The role of the endocannabinoid system in neuronal alterations and behavioural responding in the valproic acid model of autism
Thornton, Aoife M.
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Autism is a neurodevelopmental disorder which affects 1 in 54 children. Prenatal exposure to the antiepileptic drug valproic acid (VPA) is associated with an increased risk of autism. Similarly, prenatal exposure of rodents to VPA results in behavioural and neurobiological alterations that are similar to those observed clinically. The endocannabinoid system (ECS) mediates and modulates social and emotional processes and is altered in the VPA model. Furthermore, targeting the ECS has proven effective at reversing behavioural alterations in VPA-exposed rats. The data presented in this thesis demonstrate that VPA alters the proliferation of embryonic neural stem cells in vitro and show a role for the ECS and the immune mediator IL-1β in modulating the effects of VPA. These data provide insight into how in utero VPA exposure may alter neural development of the foetal brain and give rise to the behavioural symptoms associated with autism. Given that symptoms associated with autism show sexual dimorphism, this thesis then went on to examine the effects of prenatal VPA exposure on behavioural responses of male and female rats during adolescence. The data confirm sexual dimorphic behaviour in the VPA model with VPA-exposed male adolescent rats exhibiting social deficits in several paradigms while VPA-exposed female adolescent rats exhibit anxiety-like behaviour. These behavioural changes were associated with sexually dimorphic changes in the ECS, with male, but not female, rats prenatally exposed to VPA exhibiting enhanced hippocampal levels of the endocannabinoid anandamide (AEA) post social exposure. Previous data have demonstrated that acute enhancement of AEA tone reverses social impairments in VPA-exposed male rats. This thesis examined the effects of chronic increases in AEA tone and found that this did not alter social or other behavioural traits in VPA-exposed male rats. The effects of increasing 2-AG tone on social responding were also examined and found that acute, but not chronic, increases in 2-AG tone enhances social novelty preference in VPA-exposed male rats. Thus, acute but not sustained increases in AEA or 2-AG may be of benefit in the management of social impairments in males with autism. In comparison, in female VPA-exposed rats, the data revealed that acutely increasing AEA or 2-AG tone did not induce any beneficial effects on negative affective behaviour in VPA-exposed female rats, but rather increased anxiety- and despair-like behaviour. These data highlight the sexual dimorphic effects of enhancing endocannabinoid tone on behavioural responding associated with autism. Finally, as VPA-exposed female adolescent rats do not exhibit social impairments under normal testing conditions, and because anecdotal evidence indicates that social behaviour impairments are observed in female autistic individuals post viral infection, the effect of a viral immune challenge on inflammatory and behavioural responses in VPA-exposed female rats was examined. These data demonstrated that a viral immune challenge induces social deficits in VPA-, but not saline-, exposed female rats, an effect associated with a blunted TNF-α response in the hypothalamus and amygdala. Furthermore, FAAH inhibition and increasing AEA tone partially attenuated TLR3-mediated hyperthermia and social deficit in VPA-exposed female rats. These data indicate that a viral immune challenge uncovers social deficits in VPA-exposed female rats, an effect that can be modulated by enhancing AEA tone similar to that observed in male counterparts. In conclusion, the data herein have enhanced our knowledge on the role of the ECS in mediating neuronal alterations and behavioural responding in vitro and in vivo in the VPA rodent model of autism. These data may have important implications for understanding the neurobiology underling autism, the development of potential biomarkers and the use of cannabinoid-based therapies for the management of symptoms associated with autism.
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