Physiopathology of glycinergic neurotransmission: hyperekplexia an pain

Hyperplexia (OMIM 149400) is a sensorimotor syndrome of great perinatal clinical relevance. Neonates present energic startle in response to trivial stimuli that may be lethal due to apnea episodes. The ethiology is a poor glycinergic inhibition. The neuronal glycine transporter (GlyT2) removes the neurotransmitter from the synaptic cleft, recycling it to the presynapse and supplying glycine for the filling of the synaptic vesicles. The function of GlyT2 maintains the strength of glycinergic neurotransmission in vertebrates, and its dysfunction causes a presynaptic form of hyperekplexia. Additionally, GlyT2 modulates the nociceptive signal in neurons of the spinal cord. In this project it will be assessed how the GlyT2 variants alter post-translational modifications, interactome, regulation or signaling pathways controling the perinatal development of the transporter, since in this period the symptoms of the disease are more evident. The experimental systems will be cell lines, primary neuronal cultures expressing wild-type and mutant GlyT2 using transfection or infection to measure transporter expression, transport activity or electrical activity. Xenopus laevis oocytes could also be used. In vivo studies could be done using the zebrafish system. Knowledge of the causes of inactivity of GlyT2 mutants or their consequences in development, can guide future therapeutic approaches whose implementation we are interested in.