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Séminaire impromptu - Elisabete AugustoCharacterization of ecto-5’-nucleotidase (CD73) in the brain - role in adenosine A2A receptor activation

Abstract :

 Elisabete Augusto: Adenosine is an important neuromodulator that participates in different brain functions, namely through the activation of adenosine A2A receptor (A2AR)
. Since the source of adenosine as a neuromodulator is still a very debatable subject (e.g. ATP release from astrocytes vs. neuronal release of adenosine) we explored whether the extracellular ATP was involved in the generation of adenosine that activates a particular adenosine receptor subtype (A2AR). We showed that in the striatum CD73, which dephosphorylates AMP to adenosine, is in close proximity to A2AR, its activity is required for A2AR activation, and that the phenotype of CD73 KO mice mimics A2AR KO mice phenotype in physiological and pathological conditions; overall, suggesting that CD73 has an important role in A2AR activation in the striatum. Additionally, and based on the fact that adenosine is a very well known endogenous antiepileptic through the activation of adenosine A1 receptor (A1R), we explored the participation of CD73 in a mesial temporal lobe epilepsy mouse model. We showed that genetic deletion of CD73 does not aggravate KA-induced seizures, suggesting that CD73-mediated formation of adenosine does not act as an endogenous antiepileptic.

Because caffeine and other A2AR antagonist are known for its properties as cognitive enhancers, we explored whether hippocampal A2AR participates in the control of different cognitive behaviors. We showed a pro-cognitive behavior after knocking- down A2AR in the hippocampus. These results are in agreement with our recent findings showing that hippocampal A2AR activation by light is sufficient to trigger a mnemonic impairment. Moreover, we were able to observe that the quick changes operated by hippocampal A2AR are due to the presence of A2AR mRNA at the synaptic level of the hippocampus that is capable of local translation.

Overall, our work suggests that CD73 contribute to striatal A2AR activation and not to hippocampal A1R activation; and that hippocampal A2AR is a potential player in the regulation of mnemonic processes.

Selected publications

Wei CJ, Augusto E, Gomes CA, Singer P, Wang Y, Boison D, Cunha RA, Yee BK, Chen JF (2013). Regulation of Fear Responses by Striatal and Extrastriatal Adenosine A(2A) Receptors in Forebrain. Biological Psychiatry, 75 (11), 855-63.

 Li P, Rial D, Canas PM, Yoo JH, Li W, Zhou X, Wang Y, van Westen GJ, Payen MP, Augusto E, Gonçalves N, Tomé AR, Li Z, Wu Z, Hou X, Zhou Y, PIJzerman A, Boyden ES, Cunha RA, Qu J and Chen JF (2015). Optogenetic activation of intracellular adenosine A2A receptor signaling in hippocampus is sufficient to trigger CREB phosphorylation and impair memory. Molecular Psychiatry, 20(11):1481.

Augusto E, Matos M, Sévigny J, El-Tayeb A, Bynoe MS, Müller CE, Cunha RA, Chen JF (2013). Ecto-5'-nucleotidase (CD73)-mediated formation of adenosine is critical for the striatal adenosine A2A receptor functions. Journal of Neuroscience, 33(28), 11390-11399.

Matos M, Augusto E, Santos-Rodrigues A, Schwarzschild MA, Chen J-F, Cunha RA, Agostinho P (2012). Adenosine A2A receptors modulate glutamate uptake in cultured astrocytes and gliosomes. Glia, 60 (5), 702-716.

Matos M, Augusto E, Machado NJ, Dos Santos-Rodrigues A, Cunha RA, Agostinho P (2012). Astrocytic Adenosine A2A Receptors Control the Amyloid-β Peptide-Induced Decrease of Glutamate Uptake. Journal of Alzheimer’s Disease, 31(3), 555-567.

Matos M, Augusto E, Agostinho P, Cunha RA, Chen JF (2013). Antagonistic interaction between adenosine A2A receptors and Na+/K+-ATPase-α2 controlling glutamate uptake in astrocytes. Journal of Neuroscience, 33 (47), 18492-18502.

Matos M, Shen HY, Augusto E, Wang Y, Wei CJ, Wang YT, Agostinho P, Boison D, Cunha RA, Chen JF (2015). Deletion of adenosine A2A receptors from astrocytes disrupts glutamate homeostasis leading to psychomotor and cognitive impairment: relevance to schizophrenia. Biological Psychiatry, 78(11):763-74.

 Yao SQ, Li ZZ, Huang QY, Li F, Wang ZW, Augusto E, He JC, Wang XT, Chen JF, Zheng RY (2012). Genetic inactivation of the adenosine A(2A) receptor exacerbates brain damage in mice with experimental autoimmune encephalomyelitis. Journal of Neurochemistry, 123(1), 100-112.

Matos M, Augusto E, Oliveira CR, Agostinho P (2008). Amyloid-beta peptide decreases glutamate uptake in cultured astrocytes: involvement of oxidative stress and MAP Kinase cascades. Neuroscience, 156, 898-910.