Abstract
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.
Highlights
Amyotrophic Lateral Sclerosis (ALS), known as Lou Gehrig’s disease, is a rapidly progressive neurodegenerative disease that targets motor neurons (MNs)
Neuroscience transgenic mouse model SOD1G93A (SOD, Gly93fiAla substitution), which expresses a large degree of human mutant SOD1 and faithfully recapitulates a vast majority of the pathology’s abnormalities seen in ALS patients (Fogarty, 2018), we previously found that SOD MNs are hyperexcitable at the prenatal (embryonic day (E) 17.5) stage because of a shorter dendritic tree and increased input resistance (Martin et al, 2013)
Our findings show that the presynaptic network of SOD MNs is altered at fetal stages, cellular mechanisms leading to long-lasting IPSCs operate to compensate for the depolarized EGABAAR and hyperexcitability of E17.5 SOD MNS in order to maintain a coordinated locomotor activity
Summary
Amyotrophic Lateral Sclerosis (ALS), known as Lou Gehrig’s disease, is a rapidly progressive neurodegenerative disease that targets motor neurons (MNs). It is one of the most common and most devastating neurodegenerative diseases. Our result show a significantly slower decay time in SOD IPSCs and GABAAR-currents compared to WT This slower decay is associated with a higher intracellular chloride concentration [Cl-]i in SOD MNs compared to WT. Our findings show that the presynaptic network of SOD MNs is altered at fetal stages, cellular mechanisms leading to long-lasting IPSCs operate to compensate for the depolarized EGABAAR and hyperexcitability of E17.5 SOD MNS in order to maintain a coordinated locomotor activity
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