Cortical Hyperexcitability and the Effect of Anti-CGRP Antibodies Treatment in Migraine: Evidence by Sound Induced Flash Illusions

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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Cortical hyperexcitability: Diagnostic and pathogenic biomarker of ALS

Neuroscience Letters ◽

10.1016/j.neulet.2021.136039 ◽

2021 ◽

pp. 136039

Author(s):

Steve Vucic ◽

Nathan Pavey ◽

Mouna Haidar ◽

Bradley J. Turner ◽

Matthew C. Kiernan

Keyword(s):

Cortical Hyperexcitability

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Charles Bonnet Syndrome: Cortical Hyperexcitability and Visual Hallucination

Current Biology ◽

10.1016/j.cub.2018.09.007 ◽

2018 ◽

Vol 28 (21) ◽

pp. R1253-R1254 ◽

Cited By ~ 1

Author(s):

Max Coltheart

Keyword(s):

Visual Hallucination ◽

Charles Bonnet Syndrome ◽

Cortical Hyperexcitability

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Partial loss of CFIm25 causes learning deficits and aberrant neuronal alternative polyadenylation

eLife ◽

10.7554/elife.50895 ◽

2020 ◽

Vol 9 ◽

Cited By ~ 4

Author(s):

Callison E Alcott ◽

Hari Krishna Yalamanchili ◽

Ping Ji ◽

Meike E van der Heijden ◽

Alexander Saltzman ◽

...

Keyword(s):

Intellectual Disability ◽

Protein Level ◽

Alternative Polyadenylation ◽

Copy Number Variations ◽

Human Stem Cell ◽

Partial Loss ◽

Learning Deficits ◽

Cortical Hyperexcitability ◽

The Brain ◽

Cognate Protein

We previously showed that NUDT21-spanning copy-number variations (CNVs) are associated with intellectual disability (Gennarino et al., 2015). However, the patients’ CNVs also included other genes. To determine if reduced NUDT21 function alone can cause disease, we generated Nudt21+/- mice to mimic NUDT21-deletion patients. We found that although these mice have 50% reduced Nudt21 mRNA, they only have 30% less of its cognate protein, CFIm25. Despite this partial protein-level compensation, the Nudt21+/- mice have learning deficits, cortical hyperexcitability, and misregulated alternative polyadenylation (APA) in their hippocampi. Further, to determine the mediators driving neural dysfunction in humans, we partially inhibited NUDT21 in human stem cell-derived neurons to reduce CFIm25 by 30%. This induced APA and protein level misregulation in hundreds of genes, a number of which cause intellectual disability when mutated. Altogether, these results show that disruption of NUDT21-regulated APA events in the brain can cause intellectual disability.

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Astroglial FMRP modulates synaptic signaling and behavior phenotypes in FXS mouse model

10.1101/2020.02.10.941971 ◽

2020 ◽

Author(s):

Shan-Xue Jin ◽

Haruki Higashimori ◽

Christina Schin ◽

Alessandra Tamashiro ◽

Yuqin Men ◽

...

Keyword(s):

Glutamate Uptake ◽

Fragile X ◽

Cell Types ◽

Skill Learning ◽

Spine Density ◽

Novelty Preference ◽

Synaptic Signaling ◽

Selective Loss ◽

State Duration ◽

Cortical Hyperexcitability

AbstractFragile X syndrome (FXS) is one of the most common inherited intellectual disability (ID) disorders, in which the loss of FMRP protein induces a range of cellular signaling changes primarily through excess protein synthesis. Although neuron-centered molecular and cellular events underlying FXS have been characterized, how different CNS cell types are involved in typical FXS synaptic signaling changes and behavioral phenotypes is largely unknown. Recent evidence suggests that selective loss of astroglial FMRP is able to dysregulate glutamate uptake, increase spine density, and impair motor-skill learning. Here we investigated the effect of astroglial FMRP on synaptic signaling and FXS-related behavioral and learning phenotypes in astroglial Fmr1 cKO and cON mice in which FMRP expression is selectively diminished or restored in astroglia. We found that selective loss of astroglial FMRP contributes to cortical hyperexcitability by enhancing NMDAR-mediated evoked but not spontaneous miniEPSCs and elongating cortical UP state duration. Selective loss of astroglial FMRP is also sufficient to increase locomotor hyperactivity, significantly diminish social novelty preference, and induce memory acquisition and extinction deficits in astroglial Fmr1 cKO mice. Importantly, re-expression of astroglial FMRP is able to significantly rescue the hyperactivity (evoked NMDAR response, UP state duration, and open field test) and social novelty preference in astroglial Fmr1 cON mice. These results demonstrate a profound role of astroglial FMRP in the evoked synaptic signaling, spontaneously occurring cortical UP states, and FXS-related behavioral and learning phenotypes and provide important new insights in the cell type consideration for the FMRP reactivation strategy.

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