Differential effects of VEGF and BDNF on injury-induced upregulation of the NKCC1 cotransporter in extraocular motoneurons.

The NKCC1 cotransporter mediates chloride influx into neurons, playing a crucial role in maintaining chloride homeostasis. An increase in NKCC1 raises intracellular chloride concentration, which shifts the polarity of inhibitory synaptic potentials mediated by GABA and glycine towards depolarization. NKCC1 levels are upregulated in certain neurological diseases and psychiatric disorders associated with neuronal hyperactivity. However, the response of NKCC1 in motoneurons following nerve injury, as well as the influence of target-derived neurotrophic factors on this cotransporter, has been scarcely investigated. Here, we have addressed these questions using the oculomotor system as the experimental model. In particular, we evaluated the changes in NKCC1 levels induced by axotomy in extraocular motoneurons, as well as the effects of administering VEGF or BDNF. For this purpose, we performed monocular enucleation of adult rats to induce axotomy of extraocular motoneurons and used immunofluorescence at the confocal microscopy level for image analysis. Our time course study demonstrated that NKCC1 was upregulated in axotomized motoneurons, reaching a maximum at 15 days post-lesion. An interesting finding was that the administration of VEGF prevented this upregulation. BDNF delivery resulted in NKCC1 levels intermediate between control and axotomy. Axotomized motoneurons also showed an increase in soma size that was prevented by administration of VEGF, but not BDNF, consistent with the ability of NKCC1 to transport water into the cell along with ions. The present data suggest that VEGF may have therapeutic potential for neuronal diseases or injuries characterized by increased NKCC1 expression and associated hyperactivity.