Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Caffeine reverses sleep deprivation-induced synaptic and social memory deficits via adenosine receptor modulation in the male mouse hippocampal CA2 region

Neuropsychopharmacology (2026)Cite this article

Subjects

Abstract

Sleep deprivation (SD) is a critical risk factor for cognitive decline and is closely linked to psychiatric disorders. The hippocampal CA2 region is critically involved in encoding social memory and regulating emotional behavior, and it has been implicated in various neuropsychiatric conditions. However, how SD affects CA2-dependent synaptic plasticity and related behaviors remains poorly understood. Here, we subjected mice to 5 h of SD via gentle handling and examined synaptic plasticity, molecular signaling, and social recognition memory. Electrophysiological recordings revealed that SD markedly impaired long-term potentiation (LTP) in CA2 and disrupted social recognition memory, as evidenced by failure to distinguish novel from familiar conspecifics. These deficits were accompanied by upregulation of adenosine A1 receptors and PDE4A5, along with reduced expression of plasticity-related proteins including PKMζ, ERK, and BDNF. Moreover, caffeine-induced synaptic potentiation was diminished in SD mice, whereas caffeine supplementation reversed both synaptic and behavioral impairments. Together, these findings demonstrate that SD compromises CA2-dependent plasticity and social cognition through adenosine receptor signaling and identify CA2 as a vulnerable, therapeutically relevant region. Targeting adenosine pathways may represent a novel strategy to mitigate sleep loss–related cognitive dysfunction in neuropsychiatric disorders.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Sleep deprivation impairs long-term potentiation in EC-CA2 synapses.
Fig. 2: Sleep deprivation impairs social recognition memory.
Fig. 3: Sleep deprivation increases A1R expression and has limited effects onto plasticity changes in CA2 synapses following adenosine receptor antagonist application.
Fig. 4: Effects of sleep deprivation on PDE4A5, PKMζ, ERK1/2, and BDNF levels in the hippocampal CA2 area.
Fig. 5: Caffeine administration reverses sleep deprivation-induced impairments in long-term plasticity and social memory.

Similar content being viewed by others

Data availability

The datasets generated from this study are available upon request to the corresponding authors.

References

  1. Wong L-W, Tann JY, Ibanez CF, Sajikumar S. The p75 Neurotrophin Receptor Is an Essential Mediator of Impairments in Hippocampal-Dependent Associative Plasticity and Memory Induced by Sleep Deprivation. J Neurosci Off J Soc Neurosci. 2019;39:5452–65.

    Article  CAS  Google Scholar 

  2. Wong L-W, Chong YS, Wong W, Sajikumar S. Inhibition of Histone Deacetylase Reinstates Hippocampus-Dependent Long-Term Synaptic Plasticity and Associative Memory in Sleep-Deprived Mice. Cereb Cortex. 2020;30:4169–82.

    Article  PubMed  Google Scholar 

  3. Bolsius YG, Heckman P, Paraciani C, Wilhelm S, Raven F, Meijer EL, et al. Recovering object-location memories after sleep deprivation-induced amnesia. Curr Biol. 2023;33:298–308.e5.

    Article  PubMed  CAS  Google Scholar 

  4. Hagewoud R, Whitcomb SN, Heeringa AN, Havekes R, Koolhaas JM, Meerlo P. A time for learning and a time for sleep: the effect of sleep deprivation on contextual fear conditioning at different times of the day. Sleep. 2010;33:1315–22.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Vecsey CG, Baillie GS, Jaganath D, Havekes R, Daniels A, Wimmer M, et al. Sleep deprivation impairs cAMP signalling in the hippocampus. Nature. 2009;461:1122–5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Havekes R, Park AJ, Tudor JC, Luczak VG, Hansen RT, Ferri SL, et al., Sleep deprivation causes memory deficits by negatively impacting neuronal connectivity in hippocampal area CA1. eLife. 2016;5:e13424.

  7. Hitti FL, Siegelbaum SA. The hippocampal CA2 region is essential for social memory. Nature. 2014;508:88–92.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Alexander GM, Farris S, Pirone JR, Zheng C, Colgin LL, Dudek SM. Social and novel contexts modify hippocampal CA2 representations of space. Nat Commun. 2016;7:10300.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Donegan ML, Stefanini F, Meira T, Gordon JA, Fusi S, Siegelbaum SA. Coding of social novelty in the hippocampal CA2 region and its disruption and rescue in a 22q11. 2 microdeletion mouse model. Nat Neurosci. 2020;23:1365–75.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Pedersen NP, Ferrari L, Venner A, Wang JL, Abbott S, Vujovic N, et al. Supramammillary glutamate neurons are a key node of the arousal system. Nat Commun. 2017;8:1–16.

