Intermittent hypoxia induces plasticity in spinal synaptic pathways to phrenic motor neurons: A potential therapeutic approach to spinal cord injury

Respiratory-related complications are the leading cause of death in SCI patients after the first year post-injury (Frankel et al, 1998). Few treatments for SCI exist after the initial acute treatment of the injury (i.e. stabilization of the spine and attempts to prevent further damage to the spinal cord) (Winslow and Rozovsky, 2003). The International Spinal Research Trust---an international foundation seeking a "cure" for spinal cord injury---set out four major goals that need to be accomplished in order to further treatment options. One of these goals is "optimizing the function of surviving systems" (Ramer et al., 2000). The fundamental purpose of this thesis is to determine if endogenous plasticity mechanisms can be harnessed to optimize the function of surviving respiratory related circuitry. This thesis addresses to primary two questions: can plasticity be induced in spinal synaptic pathways to respiratory motor neurons and can this plasticity be harnessed to improve respiratory function after spinal cord injury. The data presented in this dissertation demonstrate that: (1) episodic spinal serotonin (5-HT) receptor activation is sufficient to induce long term facilitation (LTF) in cervical and thoracic respiratory motor pools in neonatal rats (2) daily acute intermittent hypoxia (dAIH) restores ventilation to uninjured levels after cervical spinal injury and that this recovery is due, in part, to plasticity at premotor-motor synapse in the phrenic motor nucleus, and (3) dAIH treatment changes the levels of key proteins implicated in other acute intermittent hypoxia (AIH) induced facilitation studies (BDNF & TrkB). This work also established for the first time an in vitro brainstem-spinal cord preparation as an in vitro model of long-term facilitation. Collectively these studies show that plasticity can be induced in spinal synaptic pathways to respiratory motor neurons in response to endogenous or pharmacological triggers and that this endogenous spinal plasticity can be harnessed to improve functional recovery of respiration after spinal injury.