Regulatory effect of lithium on hippocampal blood-brain barrier integrity in a rat model of depressive-like behavior

Michal Taler, Ramona Aronovich, Shay Henry Hornfeld, Shira Dar, Efrat Sasson, Abraham Weizman, Eldar Hochman

Research output: Contribution to journalArticlepeer-review

30 Scopus citations


Objectives: Recent evidence has associated mood disorders with blood-brain barrier (BBB)/ neurovascular unit (NVU) dysfunction, and reduction in blood vessels coverage by the water channel aquaporin-4 (AQP4) immunoreactive astrocytes. Lithium is an established treatment for mood disorders, yet, its mechanism of action is partially understood. We investigated the effects of lithium on BBB integrity and NVU-related protein expression in chronic mild stress (CMS) rat model of depressive-like behavior. Methods: Male Wistar rats were exposed for 5 weeks to unpredictable mild stressors with daily co-administration of lithium chloride to half of the stressed and unstressed groups. Sucrose preference and open field tests were conducted to validate the depressive-like phenotype, and dynamic contrast-enhanced MRI analysis was utilized to assess BBB integrity in brain regions relevant to the pathophysiology of depression. Hippocampal AQP4 and claudin-5 expression were studied using immunofluorescence, western blot, and enzyme-linked immunosorbent assays. Results: Lithium administration to the stressed rats prevented the reductions in sucrose preference and distance traveled in the open field, and normalized the stress-induced hippocampal BBB hyperpermeability, whereas lithium administration to the unstressed rats increased hippocampal BBB permeability. Additionally, lithium treatment attenuated the decrease in hippocampal AQP4 to glial fibrillary acidic protein immunoreactivity ratio in the stressed rats and upregulated hippocampal claudin-5 and BDNF proteins expression. Conclusions: Our findings suggest that lithium administration in a rat CMS model of depressive-like behavior is associated with attenuation of stressed-induced hippocampal BBB/NVU disruption. These protective effects may be relevant to the mode of action of lithium in depression.

Original languageEnglish
Pages (from-to)55-65
Number of pages11
JournalBipolar Disorders
Issue number1
StatePublished - Feb 2021
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd


This research was supported by The Israel Science Foundation (Grant No. 2089/16 to Eldar Hochman) and by the Mordechai Ofer Foundation, Sackler Faculty of Medicine, Tel Aviv University (Grant No. 0601242342 to Eldar Hochman). The authors would like to thank Dr Ella Kaganovsky for her assistance in the immunofluorescence staining and Mr Joshua Satz for his help with the immunofluorescence analysis.

FundersFunder number
Mordechai Ofer Foundation
Israel Science Foundation2089/16
Sackler Faculty of Medicine, Tel-Aviv University0601242342


    • Lithium
    • aquaporin-4 (AQP4)
    • blood-brain barrier (BBB)
    • chronic mild stress (CMS)
    • claudin-5
    • neurovascular unit (NVU)


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