Early and transient alteration of adenosine A2A receptor signaling in a mouse model of Huntington disease.
Huntington Disease (HD) is characterized by choreic involuntary movements and striatal vulnerability. A2A receptors expressed on GABAergic striatal neurons have been suggested to play a pathogenetic role. Previous data demonstrated the presence of an aberrant alteration of A2A receptor-dependent adenylyl cyclase in an in vitro model of the disease (striatal cells expressing mutant huntingtin) and in peripheral circulating cells of HD patients. Here, we investigated whether this dysfunction is present in the R6/2 HD transgenic mouse model, by analyzing striatal A2A receptor-binding and adenylyl cyclase activity at different developmental stages in comparison with age-matched wild type animals. A transient increase in A2A receptor density (Bmax) and A2A receptor-dependent cAMP production at early presymptomatic ages (7-14 postnatal days) was found. Both alterations normalized to control values starting from postnatal day 21. In contrast, A2A receptor mRNA, as detected by real time PCR, dramatically decreased starting from PND21 until late symptomatic stages (12 weeks of age). The discrepancy between A2A receptor expression and density suggests compensatory mechanisms. These data, reproducing ex vivo the previous observations in vitro, support the hypothesis that an alteration of A2A receptor signaling is present in HD and might represent an interesting target for neuroprotective therapies.
Tarditi
Alessia
A
Department of Pharmacological Sciences, University of Milan, Via Balzaretti 9, 20133 Milan, Italy.
Camurri
Alessandra
A
Varani
Katia
K
Borea
Pier Andrea
PA
Woodman
Ben
B
Bates
Gillian
G
Cattaneo
Elena
E
Abbracchio
Maria P
MP
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001479:Basal Ganglia / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D004195:Disease Models, Animal; D006816:Huntington Disease / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000032:analysis; D043683:Receptors, Adenosine A2 / Q000187:drug effects / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D014227:Triazines / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology
D012333:RNA, Messenger; D043683:Receptors, Adenosine A2; D014227:Triazines; D014230:Triazoles; C097270:ZM 241385; D000242:Cyclic AMP; D000262:Adenylyl Cyclases