Toll-like receptor 3 inhibits memory retention and constrains adult hippocampal neurogenesis

Eitan Okun, Kathleen Griffioen, Boaz Barak, Nicholas J. Roberts, Kamilah Castro, Mario A. Pita, Aiwu Cheng, Mohamed R. Mughal, Ruiqian Wan, Uri Ashery, Mark P. Mattson

Research output: Contribution to journalArticlepeer-review

162 Scopus citations


Toll-like receptors (TLRs) are innate immune receptors that have recently emerged as regulators of neuronal survival and developmental neuroplasticity. Adult TLR3-deficient mice exhibited enhanced hippocampus-dependent working memory in the Morris water maze, novel object recognition, and contextual fear-conditioning tasks. In contrast, TLR3-deficient mice demonstrated impaired amygdala related behavior and anxiety in the cued fear-conditioning, open field, and elevated plus maze tasks. Further, TLR3-deficient mice exhibited increased hippocampal CA1 and dentate gyrus volumes, increased hippocampal neurogenesis, and elevated levels of the AMPA receptor subunit GluR1 in the CA1 region of the hippocampus. In addition, levels of activated forms of the kinase ERK and the transcription factor CREB were elevated in the hippocampus of TLR3-deficient mice, suggesting that constitutive TLR3 signaling negatively regulates pathways known to play important roles in hippocampal plasticity. Direct activation of TLR3 by intracerebroventricular infusion of a TLR3 ligand impaired working memory, but not reference memory. Our findings reveal previously undescribed roles for TLR3 as a suppressor of hippocampal cellular plasticity and memory retention.

Original languageEnglish
Pages (from-to)15625-15630
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number35
StatePublished - 31 Aug 2010
Externally publishedYes


FundersFunder number
National Institute on AgingZIAAG000330


    • Anxiety
    • CREB
    • Cognition
    • GluR1


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