GLIOTRANSMISSION IS DYSFUNCTIONAL IN SPINAL MOTOR NETWORKS OF PRESYMPTOMATIC ALS MICE

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of upper and lower motor neurons (MNs). Neuronal hyperexcitability is a hallmark of ALS and precedes MN loss. Astrocytes provide inhibitory modulation to neurons: a function known as 'gliotransmission'. Prior to MN loss, astrocytes are dysfunctional. Disruption to gliotransmission may thus contribute to neuronal hyperexcitability in ALS and represent a novel therapeutic avenue. We thus aimed to investigate whether gliotransmission is perturbed in early stages of ALS. Experiments were conducted using ex vivo spinal cord preparations obtained from a presymptomatic ALS mouse model carrying the SOD1 ALS mutation. Electrophysiology recordings from ventral roots during pharmacological activation of spinal locomotor circuits revealed hyperactivity in ALS mice. Interestingly, exogenous astrocytic stimulation reduced motor network output in wildtype mice but failed to modulate network activity in ALS mice. Whole-cell patch-clamp recordings from spinal cord ventral interneurons also revealed neuronal hyperexcitability in ALS mice. Notably, astrocytic stimulation induced a hyperpolarizing current in wildtype interneurons but failed to in ALS mice. However, further network-level recordings revealed that ALS astrocytes were not incapable of gliotransmission but were instead overactive. Pharmacological inhibition of the target for inhibitory gliotransmission (A1 adenosine receptor) significantly increased spinal motor network activity in ALS mice compared to wildtype mice. These results indicate that a key gliotransmission pathway is dysfunctional in ALS mice prior to MN loss and represent a promising target for early therapeutic intervention.