A Brief Description of Currently Funded Research Grants 2012-2013

A Brief Description of Currently Funded  Research Grants 2012-2013

 

Dr. Roberto Araya
Université de Montréal
Montreal, QC

Purpose of the research: Fragile X mental retardation syndrome (FXS) is the most frequent form of inherited mental retardation and the most common known cause of autism. FXS is caused by inactivation of the Fragile X Mental retardation 1 gene. In FSX patients this gene fails to generate the Fragile X Mental Retardation Protein (FMRP), a protein that has a major role in regulating the connections between neurons, named synapses.The post-mortem brains of FXS patients are almost intact. However, at the micro-anatomical level FXS is characterized by mayor alterations in dendritic spines. Spines are tiny protrusionsthat cover the dendrites (branches that are specialized for receiving information) of excitatory neurons in the brain. These protrusions receive the majority of the excitatory connections, whichare key for brain function.Recent technological advances have made possible to image and activate live spines deep in thetissue. Using these novel techniques I have demonstrated that a) spines are electrical devices thatcan activate channels present in their membranes and modify the relative importance of aparticular neuronal connection, and b) promote that the information received by the manyconnections of a neuron are added in a linear fashion. Both functions are dependent on the shap eof the spines and it is known that the spine shape in FSX neurons is abnormal. However, none of these spine functions have been studied in FXS.
Proposed research plan: The main objective of this project is to investigate spine function in the reception, storage(plasticity) and integration of the excitatory information received along the dendrites of the neurons in a mouse model of FXS – the Fmr1 mice. My hypothesis is that the function of neuronal spines is dependent on a finely tuned interplay between spine morphology and the presence of spine channels. Thus, alterations in spine shape, like those found in FXS, will affect the spine function in regulating how the information is received and processed by a neuron. Thi sproposal has three aims. The first aim is to determine how the morphological impairment found in the spines of the FXS-mouse model affects the transmission of information and the activation of channels. The second aim is to unravel the role of spines in the integration of the information in the FXS-mouse model. Finally, the third aim is to unravel how the spine defects found in theFXS-mouse model can affect learning and memory. To address these aims I will use a multifaceted approach including state of-the-art imaging and electrophysiological techniques.
Anticipated outcome: I expect to find for the first time that in FXS there is an impairment in spine function that results in a significant increase in the number of connections that a