Gender-specific perturbations in modulatory inputs to motoneurons in a mouse model of amyotrophic lateral sclerosis

Herron, Lissa R.; Miles, Gareth B.

doi:10.1016/j.neuroscience.2012.09.031

Cited by 59 publications

(86 citation statements)

References 80 publications

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“…While motor unit studies have been performed in numerous species to date (Heckman and Enoka 2012), the development of transgenic mouse models of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) motivates an increase in motor unit studies in mice (Herron and Miles 2012). Briefly, our findings show rate modulation across a wide range of firing rates that is inconsistent with predictions from previous studies in anesthetized preparations.…”

Section: Discussioncontrasting

confidence: 79%

Characterization of motor units in behaving adult mice shows a wide primary range

Ritter

Tresch

Heckman

et al. 2014

Journal of Neurophysiology

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Section: Discussioncontrasting

confidence: 79%

Characterization of motor units in behaving adult mice shows a wide primary range

Ritter

Tresch

Heckman

et al. 2014

Journal of Neurophysiology

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“…5Q). Next, and in line with recent data from SOD1 G93A mutant ALS mice (49,50), C-bouton nerve terminal input (apposed VAChT/Kv2.1 synaptic densities) on surviving large ventral horn motor neurons remained relatively stable during disease in SOD1 G37R mice expressing C1q (Fig. 5 S and T).…”

Section: G37r /C1qsupporting

confidence: 86%

“…5 S and T). As loss of the corresponding postsynaptic (Kv2.1-positive) density was less pronounced, it is possible that C1q could play a protective role against mutant SOD1 mutant-mediated toxicity in the corresponding cholinergic VO c interneurons, especially as no major loss of C-boutons on motor neurons was reported in ALS mice with normal C1q content (49,50).…”

Section: Discussionmentioning

confidence: 99%

C1q induction and global complement pathway activation do not contribute to ALS toxicity in mutant SOD1 mice

Lobsiger

Boillée

Pozniak³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Accumulating evidence from mice expressing ALS-causing mutations in superoxide dismutase (SOD1) has implicated pathological immune responses in motor neuron degeneration. This includes microglial activation, lymphocyte infiltration, and the induction of C1q, the initiating component of the classic complement system that is the protein-based arm of the innate immune response, in motor neurons of multiple ALS mouse models expressing dismutase active or inactive SOD1 mutants. Robust induction early in disease course is now identified for multiple complement components (including C1q, C4, and C3) in spinal cords of SOD1 mutantexpressing mice, consistent with initial intraneuronal C1q induction, followed by global activation of the complement pathway. We now test if this activation is a mechanistic contributor to disease. Deletion of the C1q gene in mice expressing an ALS-causing mutant in SOD1 to eliminate C1q induction, and complement cascade activation that follows from it, is demonstrated to produce changes in microglial morphology accompanied by enhanced loss, not retention, of synaptic densities during disease. C1q-dependent synaptic loss is shown to be especially prominent for cholinergic C-bouton nerve terminal input onto motor neurons in affected C1q-deleted SOD1 mutant mice. Nevertheless, overall onset and progression of disease are unaffected in C1q-and C3-deleted ALS mice, thus establishing that C1q induction and classic or alternative complement pathway activation do not contribute significantly to SOD1 mutant-mediated ALS pathogenesis in mice.amyotrophic lateral sclerosis | motoneuron | synaptic density | gender differences | neuroinflammation

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“…In ALS, there has been interest in potential neuroprotective roles for C-boutons and this view is bolstered by studies that show an early increase in C-bouton size (Pullen and Athanasiou, 2009; Herron and Miles, 2012; Saxena et al, 2013); however, diminished C-bouton and V0c interneuronal ChAT/VAChT content (Nagao et al, 1998; Casas et al, 2013) and S1R expression (Casas et al, 2013; see Witts et al, 2014) have also been observed in similar murine models of the disease. The structural changes in animal models may also reflect a propensity for C-bouton reorganization to occur first in larger, less excitable, and more vulnerable α-MNs (Saxena et al, 2013), and the changes may be more pronounced in males (Herron and Miles, 2012). There is minimal data from autopsied human spinal cord from ALS patients, mostly from late stages of the disease, showing continued presence of C-boutons on degeneration-resistant sphinteric α-MNs (Pullen, 1992).…”

Section: C-boutons In Human Health and Diseasementioning

confidence: 99%

Swimming against the tide: investigations of the C-bouton synapse

Deardorff

Romer

Sonner

et al. 2014

Front. Neural Circuits.

111

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C-boutons are important cholinergic modulatory loci for state-dependent alterations in motoneuron firing rate. m2 receptors are concentrated postsynaptic to C-boutons, and m2 receptor activation increases motoneuron excitability by reducing the action potential afterhyperpolarization. Here, using an intensive review of the current literature as well as data from our laboratory, we illustrate that C-bouton postsynaptic sites comprise a unique structural/functional domain containing appropriate cellular machinery (a “signaling ensemble”) for cholinergic regulation of outward K+ currents. Moreover, synaptic reorganization at these critical sites has been observed in a variety of pathologic states. Yet despite recent advances, there are still great challenges for understanding the role of C-bouton regulation and dysregulation in human health and disease. The development of new therapeutic interventions for devastating neurological conditions will rely on a complete understanding of the molecular mechanisms that underlie these complex synapses. Therefore, to close this review, we propose a comprehensive hypothetical mechanism for the cholinergic modification of α-MN excitability at C-bouton synapses, based on findings in several well-characterized neuronal systems.

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Gender-specific perturbations in modulatory inputs to motoneurons in a mouse model of amyotrophic lateral sclerosis

Cited by 59 publications

References 80 publications

Characterization of motor units in behaving adult mice shows a wide primary range

Characterization of motor units in behaving adult mice shows a wide primary range

C1q induction and global complement pathway activation do not contribute to ALS toxicity in mutant SOD1 mice

Swimming against the tide: investigations of the C-bouton synapse

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