Spinal metaplasticity in respiratory motor control

Abstract

A hallmark feature of the neural system controlling breathing is its ability to exhibit plasticity. Less appreciated is the ability to exhibit metaplasticity, a change in the capacity to express plasticity (i.e., “plastic plasticity”). Recent advances in our understanding of cellular mechanisms giving rise to respiratory motor plasticity lay the groundwork for (ongoing) investigations of metaplasticity. This detailed understanding of respiratory metaplasticity will be essential as we harness metaplasticity to restore breathing capacity in clinical disorders that compromise breathing, such as cervical spinal injury, motor neuron disease and other neuromuscular diseases. In this brief review, we discuss key examples of metaplasticity in respiratory motor control, and our current understanding of mechanisms giving rise to spinal plasticity and metaplasticity in phrenic motor output; particularly after pre-conditioning with intermittent hypoxia. Progress in this area has led to the realization that similar mechanisms are operative in other spinal motor networks, including those governing limb movement. Further, these mechanisms can be harnessed to restore respiratory and non-respiratory motor function after spinal injury.

Spinal 5-HT7 receptors induce phrenic motor facilitation via EPAC-mTORC1 signaling

“…By minimizing crosstalk inhibition with PKA-selective inhibitors it may be possible for both 5-HT 2 and 5-HT 7 receptors to independently contribute to an enhanced form of pMF (i.e., metaplasticity; Fields and Mitchell 2015). In agreement, whereas PKA mediates cross-talk inhibition (Hoffman and Mitchell 2013), EPAC enables concurrent activation of signaling pathways operating downstream from 5-HT 2 and 5-HT 7 receptors (Johnson-Farley et al 2005).…”

“…In agreement, whereas PKA mediates cross-talk inhibition (Hoffman and Mitchell 2013), EPAC enables concurrent activation of signaling pathways operating downstream from 5-HT 2 and 5-HT 7 receptors (Johnson-Farley et al 2005). The respective contributions of reduced PKA and/or enhanced EPAC activity to enhanced AIH-induced pMF following intermittent hypoxia preconditioning (Fields and Mitchell 2015) remain to be explored.…”

Acute intermittent hypoxia with concurrent hypercapnia evokes P2X and TRPV1 receptor‐dependent sensory long‐term facilitation in naïve carotid bodies

“…This is reminiscent of the role of 5‐HT and adenosine receptors in the maintenance of phrenic LTF, for which 5‐HT and/or adenosine receptor activation is necessary to initiate but not maintain phrenic LTF following episodic hypoxia (Fuller et al . ; Fields & Mitchell, ). Also, activation of spinal orexin receptors is critical for enhancing chemoreflex phrenic responses to hypoxia after AIH (Kim et al .…”

Time Domains of the Hypoxic Ventilatory Response and Their Molecular Basis

“…This definition is consistent also with the concept of “memory” in the respiratory control system, used by Eldridge and Millhorn to describe some of the time domains of the HVR in a previous issue of the Handbook of Physiology (84). Additionally “metaplasticity” has also been defined in respiratory control as changes in the capacity to express plasticity depending on prior experience, or “plastic plasticity” (94, 255). The molecular and cellular basis for plasticity in respiratory control is presumably based on mechanisms similar to those understood to contribute to synaptic plasticity elsewhere in the CNS, as described in the aforementioned paragraph, and detailed in subsequent sections for different time domains of the HVR.…”