Gender-Specific Mechanism of Synaptic Impairment and Its Prevention by GCSF in a Mouse Model of ALS

Nikolay Naumenko,Eveliina Pollari,Anastasia Shakirzyanova,Jari Koistinaho,Rashid Giniatullin,Johanna Magga,Raisa Giniatullina,Antti Kurronen

doi:10.3389/fncel.2011.00026

Nikolay Naumenko, Eveliina Pollari + Show 6 more

Open Access

https://doi.org/10.3389/fncel.2011.00026

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Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of motoneurons which progresses differentially in males and females for unknown reason. Here we measured gender differences in pre- and post-synaptic parameters of the neuromuscular transmission in a mutant G93A-SOD1 mouse model of ALS. Using intracellular microelectrode technique we recorded miniature and evoked end-plate potentials (MEPPs and EPPs) in the diaphragm muscle of G93A-SOD1 mice at early symptomatic stage. While no evident alterations in the amplitude of MEPPs was observed in male or female G93A-SOD1 mice, G93A-SOD1 mice displayed dramatically reduced probability of spontaneous acetylcholine release. In contrast, the EPPs evoked by single nerve stimulation had unchanged amplitude and quantal content. In males, but not females, this was accompanied by reduced readily releasable transmitter pool. Transmitter release in both sexes was sensitive to the inhibitory action of reactive oxygen species (ROS), but the production of ROS was increased in the spinal cords of male but not female G93A-SOD1 mice. Treatment with granulocyte colony stimulating factor (GCSF), which we previously found to be beneficial in males, attenuated the increased ROS production indicating involvement of the antioxidant mechanisms and improved ALS-induced synaptic dysfunctions only in males being ineffective in females. Consistent with our findings at synaptic level, GCSF did not change the survival rate or motor performance of female ALS mice. In summary, neuromuscular transmission in ALS mice is impaired at early symptomatic stage when a dramatic presynaptic decline of spontaneous release occurs. Beneficial effects of GCSF treatment on survival in males may be explained by GCSF-improved presynaptic functions in male G93A-SOD1 mice. Development of efficient treatment strategies for ALS may need to be directed in a gender-specific manner.

Highlights

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease leading to motoneuron death (Boillée et al, 2006; Rothstein, 2009)
We show that granulocyte colony stimulating factor (GCSF) treatment reduced the oxidative stress in male mice to normal range and improved their compromised neurotransmission without having evident effect on the neurotransmission in female G93A-Cu/Zn superoxide dismutase (SOD1) mice
Our results are in agreement with the previously reported gender differences in the incidence and prevalence of ALS (McCombe and Henderson, 2010; Alves et al, 2011) and show that the function of neuromuscular junction can be improved in male but not female G93A-SOD1 mice with GCSF treatment

Summary

Introduction

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease leading to motoneuron death (Boillée et al, 2006; Rothstein, 2009). While 90% of the cases are sporadic, 20% of the remaining familial cases are caused by dominant mutations in the Cu/Zn superoxide dismutase (SOD1) gene (Valdmanis and Rouleau, 2008). Even though sporadic and familial forms of the disease display similar clinical features, a direct causative pathway to neuronal dysfunction and death has not yet been established. The central neuropathology of the disease, motoneuron degeneration, appears to be associated with accumulation of mutant SOD1 (Boillée et al, 2006). Such progressive neurodegeneration is observed in transgenic mice overexpressing mutant forms of human SOD1 (Shibata, 2001).

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