Single Synapse Indicators of Impaired Glutamate Clearance Derived from Fast iGluu Imaging of Cortical Afferents in the Striatum of Normal and Huntington (Q175) Mice

Dvorzhak, Anton, Helassa, Nordine ORCID: 0000-0003-3743-1886, Torok, Katalin, Schmitz, Dietmar and Grantyn, Rosemarie (2019) Single Synapse Indicators of Impaired Glutamate Clearance Derived from Fast iGluu Imaging of Cortical Afferents in the Striatum of Normal and Huntington (Q175) Mice. Journal of Neuroscience, 39 (20). pp. 3970-3982.

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Official URL: https://www.jneurosci.org/content/39/20/3970

Abstract

Changes in the balance between glutamate (Glu) release and uptake may stimulate synaptic reorganization and even synapse loss. In the case of neurodegeneration, a mismatch between astroglial Glu uptake and presynaptic Glu release could be detected if both parameters were 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 findings from individual corticostriatal synapses in acute slices prepared from mice of either sex that were >1 year of age. Contrasting patterns of short-term plasticity and a size criterion identified two classes of terminals, presumably corresponding to the previously defined IT (intratelencephalic) and PT (pyramidal tract) synapses. The latter exhibited a higher degree of frequency potentiation/residual Glu accumulation and were selected for our first iGluu single-synapse study in Q175 mice, a model of Huntington's disease (HD). In HD mice, the decay time constant of the perisynaptic Glu concentration (TauD), as an indicator of uptake, and the peak iGluu amplitude, as an indicator of release, were prolonged and reduced, respectively. Treatment of WT preparations with the astrocytic Glu uptake blocker TFB-TBOA (100 nm) mimicked the TauD changes in homozygotes. Considering the largest TauD values encountered in WT, ∼40% of PT synapses tested in Q175 heterozygotes can be classified as dysfunctional. Moreover, HD but not WT synapses exhibited a positive correlation between TauD and the peak amplitude of iGluu. Finally, EAAT2 (excitatory amino acid transport protein 2) immunoreactivity was reduced next to corticostriatal terminals. Thus, astrocytic Glu transport remains a promising target for therapeutic intervention.

Item Type:	Article
Uncontrolled Keywords:	astrocytes, EAAT2, Glu imaging, glutamate clearance, synapse pathology, tripartite synapse
Depositing User:	Symplectic Admin
Date Deposited:	08 Mar 2019 10:26
Last Modified:	19 Jan 2023 00:57
DOI:	10.1523/JNEUROSCI.2865-18.2019
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3033914