Cortical Hyperexcitability in Amyotrophic Lateral Sclerosis

Wainger, Brian J.; Cudkowicz, Merit

doi:10.1001/jamaneurol.2015.2197

Cited by 11 publications

(15 citation statements)

References 17 publications

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“…Our studies identified functional changes in PV interneurons, suggesting that abnormalities in cortical inhibition contribute to cortical dysfunction. Clinical studies have suggested that cortical hyperexcitability is in part due to impaired inhibitory mechanisms (Turner and Kiernan, 2012;King et al, 2016) and the loss of inhibitory PV interneurons (Nihei et al, 1993) and cortical GABA (Foerster et al, 2013), although not all studies have detected such changes (Ince et al, 1993;Maekawa et al, 2004;Attarian et al, 2009). Inhibitory neuron dysfunction has also been implicated in a TDP-43 mouse model (Zhang et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

“…For each cell type, genes were ranked according to their Cuffdiff2 test statistic, which integrates both confidence in the differential expression between hSOD1 G93A and hSOD1 WT as well as the direction and magnitude of the differential effect. These rankings were then used as input for a preranked Gene Set Enrichment Analysis (GSEA; Subramanian et al, 2005) against the Reactome database (MSigDB version 5.1 c2.cp.Reactome), a publicly available collection of annotated gene sets, to identify pathways and processes with coordinated significant differential enrichment. Gene sets were called significant with a Benjamini-Hochberg corrected p value of Ͻ0.05 (Kolmogorov-Smirnov test).…”

Section: Methodsmentioning

confidence: 99%

“…However, whether functional abnormalities are restricted to CSNs or involve additional cortical cell types remains unclear. Because the neocortex is composed of different classes of cortical projection neurons and inhibitory interneurons, with distinct electrophysiological, molecular, and morphological characteristics (Sugino et al, 2006;Ascoli et al, 2008; Oswald et al, 2013; Harris and Shepherd, 2015; Tremblay et al, 2016), we addressed this question by comparing the intrinsic electrophysiological properties of different classes of cortical neurons in wild-type (WT) and hSOD1 G93A mice. To assess the intrinsic excitability of CSNs and CCNs, the two major classes of cortical projection neurons found in L5b of motor cortex (Hattox and Nelson, 2007;Miller et al, 2008;Suter et al, 2013), we retrogradely labeled the two cell types with two different fluorescent tracers ( Fig.…”

Section: Intrinsic Hyperexcitability Is Not Restricted To Corticospinmentioning

confidence: 99%

“…Although the pathogenesis of ALS is likely multifactorial, it has been hypothesized that enhanced excitation or persistent depolarization of CSNs contributes to their selective degeneration in both sporadic and inherited forms of ALS (Saxena and Caroni, 2011;Taylor et al, 2016). Previous studies have primarily focused on assessing the function of spinal motor neurons from mouse models or from patient-derived cells, and a number, though not all, have identified increases in excitability during embryonic and neonatal stages (Pieri et al, 2003;Kuo et al, 2004;van Zundert et al, 2008;Elbasiouny et al, 2012;Martin et al, 2013;Leroy et al, 2014;Wainger et al, 2014;Venugopal et al, 2015), followed by progressive loss of action potential output (Delestrée et al, 2014;Devlin et al, 2015). Although altered excitability has been detected in cortical neurons (Pieri et al, 2009;Wainger and Cudkowicz, 2015;Saba et al, 2016), it is not known whether these changes in excitability are restricted to CSNs or represent more global changes in cortical physiology.…”

Section: Introductionmentioning

confidence: 99%

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Changes in the Excitability of Neocortical Neurons in a Mouse Model of Amyotrophic Lateral Sclerosis Are Not Specific to Corticospinal Neurons and Are Modulated by Advancing Disease

et al. 2017

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Cell type-specific changes in neuronal excitability have been proposed to contribute to the selective degeneration of corticospinal neurons in amyotrophic lateral sclerosis (ALS) and to neocortical hyperexcitability, a prominent feature of both inherited and sporadic variants of the disease, but the mechanisms underlying selective loss of specific cell types in ALS are not known. We analyzed the physiological properties of distinct classes of cortical neurons in the motor cortex of mice of both sexes and found that they all exhibit increases in intrinsic excitability that depend on disease stage. Targeted recordings and calcium imaging further revealed that neurons adapt their functional properties to normalize cortical excitability as the disease progresses. Although different neuron classes all exhibited increases in intrinsic excitability, transcriptional profiling indicated that the molecular mechanisms underlying these changes are cell type specific. The increases in excitability in both excitatory and inhibitory cortical neurons show that selective dysfunction of neuronal cell types cannot account for the specific vulnerability of corticospinal motor neurons in ALS. Furthermore, the stage-dependent alterations in neuronal function highlight the ability of cortical circuits to adapt as disease progresses. These findings show that both disease stage and cell type must be considered when developing therapeutic strategies for treating ALS. It is not known why certain classes of neurons preferentially die in different neurodegenerative diseases. It has been proposed that the enhanced excitability of affected neurons is a major contributor to their selective loss. We show using a mouse model of amyotrophic lateral sclerosis (ALS), a disease in which corticospinal neurons exhibit selective vulnerability, that changes in excitability are not restricted to this neuronal class and that excitability does not increase monotonically with disease progression. Moreover, although all neuronal cell types tested exhibited abnormal functional properties, analysis of their gene expression demonstrated cell type-specific responses to the ALS-causing mutation. These findings suggest that therapies for ALS may need to be tailored for different cell types and stages of disease.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Intrinsic Hyperexcitability Is Not Restricted To Corticospinmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Changes in the Excitability of Neocortical Neurons in a Mouse Model of Amyotrophic Lateral Sclerosis Are Not Specific to Corticospinal Neurons and Are Modulated by Advancing Disease

