Microglia-Neuron Communication Is Necessary for Spinal Respiratory Neuroplasticity
Maia Gumnit1, Armand Meza1, Kendra M Braegelmann1, Jyoti J Watters1, Tracy L Baker1 Department of Comparative Biosciences, University of Wisconsin-Madison
Ventilatory failure is a major of cause of death associated with multiple neuroinflammatory diseases. Understanding mechanisms whereby proper respiratory motor neuron function can be restored is critical for identifying new treatments. A form of neuroplasticity known as inactivity-induced phrenic motor facilitation (iPMF) is triggered by reductions in neural inputs to phrenic motor neurons that innervate the diaphragm, which compensate for and restore normal respiratory neural activity. Mechanisms underlying iPMF differ depending on the pattern of reduced respiratory neural activity. Prolonged reductions in phrenic synaptic inputs result in local release of tumor necrosis factor alpha (TNFa), and initiate iPMF via activation of TNF receptor 2 on phrenic motor neurons. However, iPMF triggered by intermittent reductions in phrenic synaptic inputs is TNFa-independent, and instead requires local retinoic acid synthesis and RARa activation. Little is known regarding microglia-neuron communication in respiratory neural control; since microglia are a major source of TNFa in the CNS, we tested the hypothesis that microglia are necessary for iPMF triggered by prolonged, but not brief intermittent, reductions in respiratory neural activity. Microglia were depleted by ~50% from adult Sprague Dawley rats using the CSF1R inhibitor PLX3397 (40 mg/kg, p.o., 7d), and the capacity to elicit iPMF was evaluated in urethane-anesthetized, mechanically ventilated rats. As expected, both a prolonged (30 min) and brief intermittent (5, ~1 min) reductions in respiratory neural activity induced a robust increase in phrenic inspiratory amplitude in vehicle-treated rats, indicating iPMF. Consistent with our hypothesis, preliminary data suggest iPMF induced by a prolonged reduction in respiratory neural activity is impaired in PLX3397-treated rats, but iPMF elicited by brief intermittent reductions in respiratory neural activity remains intact. These data implicate an essential role for microglia in spinal respiratory neuroplasticity triggered by prolonged, but not brief intermittent reductions in respiratory neural activity, and provide novel insights into the role of microglia-neuron communication in the control of breathing. HL105511 and NS085226.
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