Postactivation depression of the Ia EPSP in motoneurons is reduced in both the G127X SOD1 model of amyotrophic lateral sclerosis and in aged mice

Abstract

Postactivation depression (PActD) of Ia afferent excitatory postsynaptic potentials (EPSPs) in spinal motoneurons results in a long-lasting depression of the stretch reflex. This phenomenon (PActD) is of clinical interest as it has been shown to be reduced in a number of spastic disorders. Using in vivo intracellular recordings of Ia EPSPs in adult mice, we demonstrate that PActD in adult (100-220 days old) C57BL/6J mice is both qualitatively and quantitatively similar to that which has been observed in larger animals with respect to both the magnitude (with ∼20% depression of EPSPs at 0.5 ms after a train of stimuli) and the time course (returning to almost normal amplitudes by 5 ms after the train). This validates the use of mouse models to study PActD. Changes in such excitatory inputs to spinal motoneurons may have important implications for hyperreflexia and/or glutamate-induced excitotoxicity in the neurodegenerative disease amyotrophic lateral sclerosis (ALS). With the use of the G127X SOD1 mutant mouse, an ALS model with a prolonged asymptomatic phase and fulminant symptom onset, we observed that PActD is significantly reduced at both presymptomatic (16% depression) and symptomatic (17.3% depression) time points compared with aged-matched controls (22.4% depression). The PActD reduction was not markedly altered by symptom onset. Comparing these PActD changes at the EPSP with the known effect of the depression on the monosynaptic reflex, we conclude that this is likely to have a much larger effect on the reflex itself (a 20-40% difference). Nevertheless, it should also be accounted that in aged (580 day old) C57BL/6J mice there was also a reduction in PActD although, aging is not usually associated with spasticity.

Shorter axon initial segments do not cause repetitive firing impairments in the adult presymptomatic G127X SOD-1 Amyotrophic Lateral Sclerosis mouse

“…Muscle stretch usually results in high frequency trains of action potentials in Ia afferents causing Excitatory Post Synaptic Potentials (EPSPs) in spinal motoneurones which are normally reduced in amplitude at these high frequencies due to post activation depression. We have previously shown that post activation depression of the Ia EPSP is reduced in the G127X mouse at a similar presymptomatic age to the current study 39 . Such a reduction in depression equates to a subtle increase in the amplitude of Ia EPSPs which may compensate for reduction in the sensitivity of the muscle spindles potentially due to reduced gamma motoneurone excitability.…”

Repeated anodal trans‐spinal direct current stimulation results in long‐term reduction of spasticity in mice with spinal cord injury

“…; Hedegaard et al . ). It is hypothesized that the mechanisms that underlie post‐activation depression involve a decrease in the probability that neurotransmitter quantal release from Ia afferent will occur as a result of its prior activation (Kuno, ,b; Hirst et al .…”

“…RDD involves an attenuation of H-reflex amplitude following repetitive stimulations (Lloyd & Wilson, 1957;Ishikawa et al 1966;Meinck, 1976) and it is reduced in spastic humans (Nielsen et al 1993;Aymard et al 2000) and animals (Lee et al 2014b;Hedegaard et al 2015). C, blocking degradation of NKCC1 prevents a-tsDCS induced reduction of spasticity.…”

Does trans‐spinal and local DC polarization affect presynaptic inhibition and post‐activation depression?

“…; Pelletier & Cicchetti, ; Hedegaard et al . ). However, we used single conditioning stimuli rather than trains, because single stimuli resulted in a comparable post‐activation depression.…”

“…; Hedegaard et al . ). Abnormally strong presynaptic inhibition and post‐activation depression might, in contrast, contribute to the weakening of synaptic input to spinal motoneurons found in recent studies of spinal muscular atrophy by Mentis et al .…”