Cervical Spinal Cord Injury Upregulates Ventral Spinal 5-HT 2A Receptors

Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin, Madison, Wisconsin, USA.
Journal of Neurotrauma (Impact Factor: 3.71). 02/2005; 22(2):203-13. DOI: 10.1089/neu.2005.22.203
Source: PubMed


Following chronic C2 spinal hemisection (C2HS), crossed spinal pathways to phrenic motoneurons exhibit a slow, spontaneous increase in efficacy by a serotonin (5-HT)-dependent mechanism associated with 5-HT2A receptor activation. Further, the spontaneous appearance of cross-phrenic activity following C2HS is accelerated and enhanced by exposure to chronic intermittent hypoxia (CIH). We hypothesized that chronic C2HS would increase 5-HT and 5-HT2A receptor expression in ventral cervical spinal segments containing phrenic motoneurons. In addition, we hypothesized that CIH exposure would further increase 5-HT and 5-HT2A receptor density in this region. Control, sham-operated, and C2HS Sprague-Dawley rats were studied following normoxia or CIH (11% O2-air; 5-min intervals; nights 7-14 post-surgery). At 2 weeks post-surgery, ventral spinal gray matter extending from C4 and C5 was isolated ipsilateral and contralateral to C2HS. Neither C2HS nor CIH altered 5-HT concentration measured with an ELISA on either side of the spinal cord. However, 5-HT2A receptor expression assessed with immunoblots increased in ipsilateral gray matter following C2HS, an effect independent of CIH. Immunocytochemistry revealed increased 5-HT2A receptor expression on identified phrenic motoneurons (p<0.05), as well as in the surrounding gray matter. Contralateral to injury, 5-HT2A receptor expression was elevated in CIH, but not normoxic C2HS rats (p<0.05). Our data are consistent with the hypothesis that spontaneous increase in 5-HT2A receptor expression on or near phrenic motoneurons contributes to strengthened crossed-spinal synaptic pathways to phrenic motoneurons following C2HS.

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    • "The loss of 5-HT can be overcome through the direct activation of 5-HT receptors, an approach which has been convincingly associated with the induction of locomotor output following SCI (Brustein and Rossignol, 1999; Feraboli-Lohnherr et al., 1999; Kim et al., 2001b). With the reduction or loss of 5-HT input caudal to the injury in rodent models of SCI, it has been demonstrated that there is a compensatory over-expression of 5-HT receptors (Fuller et al., 2005; Navarrett et al., 2012; Ren et al., 2013). In the lamprey, a vertebrate that exhibits locomotor recovery after complete SCI, a transient over-expression of the 5-HT 1A receptor transcript is observed for several weeks after SCI (Cornide-Petronio et al., 2014). "
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    • "This is consistent with an expression pattern reported for brainstem motor neurons in rats, where HTR2A was detected via RT-PCR in nearly all motor neurons tested by P6, whereas HTR2C showed an increase over postnatal ages from P3 through P23 (Volgin et al., 2003). While multiple studies have shown changes in HTR2A and HTR2C activity and abundance following spinal cord injury (Basura et al., 2001; Zhou et al., 2001; Fuller et al., 2005; Kong et al., 2010; Ren et al., 2013), less is known about the overall developmental trajectories of these receptor subtypes in the postnatal spinal cord. "
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    • "BDNF signaling via full-length TrkB (TrkB.FL) likely enhances phrenic motoneuron excitability through serotonergic [22] and glutamatergic signaling [16], [23]. Expression of serotonergic and glutamatergic receptors within phrenic motoneurons increases following SH [6], [24], and the time course of changes generally corresponds with onset of spontaneous recovery of rhythmic phrenic activity. Unfortunately, treatment with exogenous intrathecal neurotrophins is linked to significant adverse effects related to autonomic and sensory (pain) pathways, which prevent it from being used therapeutically [25], [26], [27]. "
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