Intrinsic response of thoracic propriospinal neurons to axotomy

Abstract

BackgroundCentral nervous system axons lack a robust regenerative response following spinal cord injury (SCI) and regeneration is usually abortive. Supraspinal pathways, which are the most commonly studied for their regenerative potential, demonstrate a limited regenerative ability. On the other hand, propriospinal (PS) neurons, with axons intrinsic to the spinal cord, have shown a greater regenerative response than their supraspinal counterparts, but remain relatively understudied in regards to spinal cord injury.ResultsUtilizing laser microdissection, gene-microarray, qRT-PCR, and immunohistochemistry, we focused on the intrinsic post-axotomy response of specifically labelled thoracic propriospinal neurons at periods from 3-days to 1-month following T9 spinal cord injury. We found a strong and early (3-days post injury, p.i) upregulation in the expression of genes involved in the immune/inflammatory response that returned towards normal by 1-week p.i. In addition, several regeneration associated and cell survival/neuroprotective genes were significantly up-regulated at the earliest p.i. period studied. Significant upregulation of several growth factor receptor genes (GFRa1, Ret, Lifr) also occurred only during the initial period examined. The expression of a number of pro-apoptotic genes up-regulated at 3-days p.i. suggest that changes in gene expression after this period may have resulted from analyzing surviving TPS neurons after the cell death of the remainder of the axotomized TPS neuronal population.ConclusionsTaken collectively these data demonstrate that thoracic propriospinal (TPS) neurons mount a very dynamic response following low thoracic axotomy that includes a strong regenerative response, but also results in the cell death of many axotomized TPS neurons in the first week after spinal cord injury. These data also suggest that the immune/inflammatory response may have an important role in mediating the early strong regenerative response, as well as the apoptotic response, since expression of all of three classes of gene are up-regulated only during the initial period examined, 3-days post-SCI. The up-regulation in the expression of genes for several growth factor receptors during the first week post-SCI also suggest that administration of these factors may protect TPS neurons from cell death and maintain a regenerative response, but only if given during the early period after injury.

Peripheral nerve graft with immunosuppression modifies gene expression in axotomized CNS neurons

“…Similar results were found in a microarray study of axotomized thoracic (short) propriospinal neurons (Siebert et al, 2010a) and indeed confirmed previous reports that showed increases in expression of genes associated with axonal growth in other CNS neurons following injury (e.g., Schmitt et al, 1999;Haas et al, 2000;Carmel et al, 2001;Mason et al, 2003b;DiGiovanni et al, 2004;Vavrek et al, 2007;Vinit et al, 2009). The response of these injured propriospinal neurons differed in some respects from LVN neurons, and up to 70% of labeled propriospinal neurons died following injury.…”

“…Further, certain classes of CNS neurons do respond to axotomy by increasing their expression of genes related to axonal growth (Tetzlaff et al, 1991;Schmidt et al, 1999Schmidt et al, , 2003Haas et al, 2000;Jin et al, 2000;Carmel et al, 2001;DiGiovanni et al, 2005;Kraus and Illing 2005;Vavek et al, 2007;Siebert et al, 2010a), even though they may fail to regenerate successfully. Even corticospinal neurons, if their axons are severed close to the cell body, increase expression of genes associated with regeneration (Mason et al, 2003a).…”

Mammalian alpha beta hydrolase domain (ABHD) proteins: Lipid metabolizing enzymes at the interface of cell signaling and energy metabolism

“…Hippocampal ABHD1 expression is down-regulated by age and up-regulated by exercise in mice [8]. ABHD1 expression is also down-regulated in regenerative neurons in response to spinal cord injury in rats [9]. Together, these studies indicate that ABHD1 is highly transcriptionally controlled and may have an important function in oxidative stress.…”

Characterization of dendritic morphology and neurotransmitter phenotype of thoracic descending propriospinal neurons after complete spinal cord transection and GDNF treatment

“…Low thoracic axotomy invoked a strong regenerative response of descending thoracic propriospinal neurons to the injury (Siebert et al, 2010). Severed axons of commissural PNs can regenerate and make functional synaptic connections with spinal motoneurons (Fenrich and Rose, 2009; Siebert et al, 2010).…”

“…Low thoracic axotomy invoked a strong regenerative response of descending thoracic propriospinal neurons to the injury (Siebert et al, 2010). Severed axons of commissural PNs can regenerate and make functional synaptic connections with spinal motoneurons (Fenrich and Rose, 2009; Siebert et al, 2010). dPSTs also responded to exogenous treatment with the neurotrophic factor GDNF and Schwann cells, resulting in successful regeneration through the lesion site (Deng et al, 2013; Iannotti et al, 2003; Xu et al, 1999; Zhang et al, 2009).…”