    Article  CAS  Google Scholar 

  11. Soussi R, Zhang N, Tahtakran S, Houser CR, Esclapez M. Heterogeneity of the supramammillary–hippocampal pathways: Evidence for a unique GABAergic neurotransmitter phenotype and regional differences. Eur J Neurosci. 2010;32:771–85.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Chen S, He L, Huang A, Boehringer R, Robert V, Wintzer ME, et al. A hypothalamic novelty signal modulates hippocampal memory. Nature. 2020;586:270–4.

    Article  PubMed  CAS  Google Scholar 

  13. Diekelmann S, Born J. The memory function of sleep. Nat Rev Neurosci. 2010;11:114–26.

    Article  PubMed  CAS  Google Scholar 

  14. Rasch B, Born J. About sleep’s role in memory. Physiol Rev. 2013;93:681–766.

  15. Joo HR, Frank LM. The hippocampal sharp wave–ripple in memory retrieval for immediate use and consolidation. Nat Rev Neurosci. 2018;19:744–57.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Oliva A, Fernández-Ruiz A, Leroy F, Siegelbaum SA. Hippocampal CA2 sharp-wave ripples reactivate and promote social memory. Nature. 2020;587:264–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Clemens Z, Fabo D, Halasz P. Overnight verbal memory retention correlates with the number of sleep spindles. Neuroscience. 2005;132:529–35.

    Article  PubMed  CAS  Google Scholar 

  18. Wagner U, Kashyap N, Diekelmann S, Born J. The impact of post-learning sleep vs. wakefulness on recognition memory for faces with different facial expressions. Neurobiol Learn Mem. 2007;87:679–87.

    Article  PubMed  Google Scholar 

  19. Sawangjit A, Kelemen E, Born J, Inostroza M. Sleep enhances recognition memory for conspecifics as bound into spatial context. Front Behav Neurosci. 2017;11:28.

  20. Bin Ibrahim MZ, Benoy A, Sajikumar S. Long-term plasticity in the hippocampus: maintaining within and ‘tagging’between synapses. FEBS J. 2022;289:2176–201.

    Article  Google Scholar 

  21. Tudor JC, Davis EJ, Peixoto L, Wimmer ME, van Tilborg E, Park AJ, et al. Sleep deprivation impairs memory by attenuating mTORC1-dependent protein synthesis. Sci Signal. 2016;9:ra41

    Article  PubMed  PubMed Central  Google Scholar 

  22. Dasgupta A, Baby N, Krishna K, Hakim M, Wong YP, Behnisch T, et al. Substance P induces plasticity and synaptic tagging/capture in rat hippocampal area CA2. Proc Natl Acad Sci. 2017;114:E8741–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Benoy A, Bin Ibrahim MZ, Behnisch T, Sajikumar S. Metaplastic reinforcement of long-term potentiation in hippocampal area CA2 by cholinergic receptor activation. J Neurosci. 2021;41:9082–98.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Simons SB, Caruana DA, Zhao M, Dudek SM. Caffeine-induced synaptic potentiation in hippocampal CA2 neurons. Nat Neurosci. 2012;15:23–5.

    Article  CAS  Google Scholar 

  25. Alhaider IA, Aleisa AM, Tran TT, Alzoubi KH, Alkadhi KA. Chronic caffeine treatment prevents sleep deprivation-induced impairment of cognitive function and synaptic plasticity. Sleep. 2010;33:437–44.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Chevaleyre V, Siegelbaum SA. Strong CA2 pyramidal neuron synapses define a powerful disynaptic cortico-hippocampal loop. Neuron. 2010;66:560–72.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Zhao M, Choi YS, Obrietan K, Dudek SM. Synaptic plasticity (and the lack thereof) in hippocampal CA2 neurons. J Neurosci. 2007;27:12025–32.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Caruana DA, Dudek SM. Adenosine A1 receptor-mediated synaptic depression in the developing hippocampal area CA2. Front Synaptic Neurosci. 2020;12:21.

