C-terminal-dependent control of EAAT2 signaling, corticostriatal synaptic glutamate clearance and spontaneous motor activity in mice with hypokinesia
Hirschberg, S.; Dvorzhak, A.; Rasooli-Nejad, S. M. A.; Angelov, S.; Kirchner, M.; Mertins, P.; Lättig-Tünnemann, G.; Harms, C.; Schmitz, D.; Grantyn, R.
Show abstract
Rapid removal of glutamate from the sites of glutamate release is an essential step in excitatory synaptic transmission. Despite many years of research, the molecular mechanisms underlying the intracellular regulation of glutamate transport at tripartite synapses have remained unclear. This limits the options for pharmacological treatment of motor disorders associated with glutamate excitotoxicity. Therefore, using the Q175 mouse model of Huntingtons disease (HD), we explored the effects of structural changes in the astrocytic excitatory amino acid transporter type 2 (EAAT2). We report that expression of a C-terminal-modified variant of EAAT2 can alleviate the symptoms of hypokinesia in mice with already advanced HD. At a cellular level, this beneficial outcome correlated with faster synaptic glutamate clearance, higher astrocytic glutamate uptake and larger amounts of native EAAT2 protein. Proteomics data indicate a partial reversal of HD-induced changes in the EAAT2 interactor spectrum. Thus, astrocytic glutamate transport remains a target for therapeutic intervention.
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