Toll-like receptors (TLRs) are a family of innate immune system receptors that respond to pathogen-derived and tissue damage-related ligands. TLR signaling in immune cells, glia and neurons may play roles in the pathogenesis of stroke, Alzheimer's disease and multiple sclerosis. Recent findings suggest that TLR signaling also influences multiple dynamic processes in the developing and adult central nervous system including neurogenesis, axonal growth and structural plasticity. In addition, TLRs are implicated in the regulation of behaviors including learning and memory, and anxiety. This review describes recently discovered and unexpected roles for TLRs in neuroplasticity, and the implications of these findings for future basic and translational research studies. Toll-Like ReceptorsToll-like receptors (TLRs) are transmembrane pattern-recognition receptors (PRRs) that initiate signals in response to diverse pathogen-associated molecular patterns (PAMPs) (1). The first Toll protein was discovered in Drosophila melanogaster, where it controls dorsoventral patterning (2). A mammalian homologue for Toll, TLR4, was later found to recognize bacterial lipopolysaccharide (LPS), a major cell wall component of gram-negative bacteria (3). Subsequently, many additional homologues have been identified across diverse species (for a comprehensive evolutionary overview, see (4)). Until recently, it was believed that while Drosophila Toll plays both immune and developmental roles, mammalian TLRs mediate immune responses of two kinds: 1) Orchestration of the immediate specific and global tissue response of the innate immune system to pathogens until the acquired immune response is fully functional. This orchestration is driven primarily by cytokine and chemokine production. 2) Facilitation of adaptive immunity by activating antigen-presenting cells such as macrophages and dendritic cells. Recent findings, however, suggest that mammalian TLRs also possess developmental roles during embryogenesis, as well as physiological and metabolic roles in adults. For example, TLR5-deficient mice exhibit hyperphagia and develop hallmark features of metabolic syndrome, including hyperlipidemia, hypertension, insulin resistance, and increased adiposity (5).TLRs are expressed in a variety of mammalian immune system-related cell types including B cells (6), mast cells (7), natural killer cells (8), regulatory T cells (9), macrophages, monocytes, dendritic cells (10), neutrophils (11) and basophils (12), as well as non-immune Corresponding author: Mark P. Mattson. mattsonm@grc.nia.nih.gov. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimer...

The key roles of toll-like receptors (TLRs) as mediators of the detection and responses of immune cells to invading pathogens are well known. There are at least 13 mammalian TLRs which are integral membrane proteins with a leucine-rich extracellular domain and a cytoplasmic domain similar to that of the interleukin-1 receptor which initiates downstream signaling through kinases to activate transcription factors such as AP-1 and NFκB. TLRs are activated in glial cells (microglia, astrocytes and oligodendrocytes) and lymphocytes that infiltrate the nervous system in response to inflammation caused by infectious agents, tissue injury or autoimmune conditions. By inducing the production of pro-inflammatory cytokines and cell adhesion molecules in immune cells, TLRs may indirectly damage neurons in conditions such as ischemic stroke and multiple sclerosis. Recent findings suggest that neurons also express a subset of TLRs and that their activation promotes neuronal degeneration in experimental models of stroke and Alzheimer's disease. TLRs may also play roles in regulating the processes of neurogenesis and neurite outgrowth, suggesting roles in neuronal plasticity. A better understanding of the molecular and cellular biology of TLRs in the normal and diseases nervous system, may lead to novel approaches for preventing neuronal degeneration and promoting recovery of function in an array of neurodegenerative conditions.

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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 amygdalarelated 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.oll-like receptors (TLRs) are innate immunity-related receptors that sense pathogen-associated molecular patterns (1) as well as tissue damage-associated molecular patterns (2). Although TLRs are abundant in the immune system, some TLRs are also expressed in central nervous system (CNS) cells where they mediate infection and injury responses (3). For example, activation of TLR4 by bacterial lipopolysaccharide up-regulates proinflammatory cytokine and chemokine production in microglia, and this TLR4 action on microglia is critical for the recruitment of circulating leukocytes into the brain (4). Neurons also express TLRs, and it was recently reported that activation of TLR2 and TLR4 in cortical neurons increases their vulnerability to ischemic injury (5). TLRs mediate innate immune responses, in part, through nuclear factor-κB (NF-κB) and IFN regulatory factor (IRF)-dependent pathways (3). Recent findings suggest that some TLRs modulate neural plasticity. For example, TLR3 inhibits neural progenitor cell (NPC) proliferation in the embryonic mouse telencephalon (6) and inhibits axonal growth in DRG neurons (7). More recently, Peltier et al. (8) found that human neurons are capable of a functional TLR3 signaling mechanism. Here we provide evidence that TLR3 signaling negatively regulates hippocampus-dependent learning and memory and suppresses hippocampal neurogenesis and AMPA receptor expression in CA1 neurons. We further show that constitutive physiological TLR3 signaling suppresses ERK and CREB activities, suggesting a mechanism whereby TLR3 regulates hippocampal neurogenesis and behavioral plasticity. Results TLR3 Deficiency Enhances Hippocampus-Dependent, but ImpairsAmygdala-Dependent, Learning and Memory. To determine whether TLR3 affects cognitive function, we compared spatial memo...