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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)

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Essential hypertension is the leading contributor to premature death worldwide. Endoplasmic reticulum (ER) stress has recently been implicated in diseased blood vessels and hypertension. It is unclear whether ER stress is a cause or a consequence of hypertension. We hypothesized that ER stress inhibition would prevent the development of hypertension in the young spontaneously hypertensive rat (SHR) by improving vascular structure and function. The SHR was used as a genetic model of human essential hypertension, and the Wistar Kyoto (WKY) rat as its normotensive control. The first study conducted involved assessing the levels of ER stress in young SHRs, before they developed hypertension. The second study conducted involved treating rats with 1g/kg/day of the sodium salt of 4-phenylbutyric acid (4-PBA) orally for 8 weeks from 5 weeks of age. Blood pressure was measured weekly, noninvasively via radiotelemetry. Mesenteric arteries were collected at sacrifice. Finally, the third study conducted involved treating rats with 1g/kg/day 4-PBA orally for eight weeks from five weeks of age, and then withdrawing the drug for four weeks to determine if drug treatment created a sustained lowering of blood pressure. In the first study, ER stress markers were observed to be significantly increased in the young SHR when compared to the WKY. In the second study, blood pressure was observed to be significantly lower in the 4-PBA-treated SHR groups than in the untreated SHRs. In addition, mesenteric arteries from the 4-PBA treated SHRs had a significant decrease in media/lumen ratio, ER stress marker expressions, as well as improved vasodilatory response to carbachol and reduced contractile responses to phenylephrine. In the third study, 4-PBA was able to keep the blood pressure low for one week after withdrawal, however, blood pressure returned to similar levels as untreated SHRs by the end of three weeks. Overall, ER stress inhibition, via 4-PBA, blunted the development of hypertension in the SHR. / Thesis / Master of Science (MSc)