Effects of chronic spinal cord injury on relationships among ion channel and receptor mRNAs in mouse lumbar spinal cord

Garcia, Virginia B.; Abbinanti, Matthew D.; Harris‐Warrick, Ronald M.; Schulz, David J.

doi:10.1101/357665

Cited by 5 publications

(6 citation statements)

References 65 publications

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“…We investigated this hypothesis using simplified biophysical models of pacemaker neurons that use a single sensor of calcium concentration to control ion channel expression homeostatically. Previous work showed that this class of self-tuning models recapitulates experimental observations such a correlations in ion channel density ( Schulz et al, 2006, 2007 ; Temporal et al, 2014 ; Garcia et al, 2018 ; O’Leary et al, 2013, 2014 ). Furthermore, these models provide robustness to some forms of perturbations in membrane conductances, but can be sensitive to other perturbations like channel deletions ( O’Leary et al, 2014 ).…”

Section: Introductionsupporting

confidence: 58%

Homeostatic plasticity rules that compensate for cell size are susceptible to channel deletion

Shandilya

Marder

O'Leary³

2019

Preprint

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Neurons can increase in size dramatically during growth. In many species neurons 8 must preserve their intrinsic dynamics and physiological function across several length scales. For 9 example, neurons in crustacean central pattern generators generate similar activity patterns 10 despite multiple-fold increases in their size and changes in morphology. This scale invariance hints 11 at regulation mechanisms that compensate for size changes by somehow altering membrane 12 currents. Using conductance-based neuron models, we asked whether simple activity-dependent 13 feedback can maintain intrinsic voltage dynamics in a neuron as its size is varied. Despite relying 14 only on a single sensor that measures time-averaged intracellular calcium as a proxy for activity, we 15 found that this regulation mechanism could regulate conductance densities of ion channels, and 16 was robust to changes in the size of the neuron. By mapping changes in cell size onto 17 perturbations in the space of conductance densities of all channels, we show how robustness to 18 size change coexists with sensitivity to perturbations that alter the ratios of maximum 19 conductances of different ion channel types. Our findings suggest that biological regulation that is 20 optimized for coping with expected perturbations such as size changes will be vulnerable to other 21 kinds of perturbations such as channel deletions. 22 29 three-fold increase in cell size (Bucher and Pflüger, 2000). RPeD1, a neuron in the respiratory 30 central pattern generator in Lymnaea, maintains resting membrane potential, spike amplitude 31 and membrane resistance despite two-fold growth from juvenile to adult (McComb et al., 2003). 32 In crickets, patterns of motor neuron output responsible for song production appear up to four 33 moults before the adult form (Bentley and Hoy, 1970). In lobsters, the co-ordinated bursting activity 34 of pyloric neurons is indistinguishable between juveniles and adults, despite a many-fold increase 35 in their size (Bucher et al., 2005). Even in embryonic stages, when these cells are even smaller, 36 the pyloric circuit central pattern generator (CPG) expresses spontaneous albeit less stereotyped 37 rhythmic activity (Casasnovas and Meyrand, 1995; Richards et al., 1999). 38 Neurons achieve their target behavior by expressing specific combinations of voltage and 39 calcium gated ion channels (Prinz et al., 2003). This leads to the question of how neurons maintain 40 1 of 20 Manuscript to be submitted to eLife a target function by regulating ion channel expression as the size of the cell increases. Can regulatory 41 mechanisms preserve neuron behavior during growth? 42 Homeostatic regulation has been proposed as a mechanism that can tune neuronal parameters 43 like ion channel densities to drive neuronal activity to some desired set point (LeMasson et al.,

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Section: Introductionsupporting

confidence: 58%

Homeostatic plasticity rules that compensate for cell size are susceptible to channel deletion

