A2A receptor knockout worsens survival and motor behaviour in a transgenic mouse model of Huntington's disease

Abstract

Huntington's disease (HD) is a progressive neurodegenerative genetic disorder that leads to motor, cognitive, and psychiatric disturbances. The primary neuropathological hallmark is atrophy of the striatum. HD preferentially affects efferent striato-pallidal neurons that express enkephalin as well as dopamine D2 and A2A adenosine receptors (A2ARs). Expression and function of A2ARs are altered in HD but, despite being an important modulator of the striato-pallidal function, the subsequent pathophysiological consequence of such changes remains unclear. Whether blockade of A2ARs is of therapeutic interest in HD remains ill-defined. In the present work, we aimed to determine the pathophysiological consequences of genetic deletion of A2ARs in HD by crossing A2AR knockout mice with the N171-82Q HD transgenic model. Our data demonstrate that knockout of A2ARs moderately but significantly worsens motor performances and survival of N171-82Q mice and leads to a decrease in striatal enkephalin expression. These results support that early and chronic blockade of A2ARs might not be beneficial in HD.

Keywords

• Adenosine receptor
• A2A
• Huntington's disease
• N171-82Q
• Transgenic model
• Striatum