Relaxation of synaptic inhibitory events as a compensatory mechanism in fetal SOD spinal motor networks.
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease affecting motor neurons (MNs) during late adulthood. Here, with the aim of identifying early changes underpinning ALS neurodegeneration, we analyzed the GABAergic/glycinergic inputs to E17.5 fetal MNs from SOD1G93A (SOD) mice in parallel with chloride homeostasis. Our results show that IPSCs are less frequent in SOD animals in accordance with a reduction of synaptic VIAAT-positive terminals. SOD MNs exhibited an EGABAAR10 mV more depolarized than in WT MNs associated with a KCC2 reduction. Interestingly, SOD GABAergic/glycinergic IPSCs and evoked GABAAR-currents exhibited a slower decay correlated to elevated [Cl-]i. Computer simulations revealed that a slower relaxation of synaptic inhibitory events acts as compensatory mechanism to strengthen GABA/glycine inhibition when EGABAAR is more depolarized. How such mechanisms evolve during pathophysiological processes remain to be determined, but our data indicate that at least SOD1 familial ALS may be considered as a neurodevelopmental disease.
['Branchereau|Pascal|P|0000-0003-3972-8229', 'Martin|Elodie|E|', 'Allain|Anne-Emilie|AE|', 'Cazenave|William|W|', 'Supiot|Laura|L|', 'Hodeib|Fara|F|', 'Laupénie|Amandine|A|', 'Dalvi|Urvashi|U|', 'Zhu|Hongmei|H|', 'Cattaert|Daniel|D|']
D000690:Amyotrophic Lateral Sclerosis D000818:Animals D002712:Chlorides D004195:Disease Models, Animal D005333:Fetus D059330:GABAergic Neurons D005998:Glycine D006801:Humans D051379:Mice D008822:Mice, Transgenic D009046:Motor Neurons D009433:Neural Inhibition D013116:Spinal Cord D000072105:Superoxide Dismutase-1 D027981:Symporters D009435:Synaptic Transmission D005680:gamma-Aminobutyric Acid
SOD1G93A GABA/glycine inhibition ALS disease modelling mouse neuroscience patch-clamp relaxation time course