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Development and maturation of glycine functions in the CNS - role of GLYT2 in the switch from GABAergic to glycinergic transmission


Glycine and GABA are the two major fast inhibitory neurotransmitters of the mammalian central nervous system. The necessity for two fast inhibitory systems is a long-standing question and the functional responsibilities of each transmitter systems are not yet known. GABA and glycine act at distinct ionotropic receptors and are released by separated neurons or co-released by mixed inhibitory neurons. Although glycinergic and GABAergic receptors share structural and biophysical similarities, GABA transmission cannot compensate for a disruption in glycine transmission, for example mutations of the glycine receptors results in a severe human channelopathy that is characterized by hyperekplexia . GABAergic and glycinergic neurons share the same vesicular transporter (VIAAT) for packaging GABA and/or glycine into synaptic vesicles.

Therefore, the vesicular content in inhibitory amino acids should be solely dependent on their relative cytoplasmic concentrations. The plasma membrane transporter GLYT2 is a neuron specific plasma membrane transporter of glycine that can maintain a million fold glycine gradients across the neuronal membrane. We will use in vitro and in vivo electrophysiological and immunocytochemical techniques in to investigate the hypothesis that the expression of GLYT2 on the presynaptic neuron is the only prerequisite for an inhibitory neuron (i.e. expressing VIAAT) to store and release glycine. During brain development, some GABAergic interneurons switch their phenotype to releasing glycine.

This suggests glycine may be specifically required at some developmental time points due to an additional functional capability. We will investigate the role of GLYT2 in this GABA to glycine switch and assess the role this switch plays in developing brain networks. The successful completion of this project will be of benefit to both the candidate and the host institute, as well as to the Europeans research community as a whole.

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