Increased persistent sodium current determines cortical hyperexcitability in a genetic model of amyotrophic lateral sclerosis

Pieri, Massimo; Carunchio, Irene; Curcio, Livia; Mercuri, Nicola Biagio; Zona, Cristina

doi:10.1016/j.expneurol.2008.11.002

Cited by 128 publications

(139 citation statements)

References 73 publications

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“…Larger PICs can increase the overall excitability of a neuron (though other factors, like size, can mitigate this), and the influx of Ca 2+ could have many other consequences in cell-signaling. An increased PIC is found in cultured, embryonic, SOD1G93A-high motoneurons (both spinal and cortical), though at this point the PIC is completely Na + -based (Kuo et al, 2005, Pieri et al, 2009. Postnatally, both spinal and brainstem SOD1 motoneurons show an increased PIC (van Zundert et al, 2008, Quinlan et al, 2011, and indirect evidence suggests larger PICs persist into adulthood in SOD1 cortical and spinal motoneurons (Carunchio et al, 2010, Meehan et al, 2010.…”

Section: Calcium: No Buffer For Increased Currentsmentioning

confidence: 99%

“…These properties include an increase in excitability (as measured by both the Na + -and Ca 2+ -mediated persistent inward current; PIC) and an increased neuronal size (including increased dendritic branching and increased specific input conductance). Significantly larger PICs first appear in cultured embryonic spinal and cortical motoneurons (Kuo et al, 2005, Pieri et al, 2009), persist at an age of about one week in spinal and hypoglossal motoneurons (van Zundert et al, 2008, Quinlan et al, 2011 and are likely still present in the spinal and cortical motoneurons of adults (Carunchio et al, 2010, Meehan et al, 2010. Interestingly, although the PIC is upregulated very early, what might otherwise be the beginning of motoneuron hyperexcitability is instead moderated by changes in size and specific input conductance (Amendola and Durand, 2008, Elbasiouny et al, 2010, Quinlan et al, 2011.…”

Section: Timeline Of Deficitsmentioning

confidence: 99%

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Molecular and Electrical Abnormalities in the Mouse Model of Amyotrophic Lateral Sclerosis

Quinlan¹,

Elbasiouny²,

Heckman³

2012

Amyotrophic Lateral Sclerosis

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Section: Calcium: No Buffer For Increased Currentsmentioning

confidence: 99%

Section: Timeline Of Deficitsmentioning

confidence: 99%

Molecular and Electrical Abnormalities in the Mouse Model of Amyotrophic Lateral Sclerosis

Quinlan¹,

Elbasiouny²,

Heckman³

2012

Amyotrophic Lateral Sclerosis

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“…Starting treatment at P30 corresponds with a spike in endoplasmic reticulum stress and the earliest signs of neuromuscular junction detachment in fast fatigable motor units in this mouse model (Hegedus et al 2007(Hegedus et al , 2008Pun et al 2006;Saxena et al 2009). In addition, SSRIs are widely prescribed for depression and anxiety disorders in otherwise healthy individuals (i.e., before ALS symptoms would be detected) (Nichols and Nichols 2008).…”

mentioning

confidence: 99%

“…Starting treatment at P70 corresponds to the onset of tremor in this mouse model; however, progressive motoneuron detachment from the neuromuscular junction and death have already occurred (Hegedus et al 2007(Hegedus et al , 2008Pun et al 2006). This time period was also chosen because three well-controlled studies using clinician interviews and DSM-IV criteria reported the prevalence of depression in ALS patients at 10% (Ganzini et al 1999;Rabkin et al 2000Rabkin et al , 2005, double the rate in otherwise healthy individuals (Narrow et al 2002).…”

mentioning

confidence: 99%

“…Specifically, voltage-sensitive currents in bulbar and spinal motoneurons are upregulated and can produce hyperexcitability in some preparations (Carunchio et al 2010;Kuo et al 2004Kuo et al , 2005Pieri et al 2009;van Zundert et al 2008). However, during this neonatal time period spinal motoneuron excitability may not be increased because of a concurrent increase in input conductance and changes in morphology (Bories et al 2007;Pambo-Pambo et al 2009;Quinlan et al 2011).…”

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confidence: 99%

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Effect of fluoxetine on disease progression in a mouse model of ALS

