Ampakines and Respiratory Neuroplasticity

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ABSTRACT Respiratory-related motor dysfunction is the leading cause of morbidity and mortality following cervical spinal cord injury (SCI). Respiratory impairments largely reflect impaired bulbospinal glutamatergic synaptic transmission to spinal respiratory motoneurons. Ampakines are allosteric modulators of α-amino-3-hydroxy-5- methyl-4-isoxazolepropionic acid (AMPA) receptor channel kinetics that enhance glutamatergic synaptic transmission. Since glutamatergic bulbospinal excitation of spinal respiratory motoneurons is driven in part by motoneuron AMPA receptor activation, enhancing spinal AMPA-mediated synaptic currents could increase motoneuron output. The central hypothesis guiding this proposal is that ampakines are an effective pharmacologic approach to improve breathing function after incomplete cervical SCI. Aim 1 will test the hypothesis that acute delivery of ampakines stimulates breathing after incomplete cervical SCI, and does so by facilitating synaptic transmission in spared respiratory motor pathways in the spinal cord. These experiments will determine effective dose, safety profile and primary site of action (e.g., medullary vs. spinal). Studies will be done after both acute and chronic cervical SCI; minute ventilation and respiratory muscle electromyogram (EMG) activity will be evaluated in unanesthetized rats; phrenic nerve activity will be evaluated in anesthetized rats. Aim 2 moves beyond direct stimulation of breathing to test the hypothesis that ampakines increase the capacity for neuroplasticity in the phrenic motor circuit. Preliminary data indicate that ampakine pre-treatment greatly enhances phrenic motor plasticity induced by spinal, serotonin receptor agonist administration. Based on these data, we propose a detailed cellular model to explain the impact of ampakines on serotonin- dependent phrenic motor plasticity. Additional preliminary data show that ampakine pretreatment causes dramatic increases in phrenic motor facilitation induced by acute intermittent hypoxia (AIH). We focus on AIH since it is well-established to induce spinal, serotonin-dependent phrenic motor plasticity, and has proven to be a simple and safe neurorehabilitation approach in humans with SCI. Thus, low-dose ampakines may be useful to enhance the impact of other neurorehabilitation modalities. Hypotheses derived from the cellular model will be tested by cervical spinal delivery of serotonin receptor antagonists and/or siRNAs targeting downstream signaling molecules. A comprehensive series of outcome measures will include neurophysiological studies of phrenic output, neurochemical evaluation of signaling pathways, and assessment of respiratory capacity in awake rats. We suggest that the proposed work is significant because of the need for strategies to improve motor function in patients with SCI. Innovative aspects include: 1) the use of ampakines to stimulate breathing after cervical SCI; 2) the use of ampakines increase respiratory neuroplasticity and functional recovery, and 3) the first cellular model to explain the impact of ampakines on spinal respiratory neuroplasticity.