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C-terminal-dependent control of EAAT2 signaling, corticostriatal synaptic glutamate clearance and spontaneous motor activity in mice with hypokinesia

Item Type:Preprint
Title:C-terminal-dependent control of EAAT2 signaling, corticostriatal synaptic glutamate clearance and spontaneous motor activity in mice with hypokinesia
Creators Name:Hirschberg, S. and Dvorzhak, A. and Rasooli-Nejad, S.M.A. and Angelov, S. and Kirchner, M. and Mertins, P. and Lättig-Tünnemann, G. and Harms, C. and Schmitz, D. and Grantyn, R.
Abstract:Deficiency of the astrocytic excitatory amino acid transporter type 2 (EAAT2) and, consequently, inefficient glutamate clearance at corticostriatal synapses may contribute to the depression of self-initiated movements in Huntington’s disease (HD). Here we report that the removal of the last 68 amino-acids in the C-terminal of EAAT2 increases the levels of native EAAT2 in striatal lysates and counteracts some of the HD-related changes in the interactor spectrum of mYFP-tagged EAAT2. Using the Q175 mouse model of HD, we explored the functional consequences of C-terminal modifications. It was found that astrocytic expression of EAAT2-S506X or -4KR alleviates the HD-related decrease in the incidence and velocity of exploratory movements. It also stimulates astrocytic glutamate uptake, increases the level of synaptic EAAT2 and improves glutamate clearance at single corticostriatal synapse. The experiments illuminate a link between the intracellular regulation of astrocytic glutamate transport in the striatum and symptoms of hypokinesia in HD mice.
Keywords:Huntington's Disease, EAAT2 Interaction Proteomics, Hypokinesia, Corticostriatal Synaptic Transmission, Glutamate Clearance, Synaptic Targeting of EAAT2, Animals, Mice
Source:bioRxiv
Publisher:Cold Spring Harbor Laboratory Press
Article Number:2020.09.17.302158
Date:19 September 2020
Official Publication:https://doi.org/10.1101/2020.09.17.302158

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