Neonatal Neuronal Circuitry Shows Hyperexcitable Disturbance in a Mouse Model of the Adult-Onset Neurodegenerative Disease Amyotrophic Lateral Sclerosis

McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 11/2008; 28(43):10864-74. DOI: 10.1523/JNEUROSCI.1340-08.2008
Source: PubMed


Distinguishing the primary from secondary effects and compensatory mechanisms is of crucial importance in understanding adult-onset neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). Transgenic mice that overexpress the G93A mutation of the human Cu-Zn superoxide dismutase 1 gene (hSOD1(G93A) mice) are a commonly used animal model of ALS. Whole-cell patch-clamp recordings from neurons in acute slice preparations from neonatal wild-type and hSOD1(G93A) mice were made to characterize functional changes in neuronal activity. Hypoglossal motoneurons (HMs) in postnatal day 4 (P4)-P10 hSOD1(G93A) mice displayed hyperexcitability, increased persistent Na(+) current (PC(Na)), and enhanced frequency of spontaneous excitatory and inhibitory transmission, compared with wild-type mice. These functional changes in neuronal activity are the earliest yet reported for the hSOD1(G93A) mouse, and are present 2-3 months before motoneuron degeneration and clinical symptoms appear in these mice. Changes in neuronal activity were not restricted to motoneurons: superior colliculus interneurons also displayed hyperexcitability and synaptic changes (P10-P12). Furthermore, in vivo viral-mediated GFP (green fluorescent protein) overexpression in hSOD1(G93A) HMs revealed precocious dendritic remodeling, and behavioral assays revealed transient neonatal neuromotor deficits compared with controls. These findings underscore the widespread and early onset of abnormal neural activity in this mouse model of the adult neurodegenerative disease ALS, and suggest that suppression of PC(Na) and hyperexcitability early in life might be one way to mitigate or prevent cell death in the adult CNS.

Download full-text


Available from: Mark Bellingham,
19 Reads
    • "Motoneurons from mSOD1 embryos recorded in culture were found to be hyperexcitable (Kuo et al., 2005; van Zundert et al., 2008) in that they were recruited at lower current than WT motoneurons and their frequency of discharge (F) increased more with injected current (I) (higher F-I curve slope). Martin et al. (2013) found a similar result in an in vitro preparation of mSOD1 embryonic cord. "

    Neural Regeneration Research 01/2015; 10(9):1413-1415. DOI:10.4103/1673-5374.165308 · 0.22 Impact Factor
  • Source
    • "In some studies, this resulted in an increase in motoneuron excitability (Kuo et al. 2005; Pieri et al. 2009; van Zundert et al. 2008); however, in the Quinlan et al. (2011) study the pathological increase in the PIC is matched by a similar increase in the input conductance of the SOD1 G93A motoneurons, resulting in no net increase in excitability. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Selective serotonin reuptake inhibitors (SSRIs) and other antidepressants are often prescribed to ALS patients; however, the impact of these prescriptions on ALS disease progression has not been systematically tested. To determine if SSRIs impact disease progression, fluoxetine (Prozac®) (5 or 10mg/kg) was administered to mutant SOD1 mice during three age ranges: neonatal (postnatal day 5-11 (P5-11)), 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 controls: non-transgenic and SOD1(WT)) receiving the highest dose (10mg/kg) had a sustained decrease in weight from P30 onward. Second, the high dose SOD1G93A mice reached end stage ~8 days (~6% decrease in life span) sooner than vehicle and low dose animals due to 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 5mg/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.
    Journal of Neurophysiology 03/2014; 111(11). DOI:10.1152/jn.00425.2013 · 2.89 Impact Factor
  • Source
    • "Our results point to critical roles for nitroxidatve stress as well as Nav channel activity in inducing motoneuron death. We and others have previously used cell cultures and slice preparations obtained from transgenic mice expressing mutations in SOD1 to report that Nav channel activity and/or excitability is increased in motoneurons (Kuo et al., 2005; van Zundert et al., 2008; Pambo-Pambo et al., 2009; Pieri et al., 2009; Schuster et al., 2011; Quinlan et al., 2011 and reviewed in ElBasiouny et al., 2010 and van Zundert et al., 2012). Moreover, using the ACM-SOD1G93A model system, we recently found that neuronal hyperexcitability, mediated at least in part through elevated Nav channel activity, is essential for inducing motoneuron death. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a fatal paralytic disorder caused by dysfunction and degeneration of motor neurons. Multiple disease-causing mutations, including in the genes for SOD1 and TDP-43, have been identified in ALS. Astrocytes expressing mutant SOD1 are strongly implicated in the pathogenesis of ALS: we have shown that media conditioned by astrocytes carrying mutant SOD1(G93A) contains toxic factor(s) that kill motoneurons by activating voltage-sensitive sodium (Na v ) channels. In contrast, a recent study suggests that astrocytes expressing mutated TDP43 contribute to ALS pathology, but do so via cell-autonomous processes and lack non-cell-autonomous toxicity. Here we investigate whether astrocytes that express diverse ALS-causing mutations release toxic factor(s) that induce motoneuron death, and if so, whether they do so via a common pathogenic pathway. We exposed primary cultures of wild-type spinal cord cells to conditioned medium derived from astrocytes (ACM) that express SOD1 (ACM-SOD1(G93A) and ACM-SOD1(G86R)) or TDP43 (ACM-TDP43(A315T)) mutants; we show that such exposure rapidly (within 30-60 min) increases dichlorofluorescein (DCF) fluorescence (indicative of nitroxidative stress) and leads to extensive motoneuron-specific death within a few days. Co-application of the diverse ACMs with anti-oxidants Trolox or esculetin (but not with resveratrol) strongly improves motoneuron survival. We also find that co-incubation of the cultures in the ACMs with Na v channel blockers (including mexiletine, spermidine, or riluzole) prevents both intracellular nitroxidative stress and motoneuron death. Together, our data document that two completely unrelated ALS models lead to the death of motoneuron via non-cell-autonomous processes, and show that astrocytes expressing mutations in SOD1 and TDP43 trigger such cell death through a common pathogenic pathway that involves nitroxidative stress, induced at least in part by Na v channel activity.
    Frontiers in Cellular Neuroscience 02/2014; 8:24. DOI:10.3389/fncel.2014.00024 · 4.29 Impact Factor
Show more