Plasticity in respiratory motor neurons in response to reduced synaptic inputs: A form of homeostatic plasticity in respiratory control?

Abstract

For most individuals, the respiratory control system produces a remarkably stable and coordinated motor output—recognizable as a breath—from birth until death. Very little is understood regarding the processes by which the respiratory control system maintains network stability in the presence of changing physiological demands and network properties that occur throughout life. An emerging principle of neuroscience is that neural activity is sensed and adjusted locally to assure that neurons continue to operate in an optimal range, yet to date, it is unknown whether such homeostatic plasticity is a feature of the neurons controlling breathing. Here, we review the evidence that local mechanisms sense and respond to perturbations in respiratory neural activity, with a focus on plasticity in respiratory motor neurons. We discuss whether these forms of plasticity represent homeostatic plasticity in respiratory control. We present new analyses demonstrating that reductions in synaptic inputs to phrenic motor neurons elicit a compensatory enhancement of phrenic inspiratory motor output, a form of plasticity termed inactivity-induced phrenic motor facilitation (iPMF), that is proportional to the magnitude of activity deprivation. Although the physiological role of iPMF is not understood, we hypothesize that it may have an important role in protecting the drive to breathe during conditions of prolonged or intermittent reductions in respiratory neural activity, such as following spinal cord injury or during central sleep apnea.

Competing mechanisms of plasticity impair compensatory responses to repetitive apnoea

“…Both intermittent neural apnoea and intermittent hypoxia have been reported to reduce the apnoeic threshold (Mahamed & Mitchell, ; Baertsch & Baker, 2017 b ), an effect hypothesized to decrease susceptibility to future apnoeas through signalling mechanisms similar to phrenic inspiratory plasticity (Braegelmann et al . ). Consistent with these reports, both recurrent neural apnoea and recurrent 25 s ventilator apnoeas elicited a significant reduction in the apnoeic threshold (−3.2 ± 0.5 mmHg CO 2 and −4.0 ± 0.7 mmHg CO 2 , respectively; n = 4, each; P < 0.01; Fig.…”

“…; Braegelmann et al . ; Baertsch & Baker, 2017 b ). Similarly, intermittent hypoxia, such as would occur during cessations in breathing, elicits distinct mechanisms of plasticity that also strengthen inspiratory motor output (i.e.…”

“…reduced, but not absent respiratory neural activity) (Braegelmann et al . ) or a local, partial blockade of synaptic inputs to the motor neuron (Streeter & Baker‐Herman, 2014 a ) are sufficient to elicit iMF. Although the precise role for iMF in the control of breathing is unknown, we have recently proposed that iMF represents one of possibly many components in a continuum of ‘homeostatic plasticity’ mechanisms (Turrigiano, ) that ensure appropriate respiratory motor output throughout life (Strey et al .…”

“…; Braegelmann et al . ; Mateika & Komnenov, ) and lowering the threshold for transmission failure (Braegelmann et al . ; Baertsch & Baker, 2017 b ).…”

“…In the case of iMF, enhanced inspiratory motor output is proportional to the magnitude of activity deprivation (Braegelmann et al . ) and the reduction in the apnoeic threshold is proportional to the magnitude of iMF (Baertsch & Baker, 2017 b ). Most of our understanding regarding these distinct forms of respiratory plasticity derive from studies investigating iMF or LTF in phrenic motor neurons, which drive the diaphragm.…”