Mislocalisation of TDP‐43 to the cytoplasm causes cortical hyperexcitability and reduced excitatory neurotransmission in the motor cortex

Amyotrophic lateral sclerosis (ALS) is characterized by its marked clinical heterogeneity. Although the coexistence of upper and lower motor neuron signs is a common clinical feature for most patients, there is a wide range of atypical motor presentations and clinical trajectories, implying a heterogeneity of underlying pathogenic mechanisms. Corticomotoneuronal dysfunction is increasingly postulated as the harbinger of clinical disease, and neurophysiological exploration of the motor cortex in vivo using transcranial magnetic stimulation (TMS) has suggested that motor cortical hyperexcitability may be a critical pathogenic factor linked to clinical features and survival. Region-specific selective vulnerability at the level of the motor cortex may drive the observed differences of clinical presentation across the ALS motor phenotypes, and thus, further understanding of phenotypic variability in relation to cortical dysfunction may serve as an important guide to underlying disease mechanisms. This review article analyses the cortical excitability profiles across the clinical motor phenotypes, as assessed using TMS, and explores this relationship to clinical patterns and survival. This understanding will remain essential to unravelling central disease pathophysiology and for the development of specific treatment targets across the ALS clinical motor phenotypes.

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Motor Cortex Excitability in Patients with Migraine with Aura and Hemiplegic Migraine

Cephalalgia ◽

10.1046/j.1468-2982.2000.00011.x ◽

2000 ◽

Vol 20 (1) ◽

pp. 45-50 ◽

Cited By ~ 55

Author(s):

KJ Werhahn ◽

K Wiseman ◽

J Herzog ◽

S Foörderreuther ◽

M Dichgans ◽

...

Keyword(s):

Motor Cortex ◽

Migraine With Aura ◽

Silent Period ◽

Intracortical Inhibition ◽

Familial Hemiplegic Migraine ◽

Hemiplegic Migraine ◽

Cortical Hyperexcitability ◽

Motor Cortex Excitability ◽

Patient Groups ◽

Intracortical Inhibition And Facilitation

We studied the excitability of the motor cortex using transcranial magnetic stimulation (TMS) in 12 patients with migraine with aura (MA) and nine patients with familial hemiplegic migraine (FHM). Motor thresholds at rest, the duration of the cortical and peripheral silent period and intracortical inhibition and facilitation using paired-pulse TMS at intervals of 2 to 15 ms were measured with patients free of attacks for at least 48 h. In contrast to previous reports we could not find any significant differences between patient groups and compared to controls ( n = 17) in the parameters tested. The results suggest that there are no interictal changes of excitability of the motor cortex in migraine. This study does not support the concept of general cortical hyperexcitability in migraine secondary to a genetic predisposition or a structural alteration of inhibitory interneurones in the cortex due to repeated parenchymal insults during attacks.

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Cortical interneuron-mediated inhibition delays the onset of amyotrophic lateral sclerosis

Brain ◽

10.1093/brain/awaa034 ◽

2020 ◽

Vol 143 (3) ◽

pp. 800-810 ◽

Cited By ~ 6

Author(s):

C Sahara Khademullah ◽

Afif J Aqrabawi ◽

Kara M Place ◽

Zahra Dargaei ◽

Xinyi Liang ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Motor Cortex ◽

Primary Motor Cortex ◽

Intracortical Inhibition ◽

Motor Deficits ◽

Cortical Interneuron ◽

Neuronal Populations ◽

Cortical Hyperexcitability ◽

Symptom Progression ◽

Lateral Sclerosis

Abstract Amyotrophic lateral sclerosis is a fatal disease resulting from motor neuron degeneration in the cortex and spinal cord. Cortical hyperexcitability is a hallmark feature of amyotrophic lateral sclerosis and is accompanied by decreased intracortical inhibition. Using electrophysiological patch-clamp recordings, we revealed parvalbumin interneurons to be hypoactive in the late pre-symptomatic SOD1*G93A mouse model of amyotrophic lateral sclerosis. We discovered that using adeno-associated virus-mediated delivery of chemogenetic technology targeted to increase the activity of the interneurons within layer 5 of the primary motor cortex, we were able to rescue intracortical inhibition and reduce pyramidal neuron hyperexcitability. Increasing the activity of interneurons in the layer 5 of the primary motor cortex was effective in delaying the onset of amyotrophic lateral sclerosis-associated motor deficits, slowing symptom progression, preserving neuronal populations, and increasing the lifespan of SOD1*G93A mice. Taken together, this study provides novel insights into the pathogenesis and treatment of amyotrophic lateral sclerosis.

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Amyotrophic lateral sclerosis associated mislocalisation of TDP-43 to the cytoplasm causes cortical hyperexcitability and reduced excitatory neurotransmission in the motor cortex

10.1101/2020.06.11.147439 ◽

2020 ◽

Author(s):