et al. 2017

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“…DPR pathology is primarily observed in neurons of C9orf72 postmortem patient tissues (Zu et al, 2013;Schludi et al, 2015), suggesting neuron-specific activation of mechanisms involved in non-AUG translation. Age-dependent hyperexcitability or hypoexcitability and increased vulnerability to excitotoxicity in neurons have been reported in C9orf72 NRE models, including patient-derived motor neurons (Donnelly et al, 2013;Sareen et al, 2013;Wainger et al, 2014;Devlin et al, 2015;Shi et al, 2018) and patient tissue (Wainger & Cudkowicz, 2015). The downstream signaling that results from these events might potentially facilitate or activate mechanisms that drive non-AUG translation in neurons and explain the predominant neuronal localization of DPRs in patients.…”

Section: Introductionmentioning

confidence: 95%

Repeat‐associated non‐ AUG translation in C9orf72‐ ALS / FTD is driven by neuronal excitation and stress

et al. 2019

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Nucleotide repeat expansions (NREs) are prevalent mutations in a multitude of neurodegenerative diseases. Repeat‐associated non‐AUG (RAN) translation of these repeat regions produces mono or dipeptides that contribute to the pathogenesis of these diseases. However, the mechanisms and drivers of RAN translation are not well understood. Here we analyzed whether different cellular stressors promote RAN translation of dipeptide repeats (DPRs) associated with the G4C2 hexanucleotide expansions in C9orf72, the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). We found that activating glutamate receptors or optogenetically increasing neuronal activity by repetitive trains of depolarization induced DPR formation in primary cortical neurons and patient derived spinal motor neurons. Increases in the integrated stress response (ISR) were concomitant with increased RAN translation of DPRs, both in neurons and different cell lines. Targeting phosphorylated‐PERK and the phosphorylated‐eif2α complex reduces DPR levels revealing a potential therapeutic strategy to attenuate DPR‐dependent disease pathogenesis in NRE‐linked diseases.

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Synaptic dysfunction and altered excitability in C9ORF72 ALS/FTD

Starr

Sattler

2018

Brain Research

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Amyotrophic lateral sclerosis (ALS) is characterized by a progressive degeneration of upper and lower motor neurons, resulting in fatal paralysis due to denervation of the muscle. Due to genetic, pathological and symptomatic overlap, ALS is now considered a spectrum disease together with frontotemporal dementia (FTD), the second most common cause of dementia in individuals under the age of 65. Interestingly, in both diseases, there is a large prevalence of RNA binding proteins (RBPs) that are mutated and considered disease-causing, or whose dysfunction contribute to disease pathogenesis. The most common shared genetic mutation in ALS/FTD is a hexanucleuotide repeat expansion within intron 1 of C9ORF72 (C9). Three potentially overlapping, putative toxic mechanisms have been proposed: loss of function due to haploinsufficient expression of the C9ORF72 mRNA, gain of function of the repeat RNA aggregates, or RNA foci, and repeat-associated non-ATG-initiated translation (RAN) of the repeat RNA into toxic dipeptide repeats (DPRs). Regardless of the causative mechanism, disease symptoms are ultimately caused by a failure of neurotransmission in three regions: the brain, the spinal cord, and the neuromuscular junction. Here, we review C9 ALS/FTD-associated synaptic dysfunction and aberrant neuronal excitability in these three key regions, focusing on changes in morphology and synapse formation, excitability, and excitotoxicity in patients, animal models, and in vitro models. We compare these deficits to those seen in other forms of ALS and FTD in search of shared pathways, and discuss the potential targeting of synaptic dysfunctions for therapeutic intervention in ALS and FTD patients.

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Cortical Hyperexcitability in Amyotrophic Lateral Sclerosis

Cited by 11 publications

References 17 publications

Changes in the Excitability of Neocortical Neurons in a Mouse Model of Amyotrophic Lateral Sclerosis Are Not Specific to Corticospinal Neurons and Are Modulated by Advancing Disease

Changes in the Excitability of Neocortical Neurons in a Mouse Model of Amyotrophic Lateral Sclerosis Are Not Specific to Corticospinal Neurons and Are Modulated by Advancing Disease

Repeat‐associated non‐ AUG translation in C9orf72‐ ALS / FTD is driven by neuronal excitation and stress

Synaptic dysfunction and altered excitability in C9ORF72 ALS/FTD

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