.2 or Kv7.3 subunits. Instead, a more depolarized spike threshold in delayed‐firing motoneurons afforded a greater proportion of the total M‐current to become activated within the subthreshold voltage range, which translated to a greater influence on their recruitment with little influence on their firing rates. Pharmacological activation of M‐currents also influenced motoneuron recruitment at the population level, producing a rightward shift in the recruitment curve of monosynaptic reflexes within isolated mouse spinal cords. These results demonstrate a prominent role for M‐type potassium currents in regulating the function of motor units, which occurs primarily through the differential control of motoneuron subtype recruitment. More generally, these findings highlight the importance of active properties mediated by voltage‐sensitive ion channels in the differential control of motoneuron recruitment, which is a key mechanism for the gradation of muscle force. imageKey points M‐currents exert an inhibitory influence on spinal motor output. This inhibitory influence is exerted by controlling the recruitment, but not the firing rate, of high‐threshold fast‐like motoneurons, with limited influence on low‐threshold slow‐like motoneurons. Preferential control of fast motoneurons may be linked to a larger M‐current that is activated within the subthreshold voltage range compared to slow motoneurons. Larger M‐currents in fast compared to slow motoneurons are not accounted for by differences in Kv7.2 or Kv7.3 channel composition. The orderly recruitment of motoneuron subtypes is shaped by differences in the contribution of voltage‐gated ion channels, including KCNQ channels. KCNQ channels may provide a target to dynamically modulate the recruitment gain across the motor pool and readily adjust movement vigour.

show abstract

“…Importantly, our work here suggests that the effects of KCNQ-targeting therapies are likely to be restricted to the susceptible subsets of motoneurons in ALS. In addition, hyperexcitability leading to spasticity is a hallmark of other neurological disorders including but not limited to spinal cord injury (Elbasiouny et al, 2010;Gorassini et al, 2004), cerebral palsy (Bar-On et al, 2015;Condliffe et al, 2016;Reedich et al, 2023;Steele et al, 2020), multiple sclerosis (Beard et al, 2003), stroke (Burke et al, 2013;Mottram et al, 2014;Nielsen et al, 2019;Udby Blicher & Nielsen, 2009) and dystonia (Pocratsky et al, 2023). Although KCNQ channels have not yet been investigated as therapeutic targets in these conditions, they represent promising avenues for future study.…”

Section: Figure 5 M-currents Control Motoneuron Recruitment On a Popu...mentioning

confidence: 99%

M-type potassium currents differentially affect activation of motoneuron subtypes and tune recruitment gain

Sharples

¹

,

Broadhead

²

,

Gray

³

et al. 2023

Preprint

0

View full text Add to dashboard Cite

The size principle is a key mechanism governing the orderly recruitment of motor units and is believed to be dependent on passive properties of the constituent motoneurons. However, motoneurons are endowed with voltage-sensitive ion channels that create non-linearities in their input-output functions. Here we describe a role for the M-type potassium current, conducted by KCNQ channels, in the control of motoneuron recruitment in mice. Motoneurons were studied with whole-cell patch clamp electrophysiology in transverse spinal slices and identified based on delayed (fast) and immediate (slow) onsets of repetitive firing. M-currents were larger in delayed compared to immediate firing motoneurons, which was not reflected by variations in the expression of Kv7.2 or Kv7.3 subunits. Instead, a more depolarized spike threshold in delayed-firing motoneurons afforded a greater proportion of the total M-current to become activated within the subthreshold voltage range, which translated to a greater influence on their recruitment with little influence on their firing rates. Pharmacological activation of M-currents also influenced motoneuron recruitment at the population level, producing a rightward shift in the recruitment curve of monosynaptic reflexes within isolated mouse spinal cords. These results demonstrate a prominent role for M-type potassium currents in regulating the function of motor units, which occurs primarily through the differential control of motoneuron subtype recruitment. More generally, these findings highlight the importance of active properties mediated by voltage-sensitive ion channels in the differential control of motoneuron recruitment, which is a key mechanism for the gradation of muscle force.

show abstract

Pathophysiology of Dyt1 dystonia is mediated by spinal cord dysfunction

Cited by 7 publications

References 84 publications

Spinal microcircuits go through multiphasic homeostatic compensations in a mouse model of motoneuron degeneration

Spinal microcircuits go through multiphasic homeostatic compensations in a mouse model of motoneuron degeneration

M‐type potassium currents differentially affect activation of motoneuron subtypes and tune recruitment gain

M-type potassium currents differentially affect activation of motoneuron subtypes and tune recruitment gain

Contact Info

Product

Resources

About