Glia-mediated control of extracellular GABA/glutamate balance in the developing cortex
Zusammenfassung der Projektergebnisse
In neonatal neocortex presynaptic GABAB receptors (GABABRs) are tonically activated by ambient GABA released through GABA transporters 2/3 (GAT-2/3). Early in development GAT-3 are predominantly located to astrocytes. Therefore, the main aim of this project has been to find out mechanism(s) which reverse GAT-2/3. Because GAT-mediated GABA transport depends on the trans-membrane Na+ gradient, we looked for a mechanism which could change intracellular Na+ concentration ([Na+]i). Pharmacological blockade of EAAT1, a glutamate transporter (EAATs), which co-transport 3 Na+ with one glutamate molecule, completely eliminated GAT-2/3-mediated GABA release. GAT-3 and EAAT1 are expressed exclusively in astrocytic processes. Therefore, we have next asked whether the EAAT-GAT interaction indeed occurs in astrocytes. Unexpectedly, we failed to detect EAAT-mediated currents (TMCs) in cortical astrocytes during the first postnatal week, whereas TMCs can be recorded during the second postnatal week. Using intracellular solutions with different [Na+] we have shown that EAAT-GAT interaction depends on [Na+]i and moreover [Na+]i change in a single astrocyte influences network activity in the cortex. The above drawing demonstrates the summary of our findings: uptake of potentially excitotoxic glutamate elevates astrocytic [Na+]i, resulting in GAT-3 reverse and GABA release. As there are other Na+ dependent electrogenic transporters, we suggested that intracellular Na+ ions similar to Ca2+ may in general be considered as a new second messenger system, and treatment leading to [Na+]i changes in astrocytes might help to overcome pathophysiological conditions, like for instance hyper-excitability/epilepsy.
