Nerve Growth Factor Regulates the Firing Patterns and Synaptic Composition of Motoneurons

Abstract

Target-derived neurotrophins exert powerful synaptotrophic actions in the adult brain and are involved in the regulation of different forms of synaptic plasticity. Target disconnection produces a profound synaptic stripping due to the lack of trophic support. Consequently, target reinnervation leads to synaptic remodeling and restoration of cellular functions. Extraocular motoneurons are unique in that they normally express the TrkA neurotrophin receptor in the adult, a feature not seen in other cranial or spinal motoneurons, except after lesions such as axotomy or in neurodegenerative diseases like amyotrophic lateral sclerosis. We investigated the effects of nerve growth factor (NGF) by retrogradely delivering this neurotrophin to abducens motoneurons of adult cats. Axotomy reduced the density of somatic boutons and the overall tonic and phasic firing modulation. Treatment with NGF restored synaptic inputs and firing modulation in axotomized motoneurons. When K252a, a selective inhibitor of tyrosine kinase activity, was applied to specifically test TrkA effects, the NGF-mediated restoration of synapses and firing-related parameters was abolished. Discharge variability and recruitment threshold were, however, increased by NGF compared with control or axotomized motoneurons. Interestingly, these parameters returned to normal following application of REX, an antibody raised against neurotrophin receptor p75 (p75 NTR ). In conclusion, NGF, acting retrogradely through TrkA receptors, supports afferent boutons and regulates the burst and tonic signals correlated with eye movements. On the other hand, p75 NTR activation regulates recruitment threshold, which impacts on firing regularity. To our knowledge, this is the first report showing powerful synaptotrophic effects of NGF on motoneurons in vivo.

Improvement of Eye Alignment in Adult Strabismic Monkeys by Sustained IGF-1 Treatment

“…45–47 In cat abducens motor neurons, it also has been shown that various neurotrophic factors can regulate the firing patterns and synaptic composition of the motor neurons that control eye movements. 48,49 These studies support the hypothesis that neurotrophic factors are modulating influences on motor neuron function, and by altering the balance of these factors one has the potential to alter the balance of eye alignment/misalignment through communication between oculomotor and abducens motor neurons within the brainstem. The bilateral nature of the changes in alignment and EOM structure in the present study, after unilateral IGF-1 treatment, provides further support for this view.…”

Complementariness and Functional Parcellation of Neurotrophin Actions on the Oculomotor System

“…As motoneurons mature, they lose their dependence on neurotrophic factors for survival, but when they are disconnected from their target, they experiment several alterations in electrophysiological properties and protein expression that can be recovered if they are provided with a new target [101][102][103], but also by the exogenous administration of different neurotrophins [104][105][106][107].…”

“…Accordingly, cranial and spinal motoneurons express TrkA only transiently during development, and the later also after lesion or in response to some musculoskeletal pathologies [160,161]. Intriguingly, healthy adult extraocular motoneurons normally express the NGF high and low affinity receptors [49,105], suggesting a possible role for this neurotrophin in the maintenance of oculomotor circuitry and their motoneuron physiology. To test this hypothesis, NGF trophic support was altered on abducens motoneurons by either axotomy or applying chronically exogenous NGF to the stump of the sectioned nerve through the above mentioned substance administration device [135].…”

“…Consequently, the presence of both receptors on abducens motoneurons and the modulation of their expression after lesion might provide beneficial effects to these neurons after lesion and in musculoskeletal disease [49]. Administration of NGF to the nerve stump of abducens motoneurons immediately after the lesion, not only prevented the decay in eye position and velocity sensitivities caused by axotomy (Figure 7A, B; [36,104], but also produced a significant rapid increase in their sensitivities to eye related parameters ( Figure 7C, D) that were maintained higher than those of control motoneurons throughout the course of the experiment [105]. The short-and long-term effects of neurotrophins on synaptic transmission and plasticity have been well documented (reviewed in [170,171]).…”

“…Recruitment threshold, calculated as the abscissa intercept of the rate-position plot, changed after NGF treatment [105]. This parameter indicates the eye position at which the motoneuron first enters into activity.…”