Neurochemical correlates of synapse density in a Huntington's disease mouse model

Striatal medium spiny neurons are highly susceptible in Huntington's disease (HD), resulting in progressive synaptic perturbations that lead to neuronal dysfunction and death. Non‐invasive imaging techniques, such as proton magnetic resonance spectroscopy (1H‐MRS), are used in HD mouse models and patients with HD to monitor neurochemical changes associated with neuronal health. However, the association between brain neurochemical alterations and synaptic dysregulation remains unknown, limiting our ability to monitor potential treatments that may affect synapse function. 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, to assess the relationship between neurochemical alterations and changes in synapse density. We used the zQ175(Tg/0) 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. 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’(+/−). Changes in T‐S and C‐S synapses were accompanied by progressive alterations in numerous neurochemicals between WT and HD mice. Linear regression analyses showed C‐S synapse number positively correlated with 1H‐MRS‐measured levels of GABA, while T‐S synapse number positively correlated with levels of phosphoethanolamine and negatively correlated with total creatine levels. These associations suggest that these neurochemical concentrations measured by 1H‐MRS may facilitate monitoring circuit‐specific synaptic dysfunction in the zQ175 mouse model and in other HD pre‐clinical studies. Neurochemical alterations and decreased excitatory synapses are pathological hallmarks in Huntington's disease. To investigate the relationship between the two, we performed in vivo magnetic resonance spectroscopy and ex vivo excitatory synapse density analyses between cortico‐striatal and thalamo‐striatal synapses in WT, the zQ175 HD mouse model, and the zQ175:CK2α’ (+/−) HD mouse model which was previously shown to ameliorate aspects of HD, including synapse loss. We found correlations between circuit‐specific loss of synapses and changes in specific neurochemicals. These findings provide preliminary data on the plausibility of using neurochemic