Effect of GABAergic receptor activity on glutamate release during excitotoxic damage in mouse spinal cord injury model

MAZZONE GL; OLIVIERI D; NISTRI A; UCHITEL OD

Cordoba

Congreso; Congreso Sociedad Argentina de investigación en Neurosciencias (SAN); 2018

Sociedad Argentina de investigación en Neurosciencias (SAN)

Acute spinal cord injury induces loss of motor, sensory and autonomic functions through a process involving a primary injury and a secondary phase during which massive glutamate release occurs. This phenomenon implies dysregulation of the excitatory and inhibitory network balance. The present study on mouse organotypic spinal slices analyzed how pharmacological manipulation of GABA receptors might affect real-time glutamate release following 1 h kainate application. We used a glutamate biosensor placed in the ventral horn area and monitored neuronal survival later. Furthermore, we studied if L-amino-4-phosphonobutyrate (L-AP4; 1 µM) could inhibit glutamate release. Glutamate release evoked by kainate was significantly reduced by the allosteric GABA modulator midazolam (10 nM) or the agonist THIP (10 µM), leading to neuroprotection. On the contrary, higher release was induced by bicuculline (20 µM), while no effect was observed with gabazine (20 µM). L-AP4, an agonist of group III mGluRs, largely depressed glutamate release and protected neurons. These findings indicate that pharmacological depression of glutamate release via enhancement of GABA receptor activity or inhibition of presynaptic release with mGluR activation were effective tools to counteract excitotoxic death in spinal networks. In view of the THIP activity, the present data imply a significant role for extrasynaptic GABA receptors in sparing spinal cord neurons from injury. Supported by ICTP and CONICET.