Pascal Branchereau et al. in eLife

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.

Schematic drawing summarizing the altered inhibitory inputs to fetal SOD MNs. [Cl-]i is higher in SOD MNs (A1) than in WT MNs (A2) because of a KCC2 down-regulation, leading to an increased GABA/Gly-induced depolarizing effect (see insets). B, Consequence of increasing taudecay on the GABA/gly inhibitory effect in SOD-like MNs. Due to an accumulation in the intracellular compartment, EGABAAR exerts a strong depolarizing effect. A burst of spikes generated by MNs is hardly blocked by a barrage of GABA/gly events (see blue traces) when taudecay is set to 20 ms. Increasing taudecay to 25 ms allows a better summation of the shunting component of the depolarizing GABA/gly post-synaptic event leading to a better clamp of Em towards EGABAAR and to the blockade of MN discharge (see green traces).


Relaxation of synaptic inhibitory events as a compensatory mechanism in fetal SOD spinal motor networks. Branchereau P, Martin E, Allain AE, Cazenave W, Supiot L, Hodeib F, Laupénie A, Dalvi U, Zhu H, Cattaert D. Elife. 2019 Dec 23;8. pii: e51402.
doi: 10.7554/eLife.51402

Pascal Branchereau - Crédit : Sharpen
Pascal Branchereau

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