  29. Florian C, Vecsey CG, Halassa MM, Haydon PG, Abel T. Astrocyte-derived adenosine and A1 receptor activity contribute to sleep loss-induced deficits in hippocampal synaptic plasticity and memory in mice. J Neurosci. 2011;31:6956–62.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Redondo RL, Okuno H, Spooner PA, Frenguelli BG, Bito H, Morris RG. Synaptic tagging and capture: differential role of distinct calcium/calmodulin kinases in protein synthesis-dependent long-term potentiation. J Neurosci. 2010;30:4981–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Sajikumar S, Navakkode S, Sacktor TC, Frey JU. Synaptic tagging and cross-tagging: the role of protein kinase Mζ in maintaining long-term potentiation but not long-term depression. J Neurosci. 2005;25:5750–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Impey S, Obrietan K, Storm DR. Making new connections: role of ERK/MAP kinase signaling in neuronal plasticity. Neuron. 1999;23:11–4.

    Article  PubMed  CAS  Google Scholar 

  33. Roth TL, Sweatt JD. Rhythms of memory. Nat Neurosci. 2008;11:993–4.

    Article  PubMed  CAS  Google Scholar 

  34. Panagiotou M, Meijer M, Meijer JH, Deboer T. Effects of chronic caffeine consumption on sleep and the sleep electroencephalogram in mice. J Psychopharmacol. 2019;33:122–31.

    Article  PubMed  CAS  Google Scholar 

  35. Reichert CF, Deboer T, Landolt HP. Adenosine, caffeine, and sleep–wake regulation: state of the science and perspectives. J sleep Res. 2022;31:e13597.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Moura PJ, Gimenes-Júnior JA, Valentinuzzi VS, Xavier GF. Circadian phase and intertrial interval interfere with social recognition memory. Physiol Behav. 2009;96:51–6.

    Article  PubMed  CAS  Google Scholar 

  37. Lopez-Rojas J, de Solis CA, Leroy F, Kandel ER, Siegelbaum SA. A direct lateral entorhinal cortex to hippocampal CA2 circuit conveys social information required for social memory. Neuron. 2022;110:1559–72.e4.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Qin H, Fu L, Jian T, Jin W, Liang M, Li J, et al. REM sleep-active hypothalamic neurons may contribute to hippocampal social-memory consolidation. Neuron. 2022;110:4000–14.e6.

    Article  PubMed  CAS  Google Scholar 

  39. Bin Ibrahim MZ, Goh L, Koh N, Polepalli JS, Behnisch T, Sajikumar S. Hippocampal CA2 to CA1: A metaplastic switch for memory encoding. Proc Natl Acad Sci. 2025;122:e2505936122.

    Article  Google Scholar 

  40. Prediger RD, Takahashi RN. Modulation of short-term social memory in rats by adenosine A1 and A2A receptors. Neurosci Lett. 2005;376:160–5.

    Article  PubMed  CAS  Google Scholar 

  41. Ochiishi T, Saitoh Y, Yukawa A, Saji M, Ren Y, Shirao T, et al. High level of adenosine A1 receptor-like immunoreactivity in the CA2/CA3a region of the adult rat hippocampus. Neuroscience. 1999;93:955–67.

    Article  PubMed  CAS  Google Scholar 

  42. Wu C, Wong T, Wu X, Sheppy E, Zhang L. Adenosine as an endogenous regulating factor of hippocampal sharp waves. Hippocampus. 2009;19:205–20.

    Article  PubMed  CAS  Google Scholar 

  43. Muñoz M-D, Solís JM. Characterisation of the mechanisms underlying the special sensitivity of the CA2 hippocampal area to adenosine receptor antagonists. Neuropharmacology. 2019;144:9–18.

    Article  PubMed  Google Scholar 

  44. Angelucci ME, Cesário C, Hiroi RH, Rosalen PL, Da Cunha C. Effects of caffeine on learning and memory in rats tested in the Morris water maze. Braz J Med Biol Res. 2002;35:1201–8.

    Article  PubMed  CAS  Google Scholar 

  45. Kopf SR, Melani A, Pedata F, Pepeu G. Adenosine and memory storage. Psychopharmacology. 1999;146:214–9.

    Article  PubMed  CAS  Google Scholar 

  46. Fredholm BB, Jonzon B, Lindström K. Effect of adenosine receptor agonists and other compounds on cyclic AMP accumulation in forskolin-treated hippocampal slices. Naunyn-Schmiedebergs Arch Pharmacol. 1986;332:173–8.

  47. Fredholm BB, Bättig K, Holmén J, Nehlig A, Zvartau EE. Actions of caffeine in the brain with special reference to factors that contribute to its widespread use. Pharmacol Rev. 1999;51:83–133.

    Article  PubMed  CAS  Google Scholar 

  48. Nehlig A, Daval J-L, Debry G. Caffeine and the central nervous system: mechanisms of action, biochemical, metabolic and psychostimulant effects. Brain Res Rev. 1992;17:139–70.

