Abstract
Neurons innervating peripheral tissues display complex responses to peripheral nerve injury. These include the activation and suppression of a variety of signalling pathways that together influence regenerative growth and result in more or less successful functional recovery. However, these responses can be offset by pathological consequences including neuropathic pain. Calcium signalling plays a major role in the different steps occurring after nerve damage. As part of our studies to unravel the roles of injury-induced molecular changes in dorsal root ganglia (DRG) neurons during their regeneration, we show that the calcium calmodulin kinase CaMK1a is markedly induced in mouse DRG neurons in several models of mechanical peripheral nerve injury, but not by inflammation. Intrathecal injection of NRTN or GDNF significantly prevents the post-traumatic induction of CaMK1a suggesting that interruption of target derived factors might be a starter signal in this de novo induction. Inhibition of CaMK signalling in injured DRG neurons by pharmacological means or treatment with CaMK1a siRNA resulted in decreased velocity of neurite growth in vitro. Altogether, the results suggest that CaMK1a induction is part of the intrinsic regenerative response of DRG neurons to peripheral nerve injury, and is thus a potential target for therapeutic intervention to improve peripheral nerve regeneration.
Highlights
Peripheral nerve damage leads to adaptive responses allowing injured neurons to survive and to re-grow to their targets
We found a striking elevation of the expression of Calcium/ Calmodulin-dependant protein kinase 1 known as Calcium/ Calmodulin-dependant protein kinase 1 alpha three days after sciatic nerve axotomy
We show that up-regulation of CaMK1a expression is part of the response of adult dorsal root ganglia (DRG) neurons occurring after physical injury to the peripheral nerve
Summary
Peripheral nerve damage leads to adaptive responses allowing injured neurons to survive and to re-grow to their targets. The regeneration process is slow and incomplete [1]. It is often accompanied by disturbing motor, autonomic and sensory consequences including motor dysfunctions and neuropathic pain conditions that are difficult to treat. The molecular events underlying post-traumatic responses involve complex steps occurring in a temporal sequence and are age and type of injury dependant [2,3]. They include rapid, midand long-term changes the significance of which in terms of pathological or regenerative processes have not yet been fully elucidated. A part of this response involves the reprogramming of developmental processes implicated in neurite outgrowth as well as the induction of a set of de novo expressed genes [4,5,6] some of which play roles in mature neuron re-growth [7,8]
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