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Caffeine Reverts Memory But Not Mood Impairment in a Depression-Prone Mouse Strain with Up-Regulated Adenosine A2A Receptor in Hippocampal Glutamate Synapses

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Abstract

Caffeine prophylactically prevents mood and memory impairments through adenosine A2A receptor (A2AR) antagonism. A2AR antagonists also therapeutically revert mood and memory impairments, but it is not known if caffeine is also therapeutically or only prophylactically effective. Since depression is accompanied by mood and memory alterations, we now explored if chronic (4 weeks) caffeine consumption (0.3 g/L) reverts mood and memory impairment in helpless mice (HM, 12 weeks old), a bred-based model of depression. HM displayed higher immobility in the tail suspension and forced swimming tests, greater anxiety in the elevated plus maze, and poorer memory performance (modified Y-maze and object recognition). HM also had reduced density of synaptic (synaptophysin, SNAP-25), namely, glutamatergic (vGluT1; −22 ± 7 %) and GABAergic (vGAT; −23 ± 8 %) markers in the hippocampus. HM displayed higher A2AR density (72 ± 6 %) in hippocampal synapses, an enhanced facilitation of hippocampal glutamate release by the A2AR agonist, CGS21680 (30 nM), and a larger LTP amplitude (54 ± 8 % vs. 21 ± 5 % in controls) that was restored to control levels (30 ± 10 %) by the A2AR antagonist, SCH58261 (50 nM). Notably, caffeine intake reverted memory deficits and reverted the loss of hippocampal synaptic markers but did not affect helpless or anxiety behavior. These results reinforce the validity of HM as an animal model of depression by showing that they also display reference memory deficits. Furthermore, caffeine intake selectively reverted memory but not mood deficits displayed by HM, which are associated with an increased density and functional impact of hippocampal A2AR controlling synaptic glutamatergic function.

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Abbreviations

A2AR:

Adenosine A2A receptor

ADA:

Adenosine deaminase

BrdU:

5-Bromo-2′-deoxyuridine

CADO:

2-Chloroadenosine

CGS21680:

4-[2-[[6-amino-9-(N-ethyl-β-D-ribofuranuronamidosyl)-9H-purin-2-yl]amino]ethyl]benzene propanoic acid

DPCPX:

1,3-Dipropyl-8-cyclopentylxanthine

fEPSPs:

Field excitatory post-synaptic potentials

FR:

Fractional release

HM:

Helpless mice

LTP:

Long-term potentiation

NHM:

Non-helpless mice

PSD95:

Post-synaptic density 95 kDa

SCH58261:

{7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolol[1,5c]pyrimidine

SNAP25:

Synaptosomal-associated protein 25 kDa

vGAT:

Vesicular GABA transporters

vGluT1:

Vesicular glutamate transporter type 1

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Acknowledgments

This work was supported by NARSAD, DARPA (09-68-ESR-FP-010), Fundação para a Ciência e para a Tecnologia (PTDC/SAU-NEU/122254/2010 and PEst-C/SAU/LA0001/2013-2014), QREN (CENTRO-07-ST24-FEDER-002006), program Égide-Pessoa, CAPES-FCT, and CAPES (Ciência sem Fronteiras).

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    Authors and Affiliations

    1. CNC-Center for Neurosciences and Cell Biology, University of Coimbra, 3004-517, Coimbra, Portugal

      Nuno J. Machado, Ana Patrícia Simões, Henrique B. Silva, Ana Paula Ardais, Manuella P. Kaster, Pedro Garção, Diana I. Rodrigues, Daniela Pochmann, Ana Isabel Santos, Inês M. Araújo, Ângelo R. Tomé, Attila Köfalvi, Paula Agostinho, Rodrigo A. Cunha & Catarina A. Gomes

    2. Department of Biochemistry, Federal University of Rio Grande do Sul, Porto Alegre, RS, 90035-003, Brazil

      Ana Paula Ardais, Daniela Pochmann & Lisiane O. Porciúncula

    3. Department of Biomedical Sciences and Medicine, University of Algarve, Faro, Portugal

      Inês M. Araújo

    4. Faculty of Life Sciences, University of Coimbra, Coimbra, Portugal

      Ângelo R. Tomé

    5. EA 4651-ABTE/ToxEMAC, Faculty of Medicine and Pharmacy, University of Rouen, Rouen, France

      Jean-Marie Vaugeois

    6. Faculty of Medicine, University of Coimbra, Coimbra, Portugal

      Paula Agostinho, Rodrigo A. Cunha & Catarina A. Gomes

    7. CNRS UMR5292; INSERM U1028; Lyon Neuroscience Research Center, Bron, France

      Malika El Yacoubi

    8. Université Lyon 1, Villeurbanne, France

      Malika El Yacoubi

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    1. Nuno J. Machado
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    Correspondence to Rodrigo A. Cunha.

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    Nuno J. Machado, Ana Patrícia Simões, Henrique B. Silva, Ana Paula Ardais, Manuella P. Kaster, Pedro Garção, Diana I. Rodrigues and Catarina A. Gomes contributed equally to this work.

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    Machado, N.J., Simões, A.P., Silva, H.B. et al. Caffeine Reverts Memory But Not Mood Impairment in a Depression-Prone Mouse Strain with Up-Regulated Adenosine A2A Receptor in Hippocampal Glutamate Synapses. Mol Neurobiol 54, 1552–1563 (2017). https://doi.org/10.1007/s12035-016-9774-9

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