Do toll-like receptor innate immune responses act via autism risk genes to alter neuronal morphology and function?
- Awarded: 2016
- Award Type: Explorer
- Award #: 388449
Autism spectrum disorders (ASD) are frequently associated with immune dysregulation. Peripheral immune responses and microglial function have been the major focus in the field. However, recent studies have suggested that neurons are also able to use their own innate immune receptors, including toll-like receptors (TLRs), to detect the danger signals derived from both endogenous cells and pathogens.
Yi-Ping Hsueh and others have demonstrated that activation of TLRs, such as TLR3, TLR7 and TLR8, negatively regulate neurite or dendritic outgrowth1, 2, 3. MYD88, c-FOS, and IL-6 have been shown to function downstream of TLR73, however, it is still unknown how TLR3 and TLR8 negatively regulate neuronal morphology.
The aim of this proposal is to elucidate the TLR3 and TLR8 signaling pathways in neurons. Preliminary studies suggest that TLR3 activation (achieved via polyinosinic:polycytidylic acid [poly I:C] treatment in cultured neurons) disrupts axonal and dendritic outgrowth through the MYD88 signaling pathway. Further, TLR3 activation leads to reduced expression of a number of ASD risk genes, including DISC1, AUTS2, FMR1 and UBE3A. Hsueh and her colleagues also found that rescuing DISC1 expression in poly I:C-treated neurons restores the dendritic growth phenotype. Combined, these data suggest that TLR3-mediated innate immune responses are mediated, at least in part, via alterations in ASD-risk genes.
The researchers will further assess this hypothesis by examining the involvement of MYD88 in the downregulation of DISC1, AUTS2, FMR1 and UBE3A expression induced by TLR3 activation. They will also study the rescue effect of overexpression of AUTS2, FMR1 and UBE3A on the morphological impairments caused by TLR3 activation. The proposed experiments will help elucidate roles played by the neuronal innate immune system in neuronal morphogenesis, and will further our understanding of how environmental immune challenges and autism risk genes may interact and contribute to ASD.