Motoneuron glutamatergic receptor expression following recovery from cervical spinal hemisection

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Cervical segments of the spinal cord are most commonly involved in traumatic spinal cord injury (SCI), and, although injuries are frequently incomplete, cervical SCI results in significant respiratory impairment and the requirement for mechanical ventilation (National Spinal Cord Injury Statistical Center, 2015). In a well‐established model of incomplete cervical SCI, unilateral C2 spinal cord hemisection (SH), ipsilateral excitatory premotor drive to phrenic motoneurons is removed and the ipsilateral diaphragm muscle is inactivated. Over time after SH, there is a varying extent of spontaneous recovery of ipsilateral activity reflecting neuroplasticity and strengthening of spared excitatory drive to phrenic motoneurons (Boulenguez et al., 2007; Golder and Mitchell, 2005; Golder et al., 2003; Mantilla et al., 2013b; Miyata et al., 1995; Nantwi et al., 1999; Prakash et al., 1999; Sieck and Mantilla, 2009; Zhan et al., 1997).
Excitatory bulbospinal (premotor) respiratory drive to phrenic motoneurons is primarily glutamatergic (Greer et al., 1992; McCrimmon et al., 1989; Saji and Miura, 1990). Phrenic motoneurons express multiple excitatory glutamatergic receptor subtypes, including ionotropic N‐methyl‐D‐aspartate (NMDA) receptors and α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐proprionic acid (AMPA) receptors (Chitravanshi and Sapru, 1996; Robinson and Ellenberger, 1997). Both NMDA and AMPA receptors located in the phrenic motor nucleus play an important role in neurotransmission of inspiratory drive, although the relative contribution remains controversial (Chitravanshi and Sapru, 1996; Pierrefiche et al., 1994; Robinson and Ellenberger, 1997). Changes in glutamatergic receptor expression at motoneurons may contribute to neuroplasticity in conditions such as SCI. For instance, the time course of spontaneous recovery post‐SH correlates with changes in phrenic motoneuron receptor expression of NMDA and AMPA receptors in which NMDA receptor expression increases and AMPA receptor expression decreases after SH (Alilain and Goshgarian, 2008; Mantilla et al., 2012). Whether altered receptor expression reflects common mechanisms underlying recovery across models of spontaneous and enhanced recovery post‐SH is presently unknown.
Glutamatergic receptor expression is regulated by tropomyosin‐related kinase receptor subtype B (TrkB) signaling in various neuronal systems (Jovanovic et al., 2000; Kang and Schuman, 1995; Lin et al., 1998; Suen et al., 1997). A recent series of studies from our laboratory showed that brain‐derived neurotrophic factor (BDNF) signaling via TrkB kinase activity, specifically in phrenic motoneurons, is necessary and sufficient for recovery of ipsilateral rhythmic diaphragm muscle activity post‐SH (Gransee et al., 2013; Mantilla et al., 2013a; Martinez‐Galvez et al., 2016). Accordingly, we hypothesize that recovery of ipsilateral rhythmic diaphragm muscle activity post‐SH, whether spontaneous or enhanced by adenoassociated virus (AAV)‐mediated upregulation of TrkB receptor expression in phrenic motoneurons, is associated with increased expression of glutamatergic NMDA receptors in phrenic motoneurons.
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