Inactivation of adenosine A2A receptors reverses working memory deficits at early stages of Huntington's disease models

NEUROBIOLOGY OF DISEASE

卷:79

Article

Li, Wei^1,2  Silva, Henrique B.³  Real, Joana³  Wang, Yu-Mei¹  Rial, Daniel³  Li, Ping^1,4  Payen, Marie-Pierce¹  Zhou, Yuanguo⁴  Muller, Christa E.¹  Tome, Angelo R.³  Cunha, Rodrigo A.^3,5  Chen, Jiang-Fan¹ 

[1] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02129 USA

[2] Third Mil Med Univ, Daping Hosp, Res Inst Surg, Dept Neurol, Chongqing, Peoples R China

[3] Univ Coimbra, CNC Ctr Neurosci & Cell Biol, P-3000 Coimbra, Portugal

[4] Third Mil Med Univ, State Key Lab Trauma Burn & Combined Injury, Inst Surg Res, Mol Biol Ctr,Daping Hosp, Chongqing, Peoples R China

[5] Univ Coimbra, FMUC Fac Med, P-3000 Coimbra, Portugal

关键词: Adenosine A(2A) receptor;    Huntington's disease;    Cognition;    Working memory;    Long-term depression;    R6/2 mice;   

DOI  :  10.1016/j.nbd.2015.03.030

来源: Elsevier

【 摘 要 】

Cognitive impairments in Huntington's disease (HD) are attributed to a dysfunction of the cortico-striatal pathway and significantly affect the quality of life of the patients, but this has not been a therapeutic focus in HD to date. We postulated that adenosine A(2A) receptors (A(2A)R), located at pre- and post-synaptic elements of the cortico-striatal pathways, modulate striatal neurotransmission and synaptic plasticity and cognitive behaviors. To critically evaluate the ability of A(2A)R inactivation to prevent cognitive deficits in early HD, we cross-bred A(2A)R knockout (1(0) mice with two R6/2 transgenic lines of HD (CAG120 and CAG240) to generate two double transgenic R6/2-CAG120-A(2A)R KO and R6/2-CAG240-A(2A)R KO mice and their corresponding wild-type (WT) littermates. Genetic inactivation of A(2A)R prevented working memory deficits induced by R6/2-CAG120 at post-natal week 6 and by R6/2-CAG240 at post-natal month 2 and post-natal month 3, without modifying motor deficits. Similarly the A(2A)R antagonist KW6002 selectively reverted working memory deficits in R6/2-CAG240 mice at post-natal month 3. The search for possible mechanisms indicated that the genetic inactivation of A(2A)R did not affect ubiquitin-positive neuronal inclusions, astrogliosis or Thr-75 phosphorylation of DARPP-32 in the striatum. Importantly, A(2A)R blockade preferentially controlled long-term depression at cortico-striatal synapses in R6/2-CAG240 at post-natal week 6. The reported reversal of working memory deficits in R6/2 mice by the genetic and pharmacological inactivation of A(2A)R provides a proof-of-principle for A(2A)R as novel targets to reverse cognitive deficits in HD, likely by controlling LTD deregulation. (C) 2015 Published by Elsevier Inc.

【 授权许可】

Free