Degeneration of phrenic motor neurons induces long-term diaphragm deficits following mid-cervical spinal contusion in mice.

Kathleen Schildroth // Publications // Dec 10 2012

PubMed ID: 23176637

Author(s): Nicaise C, Putatunda R, Hala TJ, Regan KA, Frank DM, Brion JP, Leroy K, Pochet R, Wright MC, Lepore AC. Degeneration of phrenic motor neurons induces long-term diaphragm deficits following mid-cervical spinal contusion in mice. J Neurotrauma. 2012 Dec 10;29(18):2748-60. doi: 10.1089/neu.2012.2467. Epub 2012 Nov 23. PMID 23176637

Journal: Journal Of Neurotrauma, Volume 29, Issue 18, Dec 2012

A primary cause of morbidity and mortality following cervical spinal cord injury (SCI) is respiratory compromise, regardless of the level of trauma. In particular, SCI at mid-cervical regions targets degeneration of both descending bulbospinal respiratory axons and cell bodies of phrenic motor neurons, resulting in deficits in the function of the diaphragm, the primary muscle of inspiration. Contusion-type trauma to the cervical spinal cord is one of the most common forms of human SCI; however, few studies have evaluated mid-cervical contusion in animal models or characterized consequent histopathological and functional effects of degeneration of phrenic motor neuron-diaphragm circuitry. We have generated a mouse model of cervical contusion SCI that unilaterally targets both C4 and C5 levels, the location of the phrenic motor neuron pool, and have examined histological and functional outcomes for up to 6 weeks post-injury. We report that phrenic motor neuron loss in cervical spinal cord, phrenic nerve axonal degeneration, and denervation at diaphragm neuromuscular junctions (NMJ) resulted in compromised ipsilateral diaphragm function, as demonstrated by persistent reduction in diaphragm compound muscle action potential amplitudes following phrenic nerve stimulation and abnormalities in spontaneous diaphragm electromyography (EMG) recordings. This injury paradigm is reproducible, does not require ventilatory assistance, and provides proof-of-principle that generation of unilateral cervical contusion is a feasible strategy for modeling diaphragmatic/respiratory deficits in mice. This study and its accompanying analyses pave the way for using transgenic mouse technology to explore the function of specific genes in the pathophysiology of phrenic motor neuron degeneration and respiratory dysfunction following cervical SCI.