Synaptic Vesicle Glycoprotein 2A Is Affected in the Central Nervous System of Mice with Huntington Disease and in the Brain of a Human with Huntington Disease Postmortem

Abstract

Synaptic dysfunction is a primary mechanism underlying Huntington’s Disease (HD) progression. This study investigated changes in synaptic vesicle glycoprotein 2A (SV2A) density by means of ¹¹C-UCB-J microPET imaging in the central nervous system (CNS) of HD mice. <b>METHODS:</b> Dynamic ¹¹C-UCB-J microPET imaging was performed at clinically relevant disease stages (at 3, 7, 10, and 16 months, M) in the heterozygous knock-in Q175DN mouse model of HD and WT littermates (<i>n</i> = 16-18/genotype and time point). Cerebral ¹¹C-UCB-J analyses were performed to assess genotypic differences during pre-symptomatic (3M) and symptomatic (7-16M) disease stages. ¹¹C-UCB-J binding in the spinal cord was quantified at 16M. 3H-UCB-J autoradiography and SV2A immunofluorescence were performed post-mortem in mouse and human brain tissue. <b>RESULTS:</b>¹¹C-UCB-J binding was declined in symptomatic heterozygous mice compared to WT littermates in parallel with disease progression (7M: p&lt;0.01, 16M: p&lt;0.0001). Specific ¹¹C-UCB-J binding was detectable in the spinal cord, with symptomatic heterozygous mice displaying a significant reduction (p&lt;0.0001). 3H-UCB-J autoradiography and SV2A immunofluorescence corroborated the in vivo measurements demonstrating lowered SV2A in heterozygous mice (p&lt;0.05). Finally, preliminary analysis of SV2A in post-mortem human brain suggested lower SV2A in HD gene carrier compared to nondemented control. <b>CONCLUSION:</b>¹¹C-UCB-J PET detects SV2A deficits during symptomatic disease in heterozygous mice in both brain and spinal cord, offering a novel marker of synaptic integrity widely distributed in CNS. Upon clinical application, ¹¹C-UCB-J PET imaging yields promise for SV2A measurement in patients with HD during disease progression and following disease-modifying therapeutic strategies.

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