Autism is a neurodevelopmental disorder characterized by impairments in social communication and interaction and by repetitive patterns of behaviour, interests and activities. It is perhaps the most common and handicapping neurological disorder of childhood and as such represents a significant public health problem and a huge burden for education and social service systems. Currently there is no diagnostic test or cure available for autism and the molecular mechanisms underlying autistic behaviour remain to be elucidated. Mutations in genes linked to autism adversely affect molecules involved in synapse development and plasticity including brain-derived neurotrophic factor receptor (TrkB) and its downstream effector mammalian target of rapamycin (mTOR), which is increased in several forms of syndromic autism. Here, we investigated whether TrkB, mTOR and their signaling pathways are disrupted in postmortem brain tissue from subjects with idiopathic autism, that is, cases of autism without a known genetic cause and thought to be of environmental/epigenetic origin. We next further examined the contribution of defective TrkB signaling to autistic behaviour in mice exposed to the histone deacetylase inhibitor valproic acid (VPA), a well-established model of environmental/epigenetic origin of autism. We found that TrkB signaling pathways were reduced in idiopathic autism and that these disruptions were associated with decreased excitatory postsynaptic marker PSD-95, suggesting fewer excitatory synapses. Moreover, we showed that similar molecular deficits were present in VPA-exposed mice that lacked sociability and displayed increased repetitive, stereotyped behaviour. We also determined that behavioural deficits in these mice were rescued by administration of the partial TrkB agonist LM22A-4 but not by treatment with the active tripeptide fragment of the insulin-like growth factor-1, (1-3)IGF-1. Lastly, reduced TrkB signaling in VPA-exposed mice was normalized by LM22A-4 administration combined with behavioural enrichment. The present work provides a better understanding of the molecular mechanisms that contribute to autistic behaviour and implicates TrkB signaling in autism pathogenesis. Furthermore, these data demonstrate that molecular changes observed in brains of patients with idiopathic autism differ from syndromic forms and highlight that both too much and too little signaling can be equally disruptive. The present work also shows that maternal challenge with VPA resulted in social deficits, increased repetitive, restrictive behaviour and reduced TrkB signaling in mice, pointing to epigenetic modifications as a potential underlying mechanism of molecular and behavioural disruptions in autism. Lastly, these findings suggest that pharmacological activation of TrkB using compounds such as the partial TrkB agonist LM22A-4 might play a role in treating sociability and repetitive, perseverative behaviour in autism. / Thesis / Doctor of Philosophy (PhD)