Elsevier

Brain, Behavior, and Immunity

Volume 37, March 2014, Pages 142-151
Brain, Behavior, and Immunity

Sarm1, a neuronal inflammatory regulator, controls social interaction, associative memory and cognitive flexibility in mice

https://doi.org/10.1016/j.bbi.2013.12.002Get rights and content

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Abstract

Impaired neurodevelopment leads to several psychiatric disorders, including autism, schizophrenia and attention deficiency hyperactivity disorder. Our prior study showed that sterile alpha and TIR motif-containing 1 protein (Sarm1) regulates neuronal morphogenesis through at least two pathways. Sarm1 controls neuronal morphogenesis, including dendritic arborization, axonal outgrowth and establishment of neuronal polarity, through the MKK–JNK pathway. Neuronally expressed Sarm1 also regulates the expression of inflammatory cytokines in the brain, which have also been shown to impact brain development and function. Because the reduction of Sarm1 expression negatively influences neuronal development, here we investigated whether Sarm1 controls mouse behaviors. We analyzed two independent Sarm1 transgenic mouse lines using a series of behavioral assays, and found that the reduction of Sarm1 protein levels had a limited effect on locomotion and anxiety. However, Sarm1 knockdown mice exhibited impairments in cued and contextual fear conditioning as well as cognitive flexibility. Moreover, the three-chambered social test, reciprocal social interaction and social transmission of food preference further illustrated deficiencies in Sarm1 knockdown mice in social interaction. These findings suggest that Sarm1, a molecule that regulates innate immunity and neuronal morphogenesis, regulates social behaviors and cognition. We conclude that Sarm1 is involved in immune response, neural development and psychiatric disorders.

Introduction

Neurodevelopmental disorders, including autism and schizophrenia, are complex neuropsychiatric diseases (Arnold and Trojanowski, 1996, Ehninger et al., 2008, Walsh et al., 2008). Both environmental factors and genetic deficits contribute to the pathogenesis of such disorders. The most well-known environmental factor is prenatal immune challenge caused by infection. Robust cytokine production induced by the innate immune response is believed to affect neural development and lead to several neurodevelopmental disorders (Baharnoori et al., 2009, Malkova et al., 2012, Patterson, 2009). Key components of innate immune responses, such as toll-like receptors (TLRs) and inflammatory cytokines, were recently found to be involved in regulating neural function and differentiation. For example, both interleukin (IL)-6 and IL-10 are involved in infection-induced schizophrenia in mice (Deverman and Patterson, 2009, Meyer et al., 2008, Smith et al., 2007), and IL-1ß, IL-6 and tumor necrosis factor (TNF)-α inhibit dendrite outgrowth in rat cortical neurons (Gilmore et al., 2004). The TLRs are expressed in neurons and modulate neural development. For example, TLR2, TLR3 and TLR4 regulate embryonic or adult hippocampal neurogenesis (Lathia et al., 2008, Rolls et al., 2007). TLR3, TLR7 and TLR8 negatively regulate neurite outgrowth (Cameron et al., 2007, Liu et al., 2013, Ma et al., 2006). TLR3 also affects memory retention (De Miranda et al., 2010, Okun et al., 2010). The prenatal administration of polyinosinic/polycytidylic (poly I:C), which is synthetic double strand RNA ligand of TLR3, also disturbs mouse behaviors later in adult life (Deverman and Patterson, 2009, Patterson, 2009).

Sterile alpha and TIR motif containing 1 (Sarm1), an evolutionarily conserved adaptor protein, interacts with different proteins that regulate signaling pathways that are involved in diverse cellular functions. Sarm1 has a Toll/Interleukin-1 receptor (TIR)-domain, and as such has been identified as the fifth member of the myeloid differentiation primary response gene 88 (MyD88) family and functions as a negative regulator of TLR3/TLR4 signaling in the TIR-domain-containing adapter-inducing interferon-β (TRIF)-dependent signaling pathway (Carty et al., 2006, Mink et al., 2001). Sarm1 is preferentially expressed by neurons in the brain (Chen et al., 2011, Kim et al., 2007), and its deficiency leads to a reduction in the level of TNF-α expression in the brainstem following infection with the West Nile virus (Szretter et al., 2009), demonstrating a role for Sarm1 in neuronal immune response. Even without viral infection, the knockdown of Sarm1 in mice alters the expression of inflammatory and antiviral cytokines in mouse brains (Lin et al., 2013). In cultured hippocampal neurons, Sarm1 regulates neuronal morphogenesis at multiple levels, including acting downstream of syndecan-2 in controlling dendritic arborization and regulating axonal outgrowth and neuronal polarity (Chen et al., 2011). In brains, knockdown of Sarm1 reduces the dendritic arbors of neurons and brain sizes (Chen et al., 2011), further supporting the role of Sarm1 in brain development.

Because Sarm1 regulates neuroinflammation and neuronal morphogenesis, both of which are critical in the pathogenesis of neurodevelopmental disorders, we hypothesized that Sarm1 may control cognitive behaviors. In a continuation of our prior research, in this study we analyzed the behaviors of Sarm1 knockdown transgenic mice by testing their performance in a series of standardized behavioral paradigms and demonstrated the roles of Sarm1 in associative learning, social behaviors and cognitive flexibility. Our findings demonstrate that a neuronal immune regulator can control cognition and social behaviors and therefore suggest that the innate immunity of neurons is involved in the etiology of psychiatric disorders.

Section snippets

Animals and behavioral analyses

All of the animal experiments were carried out with the approval of the Academia Sinica Institutional Animal Care and Utilization Committee. Sarm1 knockdown mice were generated in a C57BL/6J background (Chen et al., 2011). The animals used in the behavioral assays were the offspring of transgenic males and wild-type C57BL/6J females to rule out a maternal effect of Sarm1 knockdown on offspring behavior. Male mice were used for behavioral assays to avoid variations due to the estrus cycle. All

Sarm1 knockdown has a limited effect on locomotion and anxiety

The appearances of Sarm1 knockdown transgenic mice (Tg) showed no significant difference from their wild-type littermates (Fig. 1A). Although Sarm1 knockdown transgenic mice tended to be smaller and have slightly reduced body weight at the age of two months, the difference was not significant (Fig. 1A and B). After confirming that Sarm1 knockdown does not obviously affect gross development except for a 5–10% reduction of total brain weight (Chen et al., 2011), we then investigated whether any

Discussion

In this report, we have provided evidence that Sarm1 controls associative memory, cognitive flexibility and social interactions in mice. Taken together with our previous findings, we propose that Sarm1 knockdown causes these behavioral impairments through at least two different mechanisms. First, Sarm1 regulates neuromorphogenesis. Reduction of Sarm1 protein levels influences dendritic arborization, axon outgrowth and the establishment of neuronal polarity and dendritic spine density (Chen et

Acknowledgments

We thank Dr. Tzyy-Nan Huang for technical assistance and Ms. Miranda Loney for English editing. This work was supported by Grants from Academia Sinica (to Y.-P.H.) and the National Science Council (NSC 99-2321-B-001-032, 100-2321-B-001-022, 101-2321-B-001-010, 102-2321-B-001-029 and 102-2321-B-001-054 to Y.-P.H.).

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