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 SOD1(G93A) (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 E(GABAAR) 10 mV more depolarized than in WT MNs associated with a KCC2 reduction. Interestingly, SOD GABAergic/glycinergic IPSCs and evoked GABA(A)R-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 E(GABAAR) 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.