Toll-like receptor 3 inhibits memory retention and constrains adult hippocampal neurogenesis - PubMed (original) (raw)

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

Eitan Okun et al. Proc Natl Acad Sci U S A. 2010.

Abstract

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.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.

Fig. 1.

Hippocampus-dependent working memory is enhanced and amygdala-dependent memory is impaired in mice lacking TLR3. (A) TLR3+/+ (n = 16) and TLR3−/− (n = 16) mice show similar latencies to reach a visible platform in a nonspatial variant of the MWM. (B) TLR3+/+ and TLR3−/− mice exhibit similar learning rates, as measured by their escape latencies. (C) Whereas TLR3+/+ mice retain memory of the platform up to 72 h; TLR3−/− mice retain memory of the platform location up to 120 h posttraining. (D) TLR3−/− mice exhibit enhanced working memory acquisition compared with TLR3+/+ mice. As early as day 2 of the test, TLR3−/− show shorter latencies to find the platform in its new location. (E) No significant difference in total exploration during object familiarization between TLR3+/+ and TLR3−/− mice. (F) TLR3−/− mice exhibit significantly higher preference for a novel object than TLR3+/+ mice in the novel object recognition test. (G) TLR3+/+ and TLR3−/− mice show similar association curves in the fear-conditioning paradigm. (H) TLR3−/− mice exhibit significantly greater hippocampus-dependent contextual fear than TLR3+/+ mice, as measured by time freezing. (I) TLR3−/− mice exhibit slower contextual memory extinction than TLR3+/+ mice. (J) TLR3−/− mice exhibit impaired cued fear and freeze less than TLR3+/+ mice in the presence of tone.

Fig. 2.

Fig. 2.

TLR3−/− mice exhibit reduced anxiety-like behaviors. (A) TLR3−/− (n = 16) mice spend more time in the center of the arena compared with TLR3+/+ (n = 16) mice. (B) TLR3−/− mice cover less distance in the periphery of the arena compared with TLR3+/+ mice. (C) TLR3−/− mice cross more between the center and peripheral zones in an open field. (D) TLR3−/− mice spend more time than TLR3+/+ mice in the open arm in an elevated plus maze.

Fig. 3.

Fig. 3.

Loss of TLR3 alters hippocampal structure. (A) TLR3 is expressed in the CA1 in adult TLR3+/+ mice. (B_–_E) Cortical thickness (B), hippocampal volume (C and D), and hippocampal perimeter (E) were similar in TLR3+/+ (n = 6) and TLR3−/− (n = 6) mice. (F) TLR3−/− mice exhibit increased DG and CA1 volumes.

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