Assessment of changes in synaptic density in the zQ175DN mouse model of Huntington's disease: a [18F]SynVesT-1 study

Abstract

Huntington's disease (HD) is a neurodegenerative disorder characterized by involuntary movements, cognitive decline and psychiatric problems. HD has been associated with synaptic dysfunction and loss of the synaptic vesicle protein 2A (SV2A). SV2A can readily be quantified via positron emission tomography (PET) using the selective and high affinity SV2A radiotracer [¹⁸F]SynVesT-1 that we previously characterized in C57BL/6J mice. Here, we performed dynamic [¹⁸F]SynVesT-1 PET to characterize SV2A levels at various disease stages in another HD mouse model, zQ175DN, at 3 and 6 months (M) (longitudinal) and 10 M and 16 M (cross-sectional). We also conducted ex vivo SV2A immunofluorescent staining and [³H]UCB-J and [³H]SynVesT-1 autoradiography at 16 M. Dynamic [¹⁸F]SynVesT-1 PET revealed comparable V_T(IDIF) values between male and female 3 M and 6 M old zQ175DN mice. A significant age effect was found in the motor cortex and hippocampus between 3 M and 6 M. From 3 M to 10 M, no significant difference was found between heterozygous and wild-type mice. At 16 M, however, significant V_T(IDIF) differences were observed between genotypes in the motor cortex (-9.1 ± 3.5 %, p = 0.038), hippocampus (-7.5 ± 3.3, p = 0.036) and thalamus (-8.9 ± 3.1 %, p = 0.016). Ex vivo analyses did not confirm the observed deficits at 16 M, likely due to the decreased sensitivity compared to PET. However, [³H]SynVesT-1 and [³H]UCB-J autoradiography displayed the same outcome, ruling out a radioligand-specific effect. [¹⁸F]SynVesT-1 PET identified mild SV2A deficits in the zQ175DN model of HD at 16 M, whereas no significant SV2A deficits were detected at younger ages.

Keywords: Huntington’s disease; Mouse model; Positron emission tomography; Synapse; Synaptic density; Synaptic vesicle protein 2A.