R6/2 Huntington's Disease Mice Develop Early and Progressive Abnormal Brain Metabolism and Seizures

Abstract

A hallmark feature of Huntington's disease pathology is the atrophy of brain regions including, but not limited to, the striatum. Though MRI studies have identified structural CNS changes in several Huntington's disease (HD) mouse models, the functional consequences of HD pathology during the progression of the disease have yet to be investigated using in vivo functional MRI (fMRI). To address this issue, we first established the structural and functional MRI phenotype of juvenile HD mouse model R6/2 at early and advanced stages of disease. Significantly higher fMRI signals [relative cerebral blood volumes (rCBVs)] and atrophy were observed in both age groups in specific brain regions. Next, fMRI results were correlated with electrophysiological analysis, which showed abnormal increases in neuronal activity in affected brain regions, thus identifying a mechanism accounting for the abnormal fMRI findings. [ 14 C] 2-deoxyglucose maps to investigate patterns of glucose utilization were also generated. An interesting mismatch between increases in rCBV and decreases in glucose uptake was observed. Finally, we evaluated the sensitivity of this mouse line to audiogenic seizures early in the disease course. We found that R6/2 mice had an increased susceptibility to develop seizures. Together, these findings identified seizure activity in R6/2 mice and show that neuroimaging measures sensitive to oxygen metabolism can be used as in vivo biomarkers, preceding the onset of an overt behavioral phenotype. Since fMRI-rCBV can also be obtained in patients, we propose that it may serve as a translational tool to evaluate therapeutic responses in humans and HD mouse models.

A comprehensive glycome profiling of Huntington's disease transgenic mice

“…In most cases, scientists have chosen diagnostic techniques based on physical examinations such as CT, PET, MRI, and fMRI scans, immunohistochemistry and neurochemistry, all of which are used to determine the levels of amino acids, lipids, small peptides and metabolic pathways in the brain [59][60][61][62]. When A.…”

Impaired Brain Energy Metabolism in the BACHD Mouse Model of Huntington's Disease: Critical Role of Astrocyte–Neuron Interactions

“…At variance to what we presently observed in BACHD mice, recently published 2-DG maps from 6-week-old R6/2 mice expressing high levels of Htt exon1 bearing 110 to 150 CAG repeats, demonstrated more widespread (striatum, primary motor cortex, and prefrontal cortex) and more pronounced decreases (up to 30%) in glucose uptake compared with WT mice. 29 In HD patients, the more recent positron emission tomography studies have shown reductions in striatal and anterior cingulate metabolic activity, associated with relative metabolic increases in the ventrolateral/ventral posterolateral thalamus, cerebellar vermis, and in the primary motor and visual regions of the cerebral cortex. 6 In addition to the expected decrease in the striatum, we found moderate metabolic defects also in the hippocampus and the cerebellum.…”

ABHD6 Blockade Exerts Antiepileptic Activity in PTZ-Induced Seizures and in Spontaneous Seizures in R6/2 Mice

“…Based on this rationale, we sought to test the ability of ABHD6 blockade to control seizures in a genetic seizure model known to be associated with impaired eCB signaling. Specifically, R6/2 mice display both spontaneous and audiogenic seizures (Cepeda-Prado et al, 2012; Mangiarini et al, 1996) and reproduce the profound dysregulation of eCB signaling described in Huntington's disease (HD) patients (Bisogno et al, 2008; Centonze et al, 2005). R6/2 mice have both decreased 2-AG availability (Bisogno et al, 2008) and CB 1 receptor down-regulation in select neuronal populations (Dowie et al, 2009; Glass et al, 2000; 1993; Horne et al, 2012).…”