Article

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

ABSTRACT

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.

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    • "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. "

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    • "These observations thus strengthen the belief that cortical hyperexciatability contributes to the ALS pathophysiology and most likely plays an important role in the appearance of the cognitive impairments described in the ALS/FTD syndrome. SOD1G93A hyperexcitability has also been reported in cultured cortical neurons (Pieri et al., 2009) and cortical slices (Carunchio et al., 2010), and in spinal (Kuo et al., 2005; Tamura et al., 2006) and brainstem MNs (Van Zundert et al., 2008). Using motor unit number estimation (MUNE) and motor evoked potentials (MEP), to evaluate motor central pathways, Mancuso et al. (2011) demonstrated, in the SOD1G93A mouse, that dysfunctions of central motor pathways coexists with peripheral motor deficits. "
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    • "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. "
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    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.
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