A Brief Description of Currently Funded Research Grants 2012-2013
Role of dendritic spines in the processing, storage and integration of excitatory inputs on a murine model of Fragile-X mental retardation syndrome
Dr. Roberto Araya
Université de Montréal
Learning Mechanisms in Fragile X Syndrome Patients
Dr. Sarah Lippé
Dr. Anthony McIntosh
Proposed research plan: In this research program, we propose to use electrophysiology, a fast and non-invasive method, to investigate short-term learning in FXS and brain network development. As we have demonstrated in previous studies trial by trial repetition suppression and trial by trial changes incomplexity of the electrophysiological signal are highly sensitive measures of short term learning. We plan to test children, adolescents and adults with FXS compared to controls with avisual and auditory short-term learning task. FXS patients should show less trial by trial repetition suppression and less trial by trial complexity in the signal, suggesting altered shortterm learning capacities. Since short-term learning can cause brain network abnormal development, brain network connectivity will also be investigated. We expect brain network todevelop abnormally. Finally, participants will be tested on behavioural measures to quantify learning accuracy. Electrophysiological measures and behavioural measures will be related.
Anticipated outcomes: The alterations in learning mechanisms of FXS children are far from being understood. We expect short-term learning and brain network connectivity to be a highly sensitive measure oflearning deficits in FXS. We also expect short-term learning to explain brain network connectivity abnormalities and cognitive symptomatology. Showing this link will help inunderstanding FXS patients phenotypes and in understanding rehabilitation possibilities. Inaddition, our highly sensitive measure will provide a crucial tool to test for treatment outcome.
Projected benefits and application of findings: Benefits for the patient and application of the findings will take place in treatment possibilities and tools for testing its efficacy. Existence of critical periods for learning in thesepopulations is unknown. Targeting them could lead to efficient treatment plan. The proposed paradigms are completely non-invasive and testing duration is very short. Abnormalities can thus be identified very early on and treatment may be recommended. We purposefully develop measures of learning adapted to infantile populations because treatment may be more effective if provided at very young age. Patients will directly benefit from the proposed project since testing efficacy of treatment can lead to the recommendation of the best suited treatment plan in the context of the syndrome severity and age of the patient.
Role of ion channels in neonatal hypoxic-ischemic injury and cerebral palsy and its potential therapeutic application
Dr. Hong-Shou Sun
University of Toronto
Proposed research plan: While perinatal/neonatal (baby) hypoxic-ischemic brain damage is a major health concern, the causesleading to ischemic tolerance against brain damage have not been fully demonstrated. Thus, our proposed research will focus on understanding the cellular and molecular causes underlying ischemic tolerance (preconditioning) against perinatal/neonatal hypoxic-ischemic brain injury, particularly therole of ATP-sensitive potassium channel (KATP) in ischemic preconditioning in the brain. The KATPchannels play an important role in (1) cell protection in the heart; (2) brain protection in stroke; and (3)ischemic preconditioning in the heart; however, their role in ischemic tolerance against perinatal/neonatal hypoxic-ischemic brain injury has not been studied yet even though the channel is expressed in the brain and involved in brain protection in stroke. With proper molecular tools, I will study the fundamental role of these KATP channels in ischemic tolerance against perinatal/neonatal hypoxic-ischemic brain injury using modern technologies and molecular, genomic, proteomic, in vivo animal models, electrophysiology, functional and behavioral approaches. I intend to develop noveltreatment plans to prevent brain cell damage and to promote brain cell survival, regeneration andfunctional recovery in the injured brain after hypoxia and ischemia.
Anticipated outcome: Our proposed research will identify the causes of perinatal/neonatal hypoxic-ischemic brain injury andthe targets for brain protection against perinatal/neonatal hypoxic-ischemic injury, and developpotential treatment for perinatal/neonatal hypoxic-ischemic brain injury. Our findings will contributesignificantly to the current knowledge in the field of ischemic preconditioning and ischemic toleranceagainst perinatal/neonatal hypoxic-ischemic brain injury. These will also considerably advance us intreatment and prevention for perinatal/neonatal hypoxic-ischemic brain injury, as well as the relatedbrain disorders, such as cerebral palsy.
Projected benefits and application of findings: The proposed research findings will help to develop potential prevention and treatment plans forperinatal/neonatal hypoxic-ischemic brain damage, thus, reducing the health care costs for cerebralpalsy and improving the quality of life in children. This will also translate into significant long-termsocial and economic benefits to Canada and worldwide.
Identifying Causes of Autism Spectrum Disorder through Next-Generation Sequencing in Combination with Genetic Linkage
Dr. Mark Woodbury-Smith
Dr. Peter Szatmari
Dr. Andrew Paterson
St. Joseph’s Healthcare
Purpose of the Research: The principal aim of this proposed research project is to identify susceptibility genes for autism spectrum disorder (ASD). ASD is a relatively common disorder of childhood development that impairs communication and social interaction and thereby impacts significantly on quality of life and the ability to live independently, such that the burden on health care is very large. Unfortunately, there are currently no treatments that have a significant impact on outcome. Moreover, although the genetic basis of this disorder is well established, only a handful of genes that cause ASD have so far been identified. It is important to find the genes that cause ASD as this represents the first step in a better understanding of its cause and offers the hope of new treatments.
Proposed Research Plan: This proposed study will take advantage of a new technology thatallows the genetic code on each chromosome to be elucidated at the most basic structural level(termed sequencing) to identify genetic abnormalities in genes that are associated with ASD. Instead of examining the sequence across all chromosomes, however, efforts will be focused on only those regions that are genetically ‘linked’ (‘genetic linkage’) with ASD. The idea of genetic linkage refers to the identification of regions where affected members of families share more genetic material than expected, thereby indicating the presence of underlying risk genes. In this proposed study, families with three or more affected children will first undergo genetic linkage analysis. Subsequently, in genes within the regions demonstrating linkage, the genetic sequence of individuals with ASD will be compared with a control sample to look for variation in the sequence (‘rare variants’) that is seen more often in the ASD cases (‘genetic association’). We plan to follow up on genes with significant genetic association by examining a wider sample of individuals with ASD.
Anticipated Outcome: We anticipate finding one or more genes within genetically linked regions that harbour rare genetic variants more frequently than is seen in a non-ASD control sample. The genes identified in this way are likely to be causally related to the ASD, representing a very significant finding in ASD genetics.
Projected Benefits and Applications of Findings: Identifying genes that cause (or increase the susceptibility to) ASD represents the first step in a better understanding of the pathogenesis of ASD (i.e. how a gene affects brain development and how this in turn impacts on behaviour). Research such as this offers to hope of understanding the cause of autism such that more effective treatments can be introduced, caregiver burden can be reduced and the quality of life for those affected can be improved.