Neurophysiological characterisation of the g93a ALS rat model

OBJECTIVES:Recently a rat model of ALS harbouring a mutant SOD1G93A gene has been generated, showing clinical features that resemble the human phenotype.Clinical characteristics and larger size of the rat model might give the opportunity for more extensive studies for a better comprehension of ALS pathogenesis and testing new therapeutic strategies.A detailed neurophysiological characterization of this model is still lacking so we performed longitudinal neurophysiological study of this ALS rat model. METHODS:We analyzed 5 wild type rats and 5 ALS rats at 60,90,100,120,140post natal days(pnd),for monitoring the development of the disease.Sciatic nerve motor conduction velocity(MCV)and Motor evoked potentials(MEP)by transcranial electric stimulation were performed to obtain peripheral and central nervous system functional parameters.An unpaired Student’s t test was performed for statistical evaluation of the data.Needle analysis of brachial biceps and triceps,vastus and gemini muscles was performed in all ALS animals. RESULTS:In ALS rats amplitude of tibial nerve(MAP)decrease at 120 pnd and dramatically falls down with statistical significance(P<0.001)at 140 pnd.F wave latency,MCV and spinal MEP latency didn’t modify at comparison with controls.Cortical MEP(cMEP)amplitude decreases, in comparison with controls,since 90pnd(p=0.02)and worsen at 120pnd(P <0.001).cMEP at 140pnd is not evocable in all affected animals.With reduction of cMEP amplitude we observed a consensual reduction of MEP/MAP ratio in all ALS rats and an increased cortical motor threshold(p=0.04at 90pnd and p=0.004at 120pnd).Needle analysis of ALS rats muscles showed active denervation(jasper and fibrillation ++)at 120pnd,that worsen at 140pnd(jasper and fibrillation+++). CONCLUSION:In peripheral nervous system of ALS rats we found an important reduction of cMAP amplitude,meaning an important axonal loss only at the end stage of the disease.In central nervous system we found an earlier reduction(until 90pnd)of cMEP amplitude and a reduction of MEP/MAPratio,that even worse at 140pnd when cMEP is inevocable.Data suggests a more evident involvement of central nervous system,but the consensual increase of cortical motor threshold could mean a reduced excitability of the system that can be due to a more early functional dysfunction of upper or spinal motoneurons.This data represent a starting point for monitoring the in vivo progression of the pathology and test the efficacy of therapeutic strategies