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TitleImpaired Replenishment of Cortico-Striatal Synaptic Glutamate in Huntington's Disease Mouse Model.
Publication TypeJournal Article
Year of Publication2020
AuthorsBuren, Caodu, Gaqi Tu, and Lynn A. Raymond
JournalJ Huntingtons Dis
Date Published2020

BACKGROUND: Huntington's disease (HD) is an inherited neurodegenerative disorder caused by expansion of CAG repeats in the Huntingtin gene (HTT). Studies suggest cortical to striatal (C-S) projections, which regulate movement and provide cell survival signals to SPNs, are altered in the pre-manifest and early symptomatic stages of HD. But whether and how presynaptic cortical terminals are affected in HD is not well explored.

OBJECTIVE: Test size and replenishment of readily releasable pool (RRP), and assess glutamate refill of C-S synapses in HD models.

METHODS: Immunocytochemistry was applied in C-S co-cultures generated from FVB/N (WT: wildtype) mice and YAC128, an HD mouse model expressing human HTT with  128 CAG repeats on the FVB/N background; Whole-cell patch clamp recordings from striatal neurons were performed both in cultures, with or without osmotic stimuli, and in acute brain slices from 6-month-old early symptomatic YAC128 mice and WT following prolonged trains of electrical stimuli in corpus callosum.

RESULTS: We found no change in the average size or vesicle replenishment rate of RRP in C-S synapses of YAC128, compared with WT, cultures at day in vitro 21, a time when immunocytochemistry showed comparable neuronal survival between the two genotypes. However, YAC128 C-S synapses showed a slowed rate of recovery of glutamate release in co-cultures as well as in acute brain slices.

CONCLUSION: Mutant HTT expression impairs glutamate refill but not RRP size or replenishment in C-S synapses. This work provides a foundation for examining the contribution of deficits in presynaptic cortical terminals on HD progression.

Alternate JournalJ Huntingtons Dis
PubMed ID32310183
Grant ListFDN-143210 / / CIHR / Canada