Working memory deficits in transgenic rats overexpressing human adenosine A2A receptors in the brain.
Adenosine receptors in the central nervous system have been implicated in the modulation of different behavioural patterns and cognitive functions although the specific role of A(2A) receptor (A(2A)R) subtype in learning and memory is still unclear. In the present work we establish a novel transgenic rat strain, TGR(NSEhA2A), overexpressing adenosine A(2A)Rs mainly in the cerebral cortex, the hippocampal formation, and the cerebellum. Thereafter, we explore the relevance of this A(2A)Rs overexpression for learning and memory function. Animals were behaviourally assessed in several learning and memory tasks (6-arms radial tunnel maze, T-maze, object recognition, and several Morris water maze paradigms) and other tests for spontaneous motor activity (open field, hexagonal tunnel maze) and anxiety (plus maze) as modification of these behaviours may interfere with the assessment of cognitive function. Neither motor performance and emotional/anxious-like behaviours were altered by overexpression of A(2A)Rs. TGR(NSEhA2A) showed normal hippocampal-dependent learning of spatial reference memory. However, they presented working memory deficits as detected by performance of constant errors in the blind arms of the 6 arm radial tunnel maze, reduced recognition of a novel object and a lack of learning improvement over four trials on the same day which was not observed over consecutive days in a repeated acquisition paradigm in the Morris water maze. Given the interdependence between adenosinic and dopaminergic function, the present results render the novel TGR(NSEhA2A) as a putative animal model for the working memory deficits and cognitive disruptions related to overstimulation of cortical A(2A)Rs or to dopaminergic prefrontal dysfunction as seen in schizophrenic or Parkinson's disease patients.
Giménez-Llort
Lydia
L
Medical Psychology Unit, Department of Psychiatry and Forensic Medicine, School of Medicine, Institute of Neuroscience, Autonomous University of Barcelona, Barcelona, Spain.
Schiffmann
Serge N
SN
Shmidt
Tanja
T
Canela
Laia
L
Camón
Lluïsa
L
Wassholm
Monica
M
Canals
Meritxell
M
Terasmaa
Anton
A
Fernández-Teruel
Albert
A
Tobeña
Adolf
A
Popova
Elena
E
Ferré
Sergi
S
Agnati
Luigi
L
Ciruela
Francisco
F
Martínez
Emili
E
Scheel-Kruger
Jörgen
J
Lluis
Carmen
C
Franco
Rafael
R
Fuxe
Kjell
K
Bader
Michael
M
D000704:Analysis of Variance; D000818:Animals; D030801:Animals, Genetically Modified; D001007:Anxiety / Q000378:metabolism; D002531:Cerebellum / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism*; D005106:Exploratory Behavior / Q000502:physiology; D005818:Genetic Engineering / Q000379:methods; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D008297:Male; D018782:Maze Learning / Q000502:physiology*; D008569:Memory Disorders / Q000235:genetics / Q000378:metabolism*; D008570:Memory, Short-Term / Q000502:physiology*; D023421:Models, Animal; D009043:Motor Activity / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043705:Receptor, Adenosine A2A / Q000235:genetics / Q000378:metabolism*; D064529:Receptor, Metabotropic Glutamate 5; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism; D018709:Statistics, Nonparametric
D043705:Receptor, Adenosine A2A; D064529:Receptor, Metabotropic Glutamate 5; D017448:Receptors, Dopamine D2; D018094:Receptors, Metabotropic Glutamate