Abstract
The poor regenerative capacity of descending neurons is one of the main causes of the lack of recovery after spinal cord injury (SCI). Thus, it is of crucial importance to find ways to promote axonal regeneration. In addition, the prevention of retrograde degeneration leading to the atrophy/death of descending neurons is an obvious prerequisite to activate axonal regeneration. Lampreys show an amazing regenerative capacity after SCI. Recent histological work in lampreys suggested that GABA, which is massively released after a SCI, could promote the survival of descending neurons. Here, we aimed to study if GABA, acting through GABAB receptors, promotes the survival and axonal regeneration of descending neurons of larval sea lampreys after a complete SCI. First, we used in situ hybridization to confirm that identifiable descending neurons of late-stage larvae express the gabab1 subunit of the GABAB receptor. We also observed an acute increase in the expression of this subunit in descending neurons after SCI, which further supported the possible role of GABA and GABAB receptors in promoting the survival and regeneration of these neurons. So, we performed gain and loss of function experiments to confirm this hypothesis. Treatments with GABA and baclofen (GABAB agonist) significantly reduced caspase activation in descending neurons 2 weeks after a complete SCI. Long-term treatments with GABOB (a GABA analogue) and baclofen significantly promoted axonal regeneration of descending neurons after SCI. These data indicate that GABAergic signalling through GABAB receptors promotes the survival and regeneration of descending neurons after SCI. Finally, we used morpholinos against the gabab1 subunit to knockdown the expression of the GABAB receptor in descending neurons. Long-term morpholino treatments caused a significant inhibition of axonal regeneration. This shows that endogenous GABA promotes axonal regeneration after a complete SCI in lampreys by activating GABAB receptors.
Highlights
In contrast to mammals, lampreys show spontaneous and successful functional recovery after a complete spinal cord injury (SCI) and this is in part due to their impressive ability for axonal regeneration[1,2,3,4,5,6,7,8]
A similar trend was observed for the M1, I4, I5, B4, B6 and Mth neurons in 1 wpl animals as compared to control unlesioned animals, statistical analyses did not reveal significant changes in the expression of the gabab[1] subunit in these neurons
This shows that the complete SCI induced an acute increase in the expression of the gabab[1] subunit in descending neurons, which, together with the accumulation of GABA around the axons of identifiable neurons[37], supports the possible role of endogenous GABA as a neuroprotective and pro-regenerative molecule after SCI in lampreys
Summary
Lampreys show spontaneous and successful functional recovery after a complete spinal cord injury (SCI) and this is in part due to their impressive ability for axonal regeneration[1,2,3,4,5,6,7,8]. (i.e. they regenerate their axon less than 50% of the times; the M1, M2, M3, I1, I2, B1, B3, B4 and Mth neurons)[4,6,12] This indicates that interactions with the extrinsic spinal cord environment and intrinsic differences between descending neurons affect their regenerative abilities after SCI. Recent work has shown that identifiable descending neurons of lampreys that are known to be “bad regenerators” slowly die after a complete SCI and are “poor survivors”[12,14,15].
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