MS Dyer ◽

KE Lewis ◽

AK Walker ◽

TC Dickson ◽

A Woodhouse ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Motor Cortex ◽

Mouse Models ◽

Rna Binding ◽

Binding Protein ◽

Synaptic Function ◽

Nuclear Localization Sequence ◽

Mechanisms Of Toxicity ◽

Cortical Hyperexcitability ◽

Lateral Sclerosis

AbstractAmyotrophic lateral sclerosis (ALS) is a chronic neurodegenerative disease pathologically characterised by mislocalisation of the RNA binding protein TAR-DNA binding protein 43 (TDP-43) from the nucleus to the cytoplasm. Changes to neuronal excitability and synapse dysfunction in the motor cortex are early pathological changes occurring in people with ALS and mouse models of disease. To investigate the effect of mislocalized TDP-43 on the function of motor cortex neurons we utilised mouse models that express either human wild-type (TDP-43WT) or nuclear localization sequence-deficient TDP-43 (TDP-43ΔNLS) on an inducible promoter that is restricted to the forebrain. Pathophysiology was investigated through immunohistochemistry and whole-cell patch-clamp electrophysiology. Thirty days expression TDP-43ΔNLS in adult mice (60 days of age) does not cause any changes in the number of NeuN positive nor CTIP2 positive neurons in the motor cortex. However at this time-point the expression of TDP-43ΔNLS drives intrinsic hyperexcitability in layer V excitatory neurons of the motor cortex. This hyperexcitability occurs concomitantly with a decrease in excitatory synaptic input to these cells. This pathophysiology is not present when TDP-43WT expression is driven, demonstrating that the localisation of TDP-43 to the cytoplasm is crucial for the altered excitability phenotype. This study has important implications for the mechanisms of toxicity of one of the most notorious proteins linked to ALS, TDP-43. We provide the first evidence that TDP-43 mislocalization causes aberrant synaptic function and a hyperexcitability phenotype in the motor cortex, linking some of the earliest dysfunctions to arise in people with ALS to mislocalisation of TDP-43.

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018 Role of transcallosal inhibition in disease spread in ALS

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2019-anzan.18 ◽

2019 ◽

Vol 90 (e7) ◽

pp. A7.2-A7

Author(s):

Mehdi Van den Bos ◽

James Howells ◽

Mana Higashihara ◽

Nimeshan Geevasinga ◽

Matthew Kiernan ◽

...

Keyword(s):

Motor Cortex ◽

Functional Disability ◽

Disease Onset ◽

Disease Spread ◽

Transcallosal Inhibition ◽

Threshold Tracking ◽

Cortical Hyperexcitability ◽

Als Patients ◽

Lateral Sclerosis

IntroductionThere is substantial evidence for the cortical origin of amyotrophic lateral sclerosis (ALS). Impaired function of the corpus callosum has been demonstrated in ALS patients and may play a role in disease spread, potentially mediating the spread of cortical hyperexcitability between hemispheres. We assessed transcallosal inhibition, utilising the threshold tracking transcranial magnetic stimulation (TMS) technique to assess transcallosal inhibition and related the changes to disease involvement.MethodsThreshold tracking TMS was undertaken in 15 ALS patients and results were compared to 16 healthy controls. Interhemispheric inhibition was assessed using a figure of eight coil over each hemisphere across interstimulus intervals ranging from 8 to 40ms.ResultsTranscallosal inhibition was reduced in ALS patients (0.9 ± 1.0%) when compared to controls (6.6 ± 1.0%, P=0.03). Importantly differences in transcallosal inhibition between hemispheres were evident in ALS patients. Specifically, transcallosal inhibition projecting from the motor cortex contralateral to disease onset (0.9 ± 1.0%) was significantly lower when compared to projection form the ipsilateral motor cortex (3.2 ± 1.0%, P=0.036). Abnormalities of transcallosal inhibition correlated with upper motor neurone dysfunction and greater functional disability in ALS.ConclusionAbnormalities of transcallosal inhibition were demonstrated in ALS patients and were associated with clinical features. Consequently, dysfunction of transcallosal fibres may contribute to development of cortical hyperexcitability, a pathogenic mechanism in ALS. Strategies aimed at modulating dysfunction may prove therapeutically useful in ALS.

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Short echo-time Magnetic Resonance Spectroscopy in ALS, simultaneous quantification of glutamate and GABA at 3 T

Scientific Reports ◽

10.1038/s41598-019-53009-4 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 1

Author(s):

J. U. Blicher ◽

S. F. Eskildsen ◽

T. G. Stærmose ◽

A. T. Møller ◽

K. Figlewski ◽

...

Keyword(s):

Magnetic Resonance ◽

Motor Cortex ◽

Magnetic Resonance Spectroscopy ◽

Healthy Subjects ◽

Primary Motor Cortex ◽

Spin Echo ◽

Occipital Lobe ◽

Resonance Spectroscopy ◽

Neuronal Marker ◽

Cortical Hyperexcitability

AbstractCortical hyperexcitability has been found in early Amyotrophic Lateral Sclerosis (ALS) and is hypothesized to be a key factor in pathogenesis. The current pilot study aimed to investigate cortical inhibitory/excitatory balance in ALS using short-echo Magnetic Resonance Spectroscopy (MRS). Patients suffering from ALS were scanned on a 3 T Trio Siemens MR scanner using Spin Echo Full Intensity Acquired Localized (SPECIAL) Magnetic Resonance Spectroscopy in primary motor cortex and the occipital lobe. Data was compared to a group of healthy subjects. Nine patients completed the scan. MRS data was of an excellent quality allowing for quantification of a range of metabolites of interest in ALS. In motor cortex, patients had Glutamate/GABA and GABA/Cr- ratios comparable to healthy subjects. However, Glutamate/Cr (p = 0.002) and the neuronal marker N-acetyl-aspartate (NAA/Cr) (p = 0.034) were low, possibly due to grey-matter atrophy, whereas Glutathione/Cr (p = 0.04) was elevated. In patients, NAA levels correlated significantly with both hand strength (p = 0.027) and disease severity (p = 0.016). In summary SPECIAL MRS at 3 T allows of reliable quantification of a range of metabolites of interest in ALS, including both excitatory and inhibitory neurotransmitters. The method is a promising new technique as a biomarker for future studies on ALS pathophysiology and monitoring of disease progression.

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