TLR 3 downregulates expression of schizophrenia gene Disc1 via MYD 88 to control neuronal morphology

Abstract

Viral infection during fetal or neonatal stages increases the risk of developing neuropsychiatric disorders such as schizophrenia and autism spectrum disorders. Although neurons express several key regulators of innate immunity, the role of neuronal innate immunity in psychiatric disorders is still unclear. Using cultured neurons and in vivo mouse brain studies, we show here that Toll‐like receptor 3 (TLR3) acts through myeloid differentiation primary response gene 88 (MYD88) to negatively control Disrupted in schizophrenia 1 (Disc1) expression, resulting in impairment of neuronal development. Cytokines are not involved in TLR3‐mediated inhibition of dendrite outgrowth. Instead, TLR3 signaling suppresses expression of several psychiatric disorder‐related genes, including Disc1. The impaired dendritic arborization caused by TLR3 activation is rescued by MYD88 deficiency or DISC1 overexpression. In addition, TLR3 activation at the neonatal stage increases dendritic spine density, but narrows spine heads at postnatal day 21 (P21), suggesting a long‐lasting effect of TLR3 activation on spinogenesis. Our study reveals a novel mechanism of TLR3 in regulation of dendritic morphology and provides an explanation for how environmental factors influence mental health.

The family of the interleukin‐1 receptors

“…Even TLR3, hitherto the exception of the rule reported to be only one using TRIF as an adapter, seems to employ MyD88 to negatively control the expression of psychiatric disorder-related genes such as Disc1 (Disrupted in schizophrenia 1) in neurons. 315 Interestingly, the molecular mechanism coupling TLR3 to downstream signaling elements via MyD88 does not seem to be through the classical TIR:TIR domain interaction, but rather depends on the N-terminal death domain of MyD88 in a novel and yet unresolved mode. 315 TLRs and members of the IL-1R family can activate very similar signaling pathways (reviewed in 298), which are partially conserved in invertebrates and vertebrates.…”

“…315 Interestingly, the molecular mechanism coupling TLR3 to downstream signaling elements via MyD88 does not seem to be through the classical TIR:TIR domain interaction, but rather depends on the N-terminal death domain of MyD88 in a novel and yet unresolved mode. 315 TLRs and members of the IL-1R family can activate very similar signaling pathways (reviewed in 298), which are partially conserved in invertebrates and vertebrates. 316 As discussed above, this is due to the fact that the activated TIR-containing receptors create intracellularly the TIR:TIR scaffold required for recruiting MyD88 (or, in the case of TLR, TRIF), which is the prerequisite for downstream signaling.…”

Toll-like receptor 3 activation impairs excitability and synaptic activity via TRIF signalling in immature rat and human neurons

“…oligodendrocytes (Okun et al, 2011) with its activation shown to negatively regulate axonal growth, reduce neural precursor cell proliferation and contribute to the long term CNS effects associated with maternal viral infection including Zika virus-induced microcephaly (Cameron et al, 2007;Lathia et al, 2008;Reisinger et al, 2015;Faizan et al, 2016;Chen et al, 2017). In addition, TLR3 was also revealed to regulate spinal cord synaptic transmission and central sensitisation, thus highlighting its critical role in pruritus (Liu et al, 2012).…”

Synaptic Formation, Neural Circuits and Neurodevelopmental Disorders Controlled by Signaling, Translation, and Epigenetic Regulation

“…Maternal immune activation increases the likelihood of offspring developing schizophrenia and ASD via both innate and adaptive immune responses (Choi et al, 2016;Filiano et al, 2016;Kugelberg, 2016;Wu et al, 2017). In addition to peripheral immune responses, neurons can also use their own Toll-like receptors to detect environmental insults and control growth of their axons, dendrites and synapses (Liu et al, 2013;Chen et al, 2017;Hung et al, 2018). Thus, both the peripheral immune system and neuronal responses are involved in the impacts of infection on neurodevelopmental disorders at early developmental stages (Figure 1).…”