Modified age-dependent expression of NaV1.6 in an ALS model correlates with motor cortex excitability alterations

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

“…Interestingly, altered intrinsic excitability is a complex and evolving phenomenon in ALS. A switch from hyper‐ to hypo‐ excitability occurs in the SOD1 G93A mouse model, potentially involving persistent sodium current alterations (Saba et al., 2019). Hypoexcitability later in ALS progression may also contribute to the reduced effectiveness of Riluzole at later disease stages.…”

“…These alterations in excitability are present in many mouse models of familial ALS, including those with familial TDP-43 transgenes, long before the onset of disease-like symptoms (Fogarty et al, 2015;Handley et al, 2017;Saba et al, 2016Saba et al, , 2019Zhang et al, 2016). In the SOD1 mouse model of ALS, cortical neuron hyperexcitability is observed in neonates, before normalising and eventually becoming hypoexcitable at a late disease stage (Saba et al, 2019). Excitability changes are a consistent feature in people with ALS, as well as mouse and other animal models of familial ALS, yet the initial cause of cortical hyperexcitability in sporadic ALS remains unknown.…”

“…Cortical hyperexcitability of the motor cortex has been detected in sporadic ALS patients prior to spinal motor neuron dysfunction and in carriers of a SOD1 mutation conferring familial ALS before symptom onset (Vucic et al., 2008; Menon et al., 2015; Van den Bos et al., 2018). These alterations in excitability are present in many mouse models of familial ALS, including those with familial TDP‐43 transgenes, long before the onset of disease‐like symptoms (Fogarty et al., 2015; Handley et al., 2017; Saba et al., 2016, 2019; Zhang et al., 2016). In the SOD1 mouse model of ALS, cortical neuron hyperexcitability is observed in neonates, before normalising and eventually becoming hypoexcitable at a late disease stage (Saba et al., 2019).…”

Advances in Applying Computer-Aided Drug Design for Neurodegenerative Diseases

“…One of the most abundant sodium channels in the human brain is the voltage-gated sodium channel Nav1.6 [ 142 , 143 ]. Nav1.6 is a potential drug target for ALS as the blockage of these channels may enhance the survival of motor neurons in excitotoxic conditions [ 144 , 145 , 146 ]. In silico analyses demonstrated the interaction of riluzole with the Nav1.6 channel.…”

Neurophysiological Mechanisms Underlying Cortical Hyper-Excitability in Amyotrophic Lateral Sclerosis: A Review

“…Several other studies reinforce this finding, including increased AP firing observed in layer V pyramidal neurons [ 15 ] and in motor cortex slices [ 54 ]. More recently, the NaV1.6 channel localized in the initial segment of the axon have been shown to be overexpressed in cortical MNs in ALS [ 55 ], to the point where AP firing initiates [ 56 ], clearly confirming sustained depolarization-induced hyper-excitability in dying cortical MNs [ 20 ]. A depolarizing stimulus will activate any PIC present to generate AP firing in MNs [ 50 ], and hence, elevated PIC observed in ALS can contribute to hyper-excitability-induced excitotoxicity [ 20 ] by directly enhancing intracellular Ca 2+ influx and MN firing frequency [ 57 , 58 ].…”