In vivo MR spectroscopy reflects synapse density in a Huntington′s disease mouse model

Background: Striatal medium spiny neurons are highly susceptible in Huntington′s disease (HD), resulting in early synaptic perturbations that lead to neuronal dysfunction and death. Non-invasive imaging techniques, such as proton magnetic resonance spectroscopy (1H-MRS), have been used in HD mouse models and patients with HD to monitor neurochemical changes associated with neuronal health. However, the molecular connection between brain neurochemical alterations and synaptic dysregulation is unknown, limiting our ability to monitor potential treatments that may affect synapse function. Objective: Assess the intersection of synapse density and 1H-MRS during disease progression in an HD mouse model. Methods: We conducted in vivo longitudinal 1H-MRS in the striatum followed by ex-vivo analyses of excitatory synapse density of two synaptic circuits disrupted in HD: thalamo-striatal (T-S) and cortico-striatal (C-S) pathways. We used the heterozygous knock-in zQ175 HD mouse model as well as zQ175 mice lacking one allele of CK2α′(zQ175(Tg/0):CK2α′(+/-)), a kinase previously shown to regulate synapse function in HD. Results: Longitudinal analyses of excitatory synapse density showed early and sustained reduction in T-S synapses in zQ175 mice, preceding C-S synapse depletion, which was rescued in zQ175:CK2α′(+/-). Linear regression analyses showed C-S synapse number correlated with 1H-MRS-measured levels of GABA while T-S synapse number positively correlated with alterations in the levels of alanine, phosphoethanolamine, lactate, and taurine relative to total creatine. Conclusion: We propose these neurochemicals could be used as surrogate biomarkers to monitor circuit-specific synaptic dysfunction using 1H-MRS in the zQ175 mouse model and perhaps in HD pre-clinical studies. ### Competing Interest Statement The authors have declared no competing interest.