Affiliations: [a] Graduate Program in Neuroscience, The University of British Columbia, Vancouver, Canada
| [b] Department of Psychiatry and Djavad Mowafaghian Centre for Brain Health, The University of British Columbia, Vancouver, Canada
| [c] School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| [d] Department of Psychology, University of Toronto, Toronto, Ontario, Canada
Correspondence:
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Correspondence to: Lynn A. Raymond, MD, PhD, Department of Psychiatry, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 4834-2255 Wesbrook Mall, Vancouver, BC V6T 1Z3, Canada. Tel.: +1 604 822 0723; Fax: +1 604 822 7981; E-mail: [email protected].
Abstract: 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.
Keywords: Cortical, presynaptic, readily releasable pool, glutamate refill
