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

Abstract

Toll like receptor 3 (TLR3) belongs to a family of pattern recognition receptors that recognise molecules found on pathogens referred to as pathogen associated molecular patterns (PAMPs). Its involvement in innate immunity is well known but despite its presence in the central nervous system (CNS), our knowledge of its function is limited. Here, we have investigated whether TLR3 activation modulates synaptic activity in primary hippocampal cultures and induced pluripotent stem cell (iPSC)-derived neurons. Synaptically driven spontaneous action potential (AP) firing was significantly reduced by the TLR3 specific activator, poly I:C, in a concentration-dependent manner following both short (5 min) and long exposures (1h) in rat hippocampal cultures. Notably, the consequence of TLR3 activation on neuronal function was reproduced in iPSC-derived cortical neurons, with poly I:C (25 μg/ml, 1h) significantly inhibiting sAP firing. We examined the mechanisms underlying these effects, with poly I:C significantly reducing peak sodium current, an effect dependent on the MyD88-independent TRIF dependent pathway. Furthermore, poly I:C (25 μg/ml, 1h) resulted in a significant reduction in miniature excitatory postsynaptic potential (mEPSC) frequency and amplitude and significantly reduced surface AMPAR expression. These novel findings reveal that TLR3 activation inhibits neuronal excitability and synaptic activity through multiple mechanisms, with this being observed in both rat and human iPSC-derived neurons. These data might provide further insight into how TLR3 activation may contribute to neurodevelopmental disorders following maternal infection and in patients with increased susceptibility to herpes simplex encephalitis.

Interleukin-16 inhibits sodium channel function and GluA1 phosphorylation via CD4- and CD9-independent mechanisms to reduce hippocampal neuronal excitability and synaptic activity

“…In agreement with our previous studies, IL-16 levels were elevated in LCM compared to hippocampal media controls, with other cytokine levels being below detectable levels (Shresha et al, 2014;Ritchie et al, 2018). Hence, we utilised rIL-16 at these quantified levels to examine the consequence of IL-16 exposure on neuronal excitability and synaptic activity in order to give us further insight into the role of IL-16 in modulating CNS function.…”

Compromised Hippocampal Neuroplasticity in the Interferon-α and Toll-like Receptor-3 Activation-Induced Mouse Depression Model

“…5e) [F(3,18) = 3.96; p = 0.025]. Since action potential threshold and frequency are dependent on Na + channels [20], we conclude that these results suggest that IFN-α and poly(I:C) impair neuronal excitability by reducing Na + channel functionality.…”

Molecular immune mechanisms of HPV‐infected HaCaT cells in vitro based on toll‐like receptors signaling pathway

“…There are many signaling pathways that can activate IFN. In the TLRs-IKK e-IRFs-IFN signaling pathway, TLR combines with pathogen-associated molecular patterns (PAMPs) to induce inflammatory response to eliminate pathogen infection, PAMP and IRF3 mediate to induce IFN expression 19 ; IKKε/TBK1 is an IKK-related activator, both of which participate in regulating IRF and play a role in IRF signaling pathway, phosphorylating IRF3 and IRF7, and activating IRF3 Function. 20 In this study, after inhibiting TLR3 and TLR9, the expression of TRAF3, IKK epsilon, and TBK1 decreased, suggesting that TLR3 and TLR9 can affect IKK epsilon signaling pathway, and TLR3 and TLR9 can inhibit the expression of IKK epsilon.…”