Working memory and the homeostatic control of brain adenosine by adenosine kinase.
Neuroscience
; 213: 81-92, 2012 Jun 28.
Article
en En
| MEDLINE
| ID: mdl-22521820
The neuromodulator adenosine maintains brain homeostasis and regulates complex behaviour via activation of inhibitory and excitatory adenosine receptors (ARs) in a brain region-specific manner. AR antagonists such as caffeine have been shown to ameliorate cognitive impairments in animal disease models but their effects on learning and memory in normal animals are equivocal. An alternative approach to reduce AR activation is to lower the extracellular tone of adenosine, which can be achieved by up-regulating adenosine kinase (ADK), the key enzyme of metabolic adenosine clearance. However, mice that globally over-express an Adk transgene ('Adk-tg' mice) were devoid of a caffeine-like pro-cognitive profile; they instead exhibited severe spatial memory deficits. This may be mechanistically linked to cortical/hippocampal N-methyl-d-aspartate receptor (NMDAR) hypofunction because the motor response to acute MK-801 was also potentiated in Adk-tg mice. Here, we evaluated the extent to which the behavioural phenotypes of Adk-tg mice might be modifiable by up-regulating adenosine levels in the cortex/hippocampus. To this end, we investigated mutant 'fb-Adk-def' mice in which ADK expression was specifically reduced in the telencephalon leading to a selective increase in cortical/hippocampal adenosine, while the rest of the brain remained as adenosine-deficient as in Adk-tg mice. The fb-Adk-def mice showed an even greater impairment in spatial working memory and a more pronounced motor response to NMDAR blockade than Adk-tg mice. These outcomes suggest that maintenance of cortical/hippocampal adenosine homeostasis is essential for effective spatial memory and deviation in either direction is detrimental with increased expression seemingly more disruptive than decreased expression.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Encéfalo
/
Adenosina
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Adenosina Quinasa
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Homeostasis
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Memoria a Corto Plazo
Límite:
Animals
Idioma:
En
Revista:
Neuroscience
Año:
2012
Tipo del documento:
Article
País de afiliación:
Suiza
Pais de publicación:
Estados Unidos