Abstract
Fragile X syndrome (FXS) is identified by abnormal dendrite morphology and altered synaptic protein expression. Astrocyte secreted factors such as Tenascin C (TNC), may contribute to the synaptic changes, including maturation of the synapse. TNC is a known endogenous ligand of toll-like receptor 4 (TLR4) that has been shown to induce the expression of pro-inflammatory cytokines such as interleukin-6 (IL-6). At the molecular level, elevated IL-6 promotes excitatory synapse formation and increases dendrite spine length. With these molecular changes linked to the phenotype of FXS, we examined the expression and the mechanism of the endogenous TLR4 activator TNC, and its downstream target IL-6 in astrocytes from the Fragile X Mental Retardation 1 (FMR1) knockout (KO) mouse model. Secreted TNC and IL-6 were significantly increased in FMR1 KO astrocytes. Addition of TNC and lipopolysaccharide (LPS) induced IL-6 secretion, whereas the antagonist of TLR4 (LPS-RS) had an opposing effect. Cortical protein expression of TNC and IL-6 were also significantly elevated in the postnatal FMR1 KO mouse. In addition, there was an increase in the number of vesicular glutamate transporter 1 (VGLUT1)/post synaptic density protein 95 (PSD95) positive synaptic puncta of both wild-type (WT) and FMR1 KO neurons when plated with astrocyte conditioned media (ACM) from FMR1 KO astrocytes, compared to those plated with media from wild type astrocytes. By assessing the cellular mechanisms involved, a novel therapeutic option could be made available to target abnormalities of synaptic function seen in FXS.
Highlights
Fragile X Syndrome (FXS) is the most common inherited form of autism which affects 1:4,000 males and 1:8,000 females (Hatton et al, 1998; Jin and Warren, 2000; Duy and Budimirovic, 2017)
In this study we investigated the developmental expression of Tenascin C (TNC), toll-like receptor 4 (TLR4) and IL-6 in cortical brain regions of WT and Fragile X Mental Retardation 1 (FMR1) KO mice, aged P1, P7, P14 and P21
We hypothesized that the levels of astrocyte derived TNC are dysregulated in the FMR1 KO mouse model, contributing to the elevated IL-6 levels, which may be responsible for the aberrant synaptic changes seen in Fragile X syndrome (FXS)
Summary
Fragile X Syndrome (FXS) is the most common inherited form of autism which affects 1:4,000 males and 1:8,000 females (Hatton et al, 1998; Jin and Warren, 2000; Duy and Budimirovic, 2017). The defects in individuals with FXS are attributed to the mutation in the Fragile X Mental Retardation 1 (FMR1) gene resulting from the expansion of the CGG untranslated region of the X chromosome (Jin and Warren, 2000). This expansion leads to the hypermethylation and silencing of the FMR1 gene, preventing the synthesis of the FMRP (Jin and Warren, 2000).
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