    Article  PubMed  CAS  Google Scholar 

  49. Ferré S. An update on the mechanisms of the psychostimulant effects of caffeine. J Neurochem. 2008;105:1067–79.

    Article  PubMed  Google Scholar 

  50. Endo M. Calcium release from the sarcoplasmic reticulum. Physiol Rev. 1977;57:71–108.

    Article  PubMed  CAS  Google Scholar 

  51. Halassa MM, Florian C, Fellin T, Munoz JR, Lee SY, Abel T, et al. Astrocytic modulation of sleep homeostasis and cognitive consequences of sleep loss. Neuron. 2009;61:213–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Granado N, Ortiz O, Suárez LM, Martín ED, Ceña V, Solís JM, et al. D1 but not D5 dopamine receptors are critical for LTP, spatial learning, and LTP-Induced arc and zif268 expression in the hippocampus. Cereb Cortex. 2007;18:1–12.

    Article  PubMed  Google Scholar 

  53. Dale E, Pehrson AL, Jeyarajah T, Li Y, Leiser SC, Smagin G, et al. Effects of serotonin in the hippocampus: how SSRIs and multimodal antidepressants might regulate pyramidal cell function. CNS Spectr. 2016;21:143–61.

    Article  PubMed  Google Scholar 

  54. Cui Z, Gerfen CR, Young WS. 3rd, Hypothalamic and other connections with dorsal CA2 area of the mouse hippocampus. J Comp Neurol. 2013;521:1844–66.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Ihara N, Ueda S, Kawata M, Sano Y. Immunohistochemical demonstration of serotonin-containing nerve fibers in the mammalian hippocampal formation. Cells Tissues Organs. 1988;132:335–46.

    Article  CAS  Google Scholar 

  56. Rey CC, Robert V, Bouisset G, Loisy M, Lopez S, Cattaud V, et al. Altered inhibitory function in hippocampal CA2 contributes in social memory deficits in Alzheimer’s mouse model. Iscience. 2022;25:103895.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Parhizkar S, Gent G, Chen Y, Rensing N, Gratuze M, Strout G, et al. Sleep deprivation exacerbates microglial reactivity and Aβ deposition in a TREM2-dependent manner in mice. Sci Transl Med. 2023;15:eade6285.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Funding

This work was supported by the NUHS Seed Fund (NUHSRO/2024/089/T1/Seed-Mar24/02) and the Ministry of Health (MOH-000641-00 and MOH-001883-00) awarded to SS, the NUHS Seed Fund (NUHSRO/2024/084/RO5 + 6/Seed-Mar24/04) awarded to L-WW and the National University of Singapore (NUS) Research Scholarship awarded to MZBI.

Author information

Authors and Affiliations

  1. Department of Physiology, National University of Singapore, Singapore City, Singapore

    Lik-Wei Wong, Mohammad Zaki Bin Ibrahim, Aiswaria Lekshmi Kannan & Sreedharan Sajikumar

  2. Life Sciences Institute Neurobiology Programme, National University of Singapore, Singapore City, Singapore

    Lik-Wei Wong, Mohammad Zaki Bin Ibrahim, Aiswaria Lekshmi Kannan & Sreedharan Sajikumar

  3. Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore City, Singapore

    Lik-Wei Wong, Mohammad Zaki Bin Ibrahim & Sreedharan Sajikumar

Authors
  1. Lik-Wei Wong
    View author publications

    Search author on:PubMed Google Scholar

  2. Mohammad Zaki Bin Ibrahim
    View author publications

    Search author on:PubMed Google Scholar

  3. Aiswaria Lekshmi Kannan
    View author publications

    Search author on:PubMed Google Scholar

  4. Sreedharan Sajikumar
    View author publications

    Search author on:PubMed Google Scholar

Contributions

L-WW and SS conceptualized the idea for the manuscript. L-WW, MZBI and ALK performed experiments. L-WW wrote the first draft. L-WW, MZBI and SS edited, read and then approved the final manuscript.

Corresponding authors

Correspondence to Lik-Wei Wong or Sreedharan Sajikumar.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wong, LW., Bin Ibrahim, M.Z., Kannan, A.L. et al. Caffeine reverses sleep deprivation-induced synaptic and social memory deficits via adenosine receptor modulation in the male mouse hippocampal CA2 region. Neuropsychopharmacol. (2026). https://doi.org/10.1038/s41386-026-02362-w

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Version of record:

  • DOI: https://doi.org/10.1038/s41386-026-02362-w

Search

Advanced search

Quick links