Toll-like receptor 3 inhibits memory retention and constrains adult hippocampal neurogenesis.
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.
Okun
Eitan
E
Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
Griffioen
Kathleen
K
Barak
Boaz
B
Roberts
Nicholas J
NJ
Castro
Kamilah
K
Pita
Mario A
MA
Cheng
Aiwu
A
Mughal
Mohamed R
MR
Wan
Ruiqian
R
Ashery
Uri
U
Mattson
Mark P
MP
D000679:Amygdala / Q000166:cytology / Q000502:physiology; D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation; D003213:Conditioning, Psychological / Q000502:physiology; D003463:Cues; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D018891:Dentate Gyrus / Q000166:cytology / Q000254:growth & development / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D005239:Fear / Q000502:physiology; D005260:Female; D006624:Hippocampus / Q000166:cytology / Q000254:growth & development / Q000502:physiology*; D007276:Injections, Intraventricular; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008568:Memory / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000502:physiology; D055495:Neurogenesis; D009473:Neuronal Plasticity / Q000502:physiology*; D011070:Poly I-C / Q000008:administration & dosage / Q000494:pharmacology; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D017362:Cyclic AMP Response Element-Binding Protein; D048049:Extracellular Signal-Regulated MAP Kinases; D011070:Poly I-C; D018091:Receptors, AMPA; D051196:Toll-Like Receptor 3