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Neurobiol Dis. 2015 Jul;79:70-80. doi: 10.1016/j.nbd.2015.03.030. Epub 2015 Apr 16.

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

Author information

1
Department of Neurology, Boston University School of Medicine, Boston, MA, USA; Department of Neurology, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing, China.
2
CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Portugal.
3
Department of Neurology, Boston University School of Medicine, Boston, MA, USA.
4
Department of Neurology, Boston University School of Medicine, Boston, MA, USA; Molecular Biology Center, State Key Laboratory of Trauma, Burn, and Combined Injury, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing, China.
5
Molecular Biology Center, State Key Laboratory of Trauma, Burn, and Combined Injury, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing, China.
6
CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Portugal; FMUC-Faculty of Medicine, University of Coimbra, Portugal.
7
Department of Neurology, Boston University School of Medicine, Boston, MA, USA. Electronic address: chenjf@bu.edu.

Abstract

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 (KO) 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 A2(A)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.

KEYWORDS:

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

PMID:
25892655
DOI:
10.1016/j.nbd.2015.03.030
[Indexed for MEDLINE]

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