Key pointsr Intrinsic hyperexcitability of spinal motoneurones is thought to contribute to excitotoxicity during amyotrophic lateral sclerosis (ALS), but it has never been demonstrated that adult motoneurones become hyperexcitable before disconnection from their muscle fibres.r We found an increased input conductance in motoneurones recorded in a mouse model of ALS. Yet, most cells retained normal excitability as measured by current onset for firing and input-output gain. This indicates successful regulation of excitability, compensating for the increase in conductance.r In contrast, some cells became hypoexcitable, losing their ability to fire repetitively to quasi-stationary inputs before denervation. Hypoexcitability might therefore be an early marker of disease progression.r We thereby demonstrate that, if excitotoxicity is indeed a mechanism leading to degeneration in ALS, it is not caused by changes in the intrinsic electrical properties of the motoneurones but most probably by extrinsic factors such as excessive synaptic excitation.Abstract In amyotrophic lateral sclerosis (ALS), an adult onset disease in which there is progressive degeneration of motoneurones, it has been suggested that an intrinsic hyperexcitability of motoneurones (i.e. an increase in their firing rates), contributes to excitotoxicity and to disease onset. Here we show that there is no such intrinsic hyperexcitability in spinal motoneurones. Our studies were carried out in an adult mouse model of ALS with a mutated form of superoxide dismutase 1 around the time of the first muscle fibre denervations. We showed that the recruitment current, the voltage threshold for spiking and the frequency-intensity gain in the primary range are all unchanged in most spinal motoneurones, despite an increased input conductance. On its own, increased input conductance would decrease excitability, but the homeostasis for excitability is maintained due to an upregulation of a depolarizing current that is activated just below the spiking threshold. However, this homeostasis failed in a substantial fraction of motoneurones, which became hypoexcitable and unable to produce sustained firing in response to ramps of current. We found similar results both in lumbar motoneurones recorded in anaesthetized mice, and in sacrocaudal motoneurones recorded in vitro, indicating that the lack of hyperexcitability is not caused by anaesthetics. Our results suggest that, if excitotoxicity is indeed a mechanism leading to degeneration in ALS, it is not caused by the intrinsic electrical properties of motoneurones but by extrinsic factors such as excessive synaptic excitation.N. Delestrée and M. Manuel contributed equally to this work.

Hyperexcitability has been suggested to contribute to motoneuron degeneration in amyotrophic lateral sclerosis (ALS). If this is so, and given that the physiological type of a motor unit determines the relative susceptibility of its motoneuron in ALS, then one would expect the most vulnerable motoneurons to display the strongest hyperexcitability prior to their degeneration, whereas the less vulnerable should display a moderate hyperexcitability, if any. We tested this hypothesis in vivo in two unrelated ALS mouse models by correlating the electrical properties of motoneurons with their physiological types, identified based on their motor unit contractile properties. We found that, far from being hyperexcitable, the most vulnerable motoneurons become unable to fire repetitively despite the fact that their neuromuscular junctions were still functional. Disease markers confirm that this loss of function is an early sign of degeneration. Our results indicate that intrinsic hyperexcitability is unlikely to be the cause of motoneuron degeneration.