Functional Motor Recovery from Motoneuron Axotomy Is Compromised in Mice with Defective Corticospinal Projections

Abstract

Brachial plexus injury (BPI) and experimental spinal root avulsion result in loss of motor function in the affected segments. After root avulsion, significant motoneuron function is restored by re-implantation of the avulsed root. How much this functional recovery depends on corticospinal inputs is not known. Here, we studied that question using Celsr3|Emx1 mice, in which the corticospinal tract (CST) is genetically absent. In adult mice, we tore off right C5–C7 motor and sensory roots and re-implanted the right C6 roots. Behavioral studies showed impaired recovery of elbow flexion in Celsr3|Emx1 mice compared to controls. Five months after surgery, a reduced number of small axons, and higher G-ratio of inner to outer diameter of myelin sheaths were observed in mutant versus control mice. At early stages post-surgery, mutant mice displayed lower expression of GAP-43 in spinal cord and of myelin basic protein (MBP) in peripheral nerves than control animals. After five months, mutant animals had atrophy of the right biceps brachii, with less newly formed neuromuscular junctions (NMJs) and reduced peak-to-peak amplitudes in electromyogram (EMG), than controls. However, quite unexpectedly, a higher motoneuron survival rate was found in mutant than in control mice. Thus, following root avulsion/re-implantation, the absence of the CST is probably an important reason to hamper axonal regeneration and remyelination, as well as target re-innervation and formation of new NMJ, resulting in lower functional recovery, while fostering motoneuron survival. These results indicate that manipulation of corticospinal transmission may help improve functional recovery following BPI.

Plasticity of motor network and function in the absence of corticospinal projection

“…As Celsr3 inactivation in the neocortex does not affect the spinal cord directly, lower motoneuron loss is likely secondary to the absence of the CST. Our previous studies indicate that the maturation and regeneration of spinal cord motoneurons are dependent on cortical inputs (Ding et al, 2014;Han et al, 2013), and the present results support the notion that the impairment of the CST in amyotrophic lateral sclerosis affects the survival of lower motoneurons. Whether CST innervation affects spinal motoneurons via some neurotrophic factors or by regulation of neural activity is unknown.…”

γδ T cells provide the early source of IFN-γ to aggravate lesions in spinal cord injury

“…The MEPs were assayed by electromyography on the mice 8 wk after surgery as described previously ( Ding et al, 2014 ), with minor modifications. A stimulation electrode was applied to the rostral extremity of the surgically exposed spinal cord region, and the recording electrode was placed in the biceps flexor cruris.…”

Regeneration of spinal motor axons: Negative regulation by Celsr2 implicating Cdc42/Rac1 and JNK/c-Jun signaling

“…These animals develop to adulthood unremarkably, without apparent neurological deficit. We carried out brachial plexus injury and motor root re-implantation as described (Ding et al, 2014). In this model, upon reimplantation of root C6, regenerating axons can reinnervate the biceps brachii and restore a partial function (Fournier, Mercier, & Menei, 2005) Figure 8E; 213 ± 16.6 versus 56 ± 3.5 NMJs / muscle in mutant and control respectively; n=3 animals in each group; P<0.001).…”