A44 Analysis of the deletion of mutant huntingtin from A2A-receptor expressing neurons

Background Alterations in the modulatory function of dopamine in the striatum have been a consistent finding in Huntington’s disease. The dopamine D2 receptor-expressing GABAergic enkephalin neurons of the indirect striatal pathway are thought to be most vulnerable and the ultimate loss of inhibitory control of this circuitry may directly be related to motor, cognitive and behavioral deficits associated with the disease. Aim The aim of this study was to investigate whether behavioral and neurochemical changes in the BACHD mouse model are directly related to the expression of mutant huntingtin protein in the indirect striatal pathway. Methods/techniques We crossed BACHD mice with mice expressing Cre-recombinase under the adenosine A2a promoter. As adenosine A2a and dopamine D2 receptors are co-expressed in the striatum, this crossing generated BACHD mice without expression of mutant HTT in the indirect striatal pathway. We evaluated striatal metabolite changes with 9.4T 1H-magnetic resonance spectroscopy and behavioral changes with the accelerating rotarod, footprints test, elevated plus maze, Porsolt forced swim test, open field test as readouts. Mice were tested at 6 months of age. Results/outcome Our results show that motor deficits, body weight changes and depressive-like behavior are present in BACHD mice of the C57BL6/J strain at 6 months of age. Notably, these impairments remain in the absence of mutant HTT in A2a-expressing cells. Analyses of striatal metabolite changes revealed alterations in metabolites involved in energy metabolism and neurotransmission such as lactate, myo-inositol, N-acetylaspartate. Finally, gene expression analyses reveal reversal in genes of the citric acid cycle with the deletion of mutant huntingtin from A2a neurons. Conclusions Together, these observations suggest that motor and psychiatric impairments in the BACHD mice at the behavioral level are not due to effects on the adenosine A2a pathway despite changes at the gene expression level.