Blunted TLR3-induced inflammatory gene expression in the prefrontal cortex of the valproic acid model of autism, an effect unaltered by increasing endocannabinoid tone

Autism spectrum disorder (ASD) is associated with immune alterations and neuroinflammation. Increasing endocannabinoid tone attenuates ASD-related behavioural changes in rodent models and modulates Toll-like receptor (TLR)-induced neuro-immune responses. This study examined the effect of TLR3 activation, in the presence or absence of a fatty acid amide hydrolase (FAAH) inhibitor, on neuroinflammatory gene expression and endocannabinoid levels, in a preclinical rodent model of ASD. Female Sprague-Dawley rats prenatally exposed to either saline or valproic acid (VPA) received 1) the TLR3 agonist and viral mimetic polyI:C (3mg/kg) or saline-vehicle and were euthanised 4h later OR 2) the FAAH inhibitor PF3845 (10mg/kg) or vehicle, prior to polyI:C or saline-vehicle, and underwent testing for nociceptive (hot plate test) & social responding (3-chamber test) behaviour 24h later and euthanised immediately after. Endocannabinoid, N-acylethanolamine and inflammatory gene expression levels were assessed in the prefrontal cortex (PFC). PolyI:C increased pro-inflammatory gene expression in saline-exposed rats at 4h and 24h. At 4hrs, polyI:C-induced increases in Il-1β, Ccl2 and Cxcl10 expression were significantly lower in VPA- versus saline-exposed counterparts. At 24hrs, polyI:C-induced increases in expression of Cxcl10 and markers of pro-inflammatory astrocytes, Gfap and C3, were reduced in VPA- versus saline-exposed rats. PF3845 increased N-acylethanolamine levels but did not alter nociceptive responding, social behaviour or PFC inflammatory gene expression in polyI:C-treated saline- or VPA-exposed rats. In conclusion, VPA-exposed female rats exhibit blunted TLR3-induced inflammatory responses in the PFC, an effect unaltered by FAAH inhibition. These data confirm altered neuroimmune responding to a viral mimetic in this model of ASD.