Koschnitzky

Quinlan

Lukas

et al. 2014

Journal of Neurophysiology

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Koschnitzky JE, Quinlan KA, Lukas TJ, Kajtaz E, Kocevar EJ, Mayers WF, Siddique T, Heckman CJ. Effect of fluoxetine on disease progression in a mouse model of ALS. J Neurophysiol 111: 2164-2176, 2014. First published March 5, 2014 doi:10.1152/jn.00425.2013.-Selective serotonin reuptake inhibitors (SSRIs) and other antidepressants are often prescribed to amyotrophic lateral sclerosis (ALS) patients; however, the impact of these prescriptions on ALS disease progression has not been systematically tested. To determine whether SSRIs impact disease progression, fluoxetine (Prozac, 5 or 10 mg/kg) was administered to mutant superoxide dismutase 1 (SOD1) mice during one of three age ranges: neonatal [postnatal day (P)5-11], adult presymptomatic (P30 to end stage), and adult symptomatic (P70 to end stage). Long-term adult fluoxetine treatment (started at either P30 or P70 and continuing until end stage) had no significant effect on disease progression. In contrast, neonatal fluoxetine treatment (P5-11) had two effects. First, all animals (mutant SOD1 G93A and control: nontransgenic and SOD1 WT ) receiving the highest dose (10 mg/kg) had a sustained decrease in weight from P30 onward. Second, the high-dose SOD1 G93A mice reached end stage ϳ8 days (ϳ6% decrease in life span) sooner than vehicle and low-dose animals because of an increased rate of motor impairment. Fluoxetine increases synaptic serotonin (5-HT) levels, which is known to increase spinal motoneuron excitability. We confirmed that 5-HT increases spinal motoneuron excitability during this neonatal time period and therefore hypothesized that antagonizing 5-HT receptors during the same time period would improve disease outcome. However, cyproheptadine (1 or 5 mg/kg), a 5-HT receptor antagonist, had no effect on disease progression. These results show that a brief period of antidepressant treatment during a critical time window (the transition from neonatal to juvenile states) can be detrimental in ALS mouse models. amyotrophic lateral sclerosis; motoneuron excitability; fluoxetine; Prozac; antidepressant

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Intranasal neuropeptide Y1 receptor antagonism improves motor deficits in symptomatic SOD1 ALS mice

Clark,

Lewis

et al. 2023

Ann Clin Transl Neurol

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ObjectiveNeuropeptide Y (NPY) is a 36 amino acid peptide widely considered to provide neuroprotection in a range of neurodegenerative diseases. In the fatal motor neuron disease amyotrophic lateral sclerosis (ALS), recent evidence supports a link between NPY and ALS disease processes. The goal of this study was to determine the therapeutic potential and role of NPY in ALS, harnessing the brain‐targeted intranasal delivery of the peptide, previously utilised to correct motor and cognitive phenotypes in other neurological conditions.MethodsTo confirm the association with clinical disease characteristics, NPY expression was quantified in post‐mortem motor cortex tissue of ALS patients and age‐matched controls. The effect of NPY on ALS cortical pathophysiology was investigated using slice electrophysiology and multi‐electrode array recordings of SOD1G93A cortical cultures in vitro. The impact of NPY on ALS disease trajectory was investigated by treating SOD1G93A mice intranasally with NPY and selective NPY receptor agonists and antagonists from pre‐symptomatic and symptomatic phases of disease.ResultsIn the human post‐mortem ALS motor cortex, we observe a significant increase in NPY expression, which is not present in the somatosensory cortex. In vitro, we demonstrate that NPY can ameliorate ALS hyperexcitability, while brain‐targeted nasal delivery of NPY and a selective NPY Y1 receptor antagonist modified survival and motor deficits specifically within the symptomatic phase of the disease in the ALS SOD1G93A mouse.InterpretationTaken together, these findings highlight the capacity for non‐invasive brain‐targeted interventions in ALS and support antagonism of NPY Y1Rs as a novel strategy to improve ALS motor function.

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Increased persistent sodium current determines cortical hyperexcitability in a genetic model of amyotrophic lateral sclerosis

Cited by 128 publications

References 73 publications

Molecular and Electrical Abnormalities in the Mouse Model of Amyotrophic Lateral Sclerosis

Molecular and Electrical Abnormalities in the Mouse Model of Amyotrophic Lateral Sclerosis

Effect of fluoxetine on disease progression in a mouse model of ALS

Intranasal neuropeptide Y1 receptor antagonism improves motor deficits in symptomatic SOD1 ALS mice

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