Dual mode of signalling of the axotomy reaction: retrograde electric stimulation or block of retrograde transport differently mimic the reaction of motoneurons to nerve transection in the rat brainstem

Abstract

Axotomy of a peripheral nerve causes a complex central response of neuronal perikarya, astroglia and microglia. The signal initiating this axotomy reaction is currently explained either by deprivation of target-derived trophic factors after interruption of transport (trophic hypothesis) or by electrophysiological disturbances of the axotomized neurons (electric hypothesis). In 108 adult Wistar rats we have compared the time course and intensity of the axotomy reaction in the hypoglossal nucleus after (1) resection of the nerve (permanent axotomy), (2) one-time electric stimulation (intact nerve, brief transient electric disturbance), and (3) colchicine block of transport (intact nerve, prolonged transient loss of trophic factors). Nerve resection activated microglia at 2-35 days post-operation (dpo), elevated GFAP in astrocytes at 3-35 dpo and increased CGRP in motoneurons at 2-15 dpo. Fluorogold prelabeling revealed neurophagocytosis and 25% neuron loss at 25 dpo. Colchicine block similarly activated microglia at 5-35 dpo, elevated GFAP at 7-35 dpo and upregulated CGRP at 7-25 dpo. Neurophagocytosis and 15% motoneuron loss were evident at 25 dpo. Electric stimulation (15 min, 4 Hz, 0.1 msec impulse, 2 mAmp) of the intact nerve activated microglia at 1-10 dpo, elevated astroglial GFAP-expression at 7-35 dpo, and upregulated CGRP at 1-10 dpo, but no neuron death and neurophagocytosis were detected. Hence electric stimulation elicited a faster, shorter-lasting response, but transport block as well as axotomy a slower, longer-lasting response. This suggests a dual mode of signaling: Onset and early phase of the axotomy reaction are triggered by electric disturbances, late phase and neuron death by deprivation of trophic factors.