Mechanisms of compensatory plasticity for respiratory motor neuron death

Abstract

Respiratory motor neuron death arises from multiple neurodegenerative and traumatic neuromuscular disorders. Despite motor neuron death, compensatory mechanisms minimize its functional impact by harnessing intrinsic mechanisms of compensatory respiratory plasticity. However, the capacity for compensation eventually reaches limits and pathology ensues. Initially, challenges to the system such as increased metabolic demand reveal sub-clinical pathology. With greater motor neuron loss, the eventual result is de-compensation, ventilatory failure, ventilator dependence and then death. In this brief review, we discuss recent advances in our understanding of mechanisms giving rise to compensatory respiratory plasticity in response to respiratory motor neuron death including: 1) increased central respiratory drive, 2) plasticity in synapses on spared phrenic motor neurons, 3) enhanced neuromuscular transmission and 4) shifts in respiratory muscle utilization from more affected to less affected motor pools. Some of these compensatory mechanisms may prolong breathing function, but hasten the demise of surviving motor neurons. Improved understanding of these mechanisms and their impact on survival of spared motor neurons will guide future efforts to develop therapeutic interventions that preserve respiratory function with neuromuscular injury/disease.

Adenosine 2A receptor inhibition protects phrenic motor neurons from cell death induced by protein synthesis inhibition

“…Thus, A2A receptor activation can trigger neurodegeneration when extracellular glutamate levels are high (Mojsilovic-Petrovic et al, 2006). This is particularly important since increased excitatory glutamatergic drive to phrenic motor neurons is a compensatory strategy of the respiratory control system in protecting against respiratory pathology (Johnson and Mitchell, 2013;Seven and Mitchell, 2019). Thus, A2A receptors are integral regulators of both compensatory and pathogenic responses when neurons are challenged by injury and/or disease.…”

“…Respiratory motor neuron loss contributes to respiratory insufficiency, ventilator dependence, and death in clinical disorders such as ALS, cervical spinal cord injury, and infectious or toxic neuropathies (Nogués and Benarroch, 2008;Johnson and Mitchell, 2013;Seven and Mitchell, 2019). Since the diaphragm is the major inspiratory muscle, improved understanding of factors exacerbating/ameliorating phrenic motor neuron death is essential in our effort to design new therapies that promote phrenic motor neuron survival to preserve breathing function.…”

Proceedings from the Neurotherapeutics Symposium on Neurological Emergencies: Shaping the Future of Neurocritical Care

“…Chronic respiratory failure is a common and extremely disabling complication of motor neuron disease and cervical spinal cord injury [ 56 ], rendering patients dependent on mechanical ventilation and prone to have respiratory tract infections. The mechanisms underlying respiratory motor neuron plasticity and resilience to injury remain poorly understood, hindering advancement in neurotherapeutics focused on respiratory function rehabilitation [ 57 ].…”

“…Ischemic preconditioning through acute intermittent hypoxia (AIH) is a promising therapy with potential to prevent respiratory deconditioning and enhance rehabilitation in chronic respiratory failure [ 58 , 59 ]. AIH promotes phrenic nerve long-term facilitation through carotid chemoreceptors and raphe nuclei modulation [ 57 ]. Respiratory motor neuron plasticity is mediated by balancing 5-HT receptor activation and adenosine (A2A) receptor antagonism at different levels of hypoxia depth and duration [ 60 , 61 ].…”

Evaluating the roles spinal plasticity and an accessory inspiratory muscle have in a rodent model of respiratory motor neuron death

“…In patients with amyotrophic lateral sclerosis (ALS), progressive loss of respiratory motor neurons results in reduced maximal inspiratory and expiratory pressures, transdiaphragmatic pressure, and capacity to produce sniff nasal pressure due to respiratory muscle weakness. In pre-symptomatic stages of the disease, no deficits in resting ventilation are observed because only innervation to muscles involved in max force are affected (e.g., sneeze and cough) (Seven and Mitchell, 2019). As respiratory muscle strength decreases, PCO2 increases (Harrison et al, 1971;Kreitzer et al, 1978b;Stone and Keltz, 1963).…”