Single synapse indicators of impaired glutamate clearance derived from fast iGlu(u) imaging of cortical afferents in the striatum of normal and Huntington (Q175) mice

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Item Type:	Article
Title:	Single synapse indicators of impaired glutamate clearance derived from fast iGlu(u) imaging of cortical afferents in the striatum of normal and Huntington (Q175) mice
Creators Name:	Dvorzhak, A., Helassa, N., Török, K., Schmitz, D. and Grantyn, R.
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 iGlu(u) We report findings from individual corticostriatal synapses in acute slices prepared from mice of either sex 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 our first iGlu(u) single synapse study in Q175 mice, a model of Huntington's disease (HD). In HD mice, the time constant of perisynaptic [Glu] decay (TauD, as indicator of uptake) and the peak iGlu(u) amplitude (as 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 (HOM). Considering the largest TauD values encountered in WT, about 40% of PT terminals tested in Q175 heterozygotes (HET) can be classified as dysfunctional. Moreover, HD but not WT synapses exhibited a positive correlation between TauD and the peak amplitude of iGlu(u) Finally, EAAT2 immunoreactivity was reduced next to corticostriatal terminals. Thus, astrocytic Glu transport remains a promising target for therapeutic intervention. SIGNIFICANCE STATEMENT: Alterations in astrocytic Glu uptake can play a role in synaptic plasticity and neurodegeneration. Until now, sensitivity of synaptic responses to pharmacological transport block and the resulting activation of NMDA receptors were regarded as reliable evidence for a mismatch between synaptic uptake and release. But the latter parameters are interdependent. Using a new genetically encoded sensor to monitor [Glu] at individual corticostriatal synapses we can now quantify the time constant of perisynaptic [Glu] decay (as indicator of uptake) and the maximal [Glu] elevation next to the active zone (as indicator of Glu release). The results provide a positive answer to the hitherto unresolved question whether neurodegeneration (e.g. Huntington's disease) associates with a glutamate uptake deficit at tripartite excitatory synapses.
Keywords:	Astrocytes, EAAT2, Glu Imaging, Glutamate Clearance, Synapse Pathology, Tripartite Synapse, Animals, Mice
Source:	Journal of Neuroscience
ISSN:	0270-6474
Publisher:	Society for Neuroscience
Volume:	39
Number:	20
Page Range:	3970-3982
Date:	15 May 2019
Official Publication:	https://doi.org/10.1523/JNEUROSCI.2865-18.2019
External Fulltext:	View full text on PubMed Central
PubMed:	View item in PubMed

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