title: Inactivation of adenosine A2A receptors reverses working memory deficits at early stages of Huntington's disease models.
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.
authors.affiliation: 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.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Portugal.
authors.forename: Henrique B
authors.initials: HB
authors.lastname: Silva
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Portugal.
authors.forename: Joana
authors.initials: J
authors.lastname: Real
authors.affiliation: Department of Neurology, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Yu-Mei
authors.initials: YM
authors.lastname: Wang
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Portugal.
authors.forename: Daniel
authors.initials: D
authors.lastname: Rial
authors.affiliation: 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.
authors.forename: Ping
authors.initials: P
authors.lastname: Li
authors.affiliation: Department of Neurology, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Marie-Pierce
authors.initials: MP
authors.lastname: Payen
authors.affiliation: Molecular Biology Center, State Key Laboratory of Trauma, Burn, and Combined Injury, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Yuanguo
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Neurology, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Christa E
authors.initials: CE
authors.lastname: Muller
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Portugal.
authors.forename: Angelo R
authors.initials: AR
authors.lastname: Tomé
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Portugal; FMUC-Faculty of Medicine, University of Coimbra, Portugal.
authors.forename: Rodrigo A
authors.initials: RA
authors.lastname: Cunha
authors.affiliation: Department of Neurology, Boston University School of Medicine, Boston, MA, USA. Electronic address: chenjf@bu.edu.
authors.forename: Jiang-Fan
authors.initials: JF
authors.lastname: Chen
mesh_terms: D058917:Adenosine A2 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D002540:Cerebral Cortex / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D003072:Cognition Disorders / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D003342:Corpus Striatum / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D018450:Disease Progression; D005911:Gliosis / Q000473:pathology / Q000503:physiopathology; D006816:Huntington Disease / Q000473:pathology / Q000503:physiopathology*; D002479:Inclusion Bodies / Q000473:pathology / Q000502:physiology; D036881:Long-Term Synaptic Depression / Q000187:drug effects / Q000502:physiology; D008297:Male; D008569:Memory Disorders / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D008570:Memory, Short-Term / Q000187:drug effects / Q000502:physiology*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011687:Purines / Q000494:pharmacology; D043705:Receptor, Adenosine A2A / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D011687:Purines; D043705:Receptor, Adenosine A2A; D025801:Ubiquitin; C111599:istradefylline
keywords: Adenosine A(2A) receptor; Cognition; Huntington's disease; Long-term depression; R6/2 mice; Working memory