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Synapses in physiology and pathology  

Areas of Current Focus:Lab members are involved in the study of the structure of peripheral and central synapses in models of neurodegenerative (1) and neurodevelopmental disorders (2).

1) Amyotrophic lateral sclerosis (ALS) is highly debilitating lethal disease caused by the progressive degeneration of lower motoneurons in the brainstem and spinal cord and of upper motoneurons in the motor cortex. The progressive failure of the neuromuscular system results in denervation of muscle fibers, weakness and atrophy of the limb musculature, progressive paralysis and eventually death from respiratory failure. As the molecular and cellular pathogenetic mechanism of ALS are not fully identified, to date, there are no effective cures for ALS, although riluzole, the only drug currently approved for ALS treatment, slows the rate of progression and may slightly prolong patients survival through mechanisms that are not completely understood. In past years, ALS has been classified as a dying back pathology in which degeneration starts at the distal end of the neurons (the neuromuscular junction in lower motoneurons) and proceeds toward the soma. I investigated in a systematic and quantitative manner, the ultrastructural changes of this synapse in a mice model of ALS, the mice expressing the G93A mutant form of SOD1, during disease progression trying to identify precocious subcellular targets of the toxicity of the mutant protein. Surprisingly, in SOD1G93A transgenic mice, muscle fibers denervation was associated to a relatively mild aberrant phenotypes in the residual presynaptic terminals thus suggesting a modest contribution of the nerve ending impairments to neuronal damage. These results prompted us to broaden our field of investigation from the neuromuscular junction alone to motoneuron as a whole and finally to the network of spinal neurons. To do this and in close collaboration with a colleague from our University (Prof. Luca Del Giacco) running the zebrafish facility, we characterized and used zebrafish expressing a mutant forms of SOD1 to identify early pathological phenotypes in the nerve-muscle apparatus of this animal. Combining several experimental approaches and tools: behavioral analyses, molecular biology, optical and electron microscopic imaging, the study of the whole organism brought us to the identification of precocious important aberrant phenotypes that involve motoneurons and interneurons hyperexcitability in zebrafish expressing mutant SOD1 and our results also suggested a possible new mechanism of action of riluzole in controlling mutant SOD1 mediated toxicity.

2) Defective formation or function of synapses in the central nervous system (CNS) during development results in disorders of learning and memory, including autism and intellectual disability. These disorders are frequently due to mutations in genes encoding synaptic proteins, involved in cytoskeleton rearrangement, synaptic plasticity, synapse formation and stability or neurotransmission; all aspects affecting either the pre- or the postsynapse structure and function and the number of synapses. In the past four years we devoted much efforts in the characterization of the structure of central synapses of specific areas of the CNS by means of ultrastructural studies on both in vitro and in vivo models of human neurodevelopmental disorders addressing simultaneously all aspects of the synapse anatomy. In fact my collaborators and myself have developed a Synapse Toolbox collecting a list of parameters of the pre- and postsynapse that we systematically analyse and compare between samples. The data we obtain are complemented by data from biochemical assays, electrophysiological recordings and finally behavioral studies that we collect from the work of our collaborators.


Maura Francolini



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