Deficient adolescent social behavior following early-life inflammation is ameliorated by augmentation of anandamide signaling

Abstract

Early-life inflammation has been shown to exert profound effects on brain development and behavior, including altered emotional behavior, stress responsivity and neurochemical/neuropeptide receptor expression and function. The current study extends this research by examining the impact of inflammation, triggered with the bacterial compound lipopolysaccharide (LPS) on postnatal day (P) 14, on social behavior during adolescence. We investigate the role that the endocannabinoid (eCB) system plays in sociability after early-life LPS. To test this, multiple cohorts of Sprague Dawley rats were injected with LPS on P14. In adolescence, rats were subjected to behavioral testing in a reciprocal social interaction paradigm as well as the open field. We quantified eCB levels in the amygdala of P14 and adolescent animals (anandamide and 2-arachidonoylglycerol) as well as adolescent amygdaloid cannabinoid receptor 1 (CB1) binding site density and the hydrolytic activity of the enzyme fatty acid amide hydrolase (FAAH), which metabolizes the eCB anandamide. Additionally, we examined the impact of FAAH inhibition on alterations in social behavior. Our results indicate that P14 LPS decreases adolescent social behavior (play and social non-play) in males and females at P40. This behavioral alteration is accompanied by decreased CB1 binding, increased anandamide levels and increased FAAH activity. Systemic administration of the FAAH inhibitor PF-04457845 (1mg/kg) prior to the social interaction task normalizes LPS-induced alterations in social behavior, while not affecting social behavior in the control group. Infusion of 10ng PF-04457845 into the basolateral amygdala normalized social behavior in LPS injected females. These data suggest that alterations in eCB signaling following postnatal inflammation contribute to impairments in social behavior during adolescence and that FAAH could be a novel target for disorders involving social deficits such as social anxiety disorders or autism.

Comorbid epilepsy in autism spectrum disorder: Implications of postnatal inflammation for brain excitability

“…PTZ acts via blockade of c-aminobutyric acid type A receptors, and previous work from our laboratory in rats has shown that there is a similar increase in susceptibility after a postnatal immune challenge at P14 to other convulsants such as kainic acid, which affect other receptors. 20 Whereas earlier work from our laboratory conducted in rats has not revealed sex-dependent effects of early LPS on emotional behaviors, 29,30 certain other neurological variables may differ. 31,32 The known sex-dependent differences in epilepsy 33 and ASD 34 mandated that we determine whether there are hormone-or sex-dependent influences on the interaction between postnatal inflammation and seizure susceptibility in this model.…”

“…Whereas earlier work from our laboratory conducted in rats has not revealed sex‐dependent effects of early LPS on emotional behaviors, certain other neurological variables may differ . The known sex‐dependent differences in epilepsy and ASD mandated that we determine whether there are hormone‐ or sex‐dependent influences on the interaction between postnatal inflammation and seizure susceptibility in this model.…”

Endocannabinoid Signaling in the Control of Social Behavior

“…These results provide evidence for a direct role of anandamide signaling in ASD-related social impairment. Recent reports have confirmed the corrective, prosocial effect of FAAH inhibition across a range of studied ASD-related insults, such as in developmental exposure to valproic acid [72] and lipopolysaccharide [73]. Inappropriate developmental exposure to cannabinoid agents, on the other hand, can also disrupt the later expression of social behavior.…”

Early Life Stress Activates Glial Cells in the Hippocampus but Attenuates Cytokine Secretion in Response to an Immune Challenge in Rat Pups

“…The OFT has also been used by other research groups to evaluate the behavior of adolescent rats [33,34]. The open field (OP) consisted of an acrylic square box (30 × 30 cm) and with 40-cm sides.…”