Enhancing Proprioceptive Input to Motoneurons Differentially Affects Expression of Neurotrophin 3 and Brain-Derived Neurotrophic Factor in Rat Hoffmann-Reflex Circuitry

Olga Gajewska-Woźniak,Ewelina Ziemlińska,Julita Czarkowska-Bauch,Małgorzata Skup,Stefan Kasicki,William Phillips

doi:10.1371/journal.pone.0065937

Olga Gajewska-Woźniak, Ewelina Ziemlińska + Show 4 more

Open Access

https://doi.org/10.1371/journal.pone.0065937

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Abstract

The importance of neurotrophin 3 (NT-3) for motor control prompted us to ask the question whether direct electrical stimulation of low-threshold muscle afferents, strengthening the proprioceptive signaling, could effectively increase the endogenous pool of this neurotrophin and its receptor TrkC in the Hoffmann-reflex (H-reflex) circuitry. The effects were compared with those of brain-derived neurotrophic factor (BDNF) and its TrkB receptor. Continuous bursts of stimuli were delivered unilaterally for seven days, 80 min daily, by means of a cuff-electrode implanted over the tibial nerve in awake rats. The H-reflex was recorded in the soleus muscle to control the strength of stimulation. Stimulation aimed at activation of Ia fibers produced a strong increase of NT-3 protein, measured with ELISA, in the lumbar L3-6 segments of the spinal cord and in the soleus muscle. This stimulation exerted much weaker effect on BDNF protein level which slightly increased only in L3-6 segments of the spinal cord. Increased protein level of NT-3 and BDNF corresponded to the changes of NT-3 mRNA and BDNF mRNA expression in L3-6 segments but not in the soleus muscle. We disclosed tissue-specificity of TrkC mRNA and TrkB mRNA responses. In the spinal cord TrkC and TrkB transcripts tended to decrease, whereas in the soleus muscle TrkB mRNA decreased and TrkC mRNA expression strongly increased, suggesting that stimulation of Ia fibers leads to sensitization of the soleus muscle to NT-3 signaling. The possibility of increasing NT-3/TrkC signaling in the neuromuscular system, with minor effects on BDNF/TrkB signaling, by means of low-threshold electrical stimulation of peripheral nerves, which in humans might be applied in non-invasive way, offers an attractive therapeutic tool.

Highlights

The role of neurotrophins in neuronal plasticity, that involved in the recovery processes following injury of the spinal cord and peripheral nerves is well documented
A robust Neurotrophin 3 (NT-3) mRNA expression was observed in intrafusal [6] and, to a lesser extent, in extrafusal muscle fibers [11] whereas TrkC mRNA expression was detected in skeletal muscles, predominantly in perisynaptic and myelinating Schwann cells [11]
In the dorsal root ganglia (DRG) the data on NT-3 mRNA expression are conflicting [12,13] albeit recent study [13] reported on NT3 mRNA and protein expression in DRG with a predominance in large neurons

Summary

Introduction

The role of neurotrophins in neuronal plasticity, that involved in the recovery processes following injury of the spinal cord and peripheral nerves is well documented (for review see [1]). Muscle receptors as well as the nerve fibers innervating them require NT-3 to recover after damage [2,3,4,6,7,8,9]. In line with this requirement, about 73% of neurons innervating muscle spindle receptors show expression of TrkC mRNA [10]. Trk C mRNA and protein were observed in neurons throughout the spinal grey matter including motoneurons of various size [15,16]

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