Shandilya

Marder

O'Leary³

2019

Preprint

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“…Our model assumes a single sensor of calcium concentration to control expression of multiple ion channels simultaneously, a so called master regulation scheme. Previous work showed that this class of self-tuning models recapitulates experimental observations such a correlated variability in ion channel density and compensation for changes in circuit activity [17][18][19][20][21][22] .…”

supporting

confidence: 54%

Activity-dependent compensation of cell size is vulnerable to targeted deletion of ion channels

Gorur-Shandilya

Marder

O’Leary

2020

Sci Rep

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In many species, excitable cells preserve their physiological properties despite significant variation in physical size across time and in a population. For example, neurons in crustacean central pattern generators generate similar firing patterns despite several-fold increases in size between juveniles and adults. This presents a biophysical problem because the electrical properties of cells are highly sensitive to membrane area and channel density. It is not known whether specific mechanisms exist to sense membrane area and adjust channel expression to keep a consistent channel density, or whether regulation mechanisms that sense activity alone are capable of compensating cell size. We show that destabilising effects of growth can be specifically compensated by feedback mechanism that senses average calcium influx and jointly regulate multiple conductances. However, we further show that this class of growth-compensating regulation schemes is necessarily sensitive to perturbations that alter the expression of subsets of ion channel types. Targeted perturbations of specific ion channels can trigger a pathological response of the regulation mechanism and a failure of homeostasis. Our findings suggest that physiological regulation mechanisms that confer robustness to growth may be specifically vulnerable to deletions or mutations that affect subsets of ion channels.

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“…In our previous work, we designed or modified and independently validated qPCR primers for use in absolute quantitation of mRNA copy number for all of the genes of interest in this study. These primer sets are previously published, and standard curves generated and used as described in our previous work (Garcia et al 2014, 2018). Briefly, qPCR reactions were carried out using SYBR mastermix (BioRad) according to the manufacturer’s instructions, and consisted of primers at final concentrations of 2.5 μM.…”

Section: Methodsmentioning

confidence: 99%

Changes in excitability and ion channel expression in neurons of the major pelvic ganglion in female type II diabetic mice

Gray

Lett

Garcia

et al. 2018

Preprint

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4Bladder cystopathy is a common urological complication of diabetes, and has been associated 3 5 with changes in parasympathetic ganglionic transmission and some measures of neuronal excitability in 3 6 male mice. To determine whether type II diabetes also impacts excitability of parasympathetic ganglionic 3 7 neurons in females, we investigated neuronal excitability and firing properties, as well as underlying ion 3 8 channel expression, in major pelvic ganglion (MPG) neurons in control, 10-week, and 21-week db/db 3 9mice. Type II diabetes in Lepr db/db animals caused a non-linear change in excitability and firing properties 4 0 of MPG neurons. At 10 weeks, cells exhibited increased excitability as demonstrated by an increased 4 1 likelihood of firing multiple spikes upon depolarization, decreased rebound spike latency, and overall 4 2 narrower action potential half-widths as a result of increased depolarization and repolarization slopes. 4 3Conversely, at 21 weeks MPG neurons of db/db mice reversed these changes, with spiking patterns and 4 4 action-potential properties largely returning to control levels. These changes are associated with 4 5 numerous time-specific changes in calcium, sodium, and potassium channel subunit mRNA levels. 4 6However, Principal Components Analysis of channel expression patterns revealed that the rectification of 4 7 excitability is not simply a return to control levels, but rather a distinct ion channel expression profile in 4 8

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Effects of chronic spinal cord injury on relationships among ion channel and receptor mRNAs in mouse lumbar spinal cord

Cited by 5 publications

References 65 publications

Homeostatic plasticity rules that compensate for cell size are susceptible to channel deletion

Homeostatic plasticity rules that compensate for cell size are susceptible to channel deletion

Activity-dependent compensation of cell size is vulnerable to targeted deletion of ion channels

Changes in excitability and ion channel expression in neurons of the major pelvic ganglion in female type II diabetic mice

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