TrkB gene therapy by adeno-associated virus enhances recovery after cervical spinal cord injury

Martínez‐Gálvez, Gabriel; Zambrano, Juan Manuel; Soto, Juan C. Diaz; Zhan, Wen Zhi; Gransee, Heather M.; Sieck, Gary C.; Mantilla, Carlos B.

doi:10.1016/j.expneurol.2015.11.007

Cited by 43 publications

(65 citation statements)

References 64 publications

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“…B). In general agreement with previous studies (Gransee et al, ; Martinez‐Galvez et al, ), the proportion of animals displaying recovery of ipsilateral diaphragm muscle activity was different across SH groups (χ² [5, n = 48] = 12.61, P = 0.027) and was significantly higher in the AAV–TrkB‐treated SH group. There were no time ( P = 0.115) or time × treatment interaction ( P = 0.147) effects on recovery.…”

Section: Resultssupporting

confidence: 94%

“…Contralateral RMS EMG amplitude was 165% ± 37% of the pre‐SH value in animals that did not display recovery at SH 14 days (n = 8) and 159% ± 23% of the pre‐SH value in animals that displayed recovery (n = 15). These results are consistent with previous studies with SH animals (Gransee et al, ; Mantilla et al, ; Martinez‐Galvez et al, ).…”

Section: Resultsmentioning

confidence: 99%

“…Intrapleural injection of cholera toxin subunit B (CTB) was used to label phrenic motoneurons retrogradely (Gransee et al, ; Issa et al, ; Mantilla et al, ; Martinez‐Galvez et al, ). We previously confirmed that intrapleural injection of CTB labels only phrenic motoneurons in the cervical spinal cord (Mantilla et al, ).…”

Section: Methodsmentioning

confidence: 99%

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Motoneuron glutamatergic receptor expression following recovery from cervical spinal hemisection

Gransee

Porras

Zhan

et al. 2016

J of Comparative Neurology

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Cervical spinal hemisection at C2 (SH) removes premotor drive to phrenic motoneurons located in segments C3–C5 in rats. Spontaneous recovery of ipsilateral diaphragm muscle activity is associated with increased phrenic motoneuron expression of glutamatergic N-methyl-D-aspartate (NMDA) receptors and decreased expression of α-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid (AMPA) receptors. Glutamatergic receptor expression is regulated by tropomyosin related kinase receptor subtype B (TrkB) signaling in various neuronal systems and increased TrkB receptor expression in phrenic motoneurons enhances recovery post-SH. Accordingly, we hypothesized that recovery of ipsilateral diaphragm muscle activity post-SH, whether spontaneous or enhanced by adeno-associated virus (AAV)-mediated upregulation of TrkB receptor expression, is associated with increased expression of glutamatergic NMDA receptors in phrenic motoneurons. Adult male Sprague-Dawley rats underwent diaphragm EMG electrode implantation and SH surgery. Rats were injected intrapleurally with AAV expressing TrkB or GFP at 3 weeks before SH. At 14 days post-SH, the proportion of animals displaying recovery of ipsilateral diaphragm activity increased in AAV-TrkB treated (9/9) compared to untreated (3/5) or AAV-GFP treated animals (4/10; p < 0.027). Phrenic motoneuron NMDA NR1 subunit mRNA expression was ~4-fold greater in AAV-TrkB vs. AAV-GFP treated SH animals (p < 0.004) and in animals displaying recovery vs. those not recovering (p < 0.005). Phrenic motoneuron AMPA GluR2 subunit mRNA expression decreased after SH and albeit increased in animals displaying recovery vs. those not recovering, levels remained lower than control. We conclude that increased phrenic motoneuron expression of glutamatergic NMDA receptors is associated with spontaneous recovery after SH and enhanced recovery following AAV-TrkB treatment.

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Section: Resultssupporting

confidence: 94%

Section: Resultsmentioning

confidence: 99%

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Motoneuron glutamatergic receptor expression following recovery from cervical spinal hemisection

Gransee

Porras

Zhan

et al. 2016

J of Comparative Neurology

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“…The recovery also may involve formation of de novo polysynaptic spinal cord circuits (Lane et al, 2009; Lane et al, 2008). The spontaneous phrenic motor recovery process can be augmented by a variety of experimental manipulations including administration of theophylline (Nantwi et al, 1996; Nantwi and Goshgarian, 1998) or serotonin receptor agonists (Zhou et al, 2001; Zhou and Goshgarian, 2000), spinal delivery of brain derived neurotrophic factor (Mantilla et al, 2013; Martinez-Galvez et al, 2016), and also exposure to intermittent hypoxia paradigms (Fuller et al, 2003; Navarrete-Opazo et al, 2015). Thus, as originally noted by Guth, the spinal “crossed phrenic pathways” which underlie the ipsilateral phrenic recovery are capable of considerable plasticity (Guth, 1976).…”

