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Glutamate uptake and release at single adult corticostriatal synapses of normal and Huntington mice

Item Type:Preprint
Title:Glutamate uptake and release at single adult corticostriatal synapses of normal and Huntington mice
Creators Name:Dvorzhak, A. and Helassa, N. and Torok, K. and Schmitz, D. and Grantyn, R.
Abstract:Changes in the balance between synaptic glutamate (Glu) release and uptake may stimulate synaptic reorganization and even synapse loss. The search for the primary cause of a potential mismatch between uptake and release should be easier if both parameters are assessed independently and at a single synapse level. This has now become possible due to a new imaging assay with the genetically encoded ultrafast Glu sensor iGluu. We report results obtained from individual corticostriatal synapses in acute slices prepared from mice aged >1 year. Contrasting patterns of short-term plasticity and a size criterion identified 2 classes of terminals, presumably corresponding to the previously defined IT and PT synapses. The latter exhibited a higher degree of frequency potentiation/residual Glu accumulation and were selected for investigation in the Q175 mouse model of Huntington disease (HD). It was found that the maximal [Glu] next to the presynaptic terminal (as indicator of release) in HD and the time constant of perisynaptic [Glu] decay (TauD, as indicator of uptake) were prolonged and reduced, respectively. According to these criteria, about 30% of P terminals tested in Q175 heterozygotes (HET) were diagnosed as sick. HD but not WT synapses exhibited a positive correlation between TauD and the peak amplitude of iGluu. Treatment of WT preparations with the Glu uptake blocker TFB-TBOA (100 nM) mimicked the TauD changes in homozygotes (HOM). The NMDAR-mediated unitary EPSCs elicited by optical activation of single ChR-expressing corticostriatal axons were prolonged, and less EAAT2 immunoreactivity was found in the environment of corticostriatal terminals. It is concluded that HD produces a mismatch between Glu uptake and release, especially in synapses with high degree of frequency potentiation. Astrocytic Glu transport therefore remains a promising target for therapeutic intervention.
Keywords:Synaptic Transmission, Transmitter Release, Glutamate Clearance, Excitotoxicity, Striatum, Neurodegeneration, Astrocytes
Publisher:Cold Spring Harbor Laboratory Press
Article Number:455758
Date:30 October 2018
Official Publication:https://doi.org/10.1101/455758

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