Monoaminergic control of spinal locomotor networks in SOD1G93A newborn mice.

Lã©A Milan,Sandrine S Bertrand,Philippe De Deurwaerdã¨Re,Grã©Gory Barriã¨Re,Jean-Renã© Cazalets

doi:10.3389/fncir.2014.00077

Abstract

Mutations in the gene that encodes Cu/Zn-superoxide dismutase (SOD1) are the cause of approximately 20% of familial forms of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease characterized by the progressive loss of motor neurons. While ALS symptoms appear in adulthood, spinal motoneurons exhibit functional alterations as early as the embryonic and postnatal stages in the murine model of ALS, the SOD1 mice. Monoaminergic – i.e., dopaminergic (DA), serotoninergic (5-HT), and noradrenergic (NA) – pathways powerfully control spinal networks and contribute significantly to their embryonic and postnatal maturation. Alterations in monoaminergic neuromodulation during development could therefore lead to impairments in the motoneuronal physiology. In this study, we sought to determine whether the monoaminergic spinal systems are modified in the early stages of development in SOD1 mice. Using a post-mortem analysis by high performance liquid chromatography (HPLC), monoaminergic neuromodulators and their metabolites were quantified in the lumbar spinal cord of SOD1 and wild-type (WT) mice aged one postnatal day (P1) and P10. This analysis underscores an increased content of DA in the SOD1 lumbar spinal cord compared to that of WT mice but failed to reveal any modification of the other monoaminergic contents. In a next step, we compared the efficiency of the monoaminergic compounds in triggering and modulating fictive locomotion in WT and SOD1 mice. This study was performed in P1–P3 SOD1 mice and age-matched control littermates using extracellular recordings from the lumbar ventral roots in the in vitro isolated spinal cord preparation. This analysis revealed that the spinal networks of SOD1G93A mice could generate normal locomotor activity in the presence of NMA-5-HT. Interestingly, we also observed that SOD1 spinal networks have an increased sensitivity to NA compared to WT spinal circuits but exhibited similar DA responses.

Highlights

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive degeneration of M1 neurons in the cerebral cortex and motor neurons in the brainstem and spinal cord
While amyotrophic lateral sclerosis (ALS) syndrome occurs during adulthood in both humans and ALS animal models, a growing body of evidence shows that spinal locomotor networks exhibit functional alterations as early as the embryonic and postnatal stages in mice expressing the human mutated SOD1 protein, the SOD1 mouse model
To assess the impact of the descending pathway maturation on monoamine contents, we performed these procedures on the lumbar spinal cord samples from both postnatal 1 (P1) and P10 animals

Summary

Introduction

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive degeneration of M1 neurons in the cerebral cortex and motor neurons in the brainstem and spinal cord. The classical rhythmogenic drug cocktail (a mixture of glutamate agonist plus serotonin) used to activate the locomotor central pattern generators (CPGs) in the isolated spinal cord preparation of newborn rodents has been shown to be inefficient in inducing fictive locomotion in SOD1G85R mice (Amendola et al, 2004). As such early alterations could prime neuronal circuits and make them more permissive to pathological changes later in life, it appears of importance to further decipher the changes undergone by the spinal motor networks in early developmental stages in the SOD1 models of ALS

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Conclusion