Section: Discussionmentioning

confidence: 99%

Intraspinal transplantation of subventricular zone-derived neural progenitor cells improves phrenic motor output after high cervical spinal cord injury

Sandhu

Ross

Lee

et al. 2017

Experimental Neurology

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Following spinal cord injury (SCI), intraspinal transplantation of neural progenitor cells (NPCs) harvested from the forebrain sub-ventricular zone (SVZ) can improve locomotor outcomes. Cervical SCI often results in respiratory-related impairments, and here we used an established model cervical SCI (C2 hemisection, C2Hx) to confirm the feasibility of mid-cervical transplantation of SVZ-derived NPCs and the hypothesis that that this procedure would improve spontaneous respiratory motor recovery. NPCs were isolated from the SVZ of enhanced green fluorescent protein (GFP) expressing neonatal rats, and then intraspinally delivered immediately caudal to an acute C2Hx lesion in adult non-GFP rats. Whole body plethysmography conducted at 4 and 8-wks post-transplant demonstrated increased inspiratory tidal volume in SVZ vs. sham transplants during hypoxic (P=0.003) or hypercapnic respiratory challenge (P=0.019). Phrenic nerve output was assessed at 8-wks post-transplant; burst amplitude recorded ipsilateral to C2Hx was greater in SVZ vs. sham rats across a wide range of conditions (e.g., quiet breathing through maximal chemoreceptor stimulation; P<0.001). Stereological analyses at 8 wks post-injury indicated survival of −50% of transplanted NPCs with −90% of cells distributed in ipsilateral white matter at or near the injection site. Peak inspiratory phrenic bursting after NPC transplant was positively correlated with the total number of surviving cells (P<0.001). Immunohistochemistry confirmed an astrocytic phenotype in a subset of the transplanted cells with no evidence for neuronal differentiation. We conclude that intraspinal transplantation of SVZ-derived NPCs can improve respiratory recovery following high cervical SCI.

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“…Indeed, we recently increased TrkB receptor expression in phrenic motor neurons using a gene therapy approach based on viral transduction (Gransee et al. ; Martinez‐Galvez et al ). However, this approach resulted in increased TrkB expression in a relatively small number of motor neurons (~15%).…”

Section: Discussionmentioning

confidence: 99%

Chronic TrkB agonist treatment in old age does not mitigate diaphragm neuromuscular dysfunction

et al. 2017

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Previously, we found that brain‐derived neurotrophic factor (BDNF) signaling through the high‐affinity tropomyosin‐related kinase receptor subtype B (TrkB) enhances neuromuscular transmission in the diaphragm muscle. However, there is an age‐related loss of this effect of BDNF/TrkB signaling that may contribute to diaphragm muscle sarcopenia (atrophy and force loss). We hypothesized that chronic treatment with 7,8‐dihydroxyflavone (7,8‐DHF), a small molecule BDNF analog and TrkB agonist, will mitigate age‐related diaphragm neuromuscular transmission failure and sarcopenia in old mice. Adult male Trk BF 616A mice (n = 32) were randomized to the following 6‐month treatment groups: vehicle‐control, 7,8‐DHF, and 7,8‐DHF and 1NMPP1 (an inhibitor of TrkB kinase activity in Trk BF 616A mice) cotreatment, beginning at 18 months of age. At 24 months of age, diaphragm neuromuscular transmission failure, muscle‐specific force, and fiber cross‐sectional areas were compared across treatment groups. The results did not support our hypothesis in that chronic 7,8‐DHF treatment did not improve diaphragm neuromuscular transmission or mitigate diaphragm muscle sarcopenia. Taken together, these results do not exclude a role for BDNF/TrkB signaling in aging‐related changes in the diaphragm muscle, but they do not support the use of 7,8‐DHF as a therapeutic agent to mitigate age‐related neuromuscular dysfunction.

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TrkB gene therapy by adeno-associated virus enhances recovery after cervical spinal cord injury

Cited by 43 publications

References 64 publications

Motoneuron glutamatergic receptor expression following recovery from cervical spinal hemisection

Motoneuron glutamatergic receptor expression following recovery from cervical spinal hemisection

Intraspinal transplantation of subventricular zone-derived neural progenitor cells improves phrenic motor output after high cervical spinal cord injury

Chronic TrkB agonist treatment in old age does not mitigate diaphragm neuromuscular dysfunction

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