Alterations in the motor neuron–renshaw cell circuit in the Sod1G93A mouse model

Wootz, Hanna; FitzSimons-Kantamneni, Eileen; Larhammar, Martin; Rotterman, Travis M.; Enjin, Anders; Patra, Kalicharan; André, Elodie; Zundert, Brigitte van; Kullander, Klas; Álvarez, Francisco J.

doi:10.1002/cne.23266

Cited by 70 publications

(74 citation statements)

References 91 publications

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“…Alterations in both the inhibitory and excitatory synaptic inputs impinging on mSOD1 motoneurons, as well as the properties of their postsynaptic receptors, have been reported in cultured motoneurons derived from embryos (Carunchio et al, 2008; Chang and Martin, 2011) as well as in motoneurons from neonates (van Zundert et al, 2008) and adults (Jiang et al, 2009; Sunico et al, 2011; Wootz et al, 2013). It has been shown that, during a critical developmental period, the morphology of the dendritic tree deeply relies on the synaptic activity received by the dendrites (Spitzer, 2006; Cline and Haas, 2008).…”

Section: Discussionmentioning

confidence: 99%

Early intrinsic hyperexcitability does not contribute to motoneuron degeneration in amyotrophic lateral sclerosis

Leroy

d’Incamps

Imhoff-Manuel

et al. 2014

eLife

141

176

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In amyotrophic lateral sclerosis (ALS) the large motoneurons that innervate the fast-contracting muscle fibers (F-type motoneurons) are vulnerable and degenerate in adulthood. In contrast, the small motoneurons that innervate the slow-contracting fibers (S-type motoneurons) are resistant and do not degenerate. Intrinsic hyperexcitability of F-type motoneurons during early postnatal development has long been hypothesized to contribute to neural degeneration in the adult. Here, we performed a critical test of this hypothesis by recording from identified F- and S-type motoneurons in the superoxide dismutase-1 mutant G93A (mSOD1), a mouse model of ALS at a neonatal age when early pathophysiological changes are observed. Contrary to the standard hypothesis, excitability of F-type motoneurons was unchanged in the mutant mice. Surprisingly, the S-type motoneurons of mSDO1 mice did display intrinsic hyperexcitability (lower rheobase, hyperpolarized spiking threshold). As S-type motoneurons are resistant in ALS, we conclude that early intrinsic hyperexcitability does not contribute to motoneuron degeneration.DOI: http://dx.doi.org/10.7554/eLife.04046.001

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Section: Discussionmentioning

confidence: 99%

Early intrinsic hyperexcitability does not contribute to motoneuron degeneration in amyotrophic lateral sclerosis

Leroy

d’Incamps

Imhoff-Manuel

et al. 2014

eLife

141

176

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“…G93A mouse by the loss of presynaptic, recurrent motor axon inputs on Renshaw cells, which implies decreased feedback inhibition of MN firing (62). This loss of inhibitory feedback in combination with excess excitatory inputs on MNs-even in the absence of hyperexcitability-could lead to increased firing and the consequent excitotoxic degeneration of MNs in ALS.…”

Section: Discussionmentioning

confidence: 99%

Gamma motor neurons survive and exacerbate alpha motor neuron degeneration in ALS

Lalancette–Hébert

Sharma

Lyashchenko

et al. 2016

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

103

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The molecular and cellular basis of selective motor neuron (MN) vulnerability in amyotrophic lateral sclerosis (ALS) is not known. In genetically distinct mouse models of familial ALS expressing mutant superoxide dismutase-1 (SOD1), TAR DNA-binding protein 43 (TDP-43), and fused in sarcoma (FUS), we demonstrate selective degeneration of alpha MNs (α-MNs) and complete sparing of gamma MNs (γ-MNs), which selectively innervate muscle spindles. Resistant γ-MNs are distinct from vulnerable α-MNs in that they lack synaptic contacts from primary afferent (I A ) fibers. Elimination of these synapses protects α-MNs in the SOD1 mutant, implicating this excitatory input in MN degeneration. Moreover, reduced I A activation by targeted reduction of γ-MNs in SOD1G93A mutants delays symptom onset and prolongs lifespan, demonstrating a pathogenic role of surviving γ-MNs in ALS. This study establishes the resistance of γ-MNs as a general feature of ALS mouse models and demonstrates that synaptic excitation of MNs within a complex circuit is an important determinant of relative vulnerability in ALS.ALS | motor neuron disease | gamma motor neuron | fusimotor A myotrophic lateral sclerosis (ALS) is a fatal disorder characterized by selective motor neuron (MN) degeneration in the brain and spinal cord (1). Not all MN subtypes are equally vulnerable in ALS, and specific subpopulations of MNs, including neurons in the oculomotor and Onuf's nuclei, are preserved even at late stages of disease (2-8). The sparing of these motor pools in ALS is complete, but within the motor pools that are affected the degree to which distinct functional subtypes of MNs are vulnerable varies: fast-fatigable motor neurons are the first to degenerate in ALS patients (9) and in mutant SOD1 mice (10, 11), followed by fatigue-resistant motor units, whereas slow motor units are preserved until late in the course of the disease (12). The reason for the selective vulnerability of distinct subpopulations of MNs in ALS is not known, but factors that determine the unique features of individual MN subtypes, including their size, morphology, and membrane properties, may play a role. In addition, the factors that influence MN vulnerability in ALS may relate to the organization and function of synaptic inputs on each MN subtype that regulate MN activity and control motor output. How the connectivity of MNs within complex motor circuits influences their relative vulnerability in ALS is not known.Extraocular muscles composed of multiple (fast-, intermediate-, and slow-twitch) fiber types (13) and innervated by ALS

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“…Elevated levels of glutamate, putatively defectively cleared by astrocytes, has been hypothesized to contribute to excitotoxicity (31). In addition, several anatomical studies have noted an increase in the ratio of excitatory to inhibitory synapses onto MNs in the context of overall synapse loss over the course of disease (32)(33)(34). Additionally, some studies have suggested broad changes in synaptic and network function that lead to abnormal MN output in the form of irregular bursting patterns (35); however, the specific nature and ultimate consequence of such network abnormalities is not understood.…”

Section: Discussionmentioning

confidence: 99%

Selective degeneration of a physiological subtype of spinal motor neuron in mice with SOD1-linked ALS

Hadzipasic

Tahvildari

Nagy

et al. 2014

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

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Amyotrophic lateral sclerosis (ALS; Lou Gehrig's disease) affects motor neurons (MNs) in the brain and spinal cord. Understanding the pathophysiology of this condition seems crucial for therapeutic design, yet few electrophysiological studies in actively degenerating animal models have been reported. Here, we report a novel preparation of acute slices from adult mouse spinal cord, allowing visualized whole cell patch-clamp recordings of fluorescent lumbar MN cell bodies from ChAT-eGFP or superoxide dismutase 1-yellow fluorescent protein (SOD1YFP) transgenic animals up to 6 mo of age. We examined 11 intrinsic electrophysiologic properties of adult ChAT-eGFP mouse MNs and classified them into four subtypes based on these parameters. The subtypes could be principally correlated with instantaneous (initial) and steady-state firing rates. We used retrograde tracing using fluorescent dye injected into fast or slow twitch lower extremity muscle with slice recordings from the fluorescent-labeled lumbar MN cell bodies to establish that fast and slow firing MNs are connected with fast and slow twitch muscle, respectively. In a G85R SOD1YFP transgenic mouse model of ALS, which becomes paralyzed by 5-6 mo, where MN cell bodies are fluorescent, enabling the same type of recording from spinal cord tissue slices, we observed that all four MN subtypes were present at 2 mo of age. At 4 mo, by which time substantial neuronal SOD1YFP aggregation and cell loss has occurred and symptoms have developed, one of the fast firing subtypes that innvervates fast twitch muscle was lost. These results begin to describe an order of the pathophysiologic events in ALS.neurodegeneration | motor neurons | amyotrophic lateral sclerosis | electrophysiology A myotrophic lateral sclerosis (ALS; Lou Gehrig's disease) is a progressive and usually lethal neurodegenerative condition prominently featuring loss of motor neurons (MNs) and muscle denervation (1-3). Inherited forms of ALS, accounting for ∼10% of cases, potentially inform about disease mechanisms, including: protein folding and quality control [e.g., mutant superoxide dismutase 1 (SOD1), ubiquilin2, and VCP]; RNA binding proteins (e.g., TDP43, FUS, and HNRNPA1); or a DNA expansion (C9ORF72 hexanucleotide expansion). The clinical courses of the various heritable forms and the 90% of cases that are considered sporadic are not distinct, however, reflecting a potentially shared progressive loss of MNs and motor circuit dysfunction (4).ALS has been modeled in mice that are transgenic for a variety of mutant forms of SOD1, allowing for the study of the trajectory of the condition at various time points (5, 6). Among the studies conducted to date are a number addressing electrophysiological changes. From these studies, however, there does not appear to be a clear consensus on the changes that occur in MNs before and during the development of symptoms (7). For example, whereas research on the neuromuscular junction has revealed preferential denervation of fast twitch (type IIb) muscle fibers (8-10), t...

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Alterations in the motor neuron–renshaw cell circuit in the Sod1^G93A mouse model

Cited by 70 publications

References 91 publications

Early intrinsic hyperexcitability does not contribute to motoneuron degeneration in amyotrophic lateral sclerosis

Early intrinsic hyperexcitability does not contribute to motoneuron degeneration in amyotrophic lateral sclerosis

Gamma motor neurons survive and exacerbate alpha motor neuron degeneration in ALS

Selective degeneration of a physiological subtype of spinal motor neuron in mice with SOD1-linked ALS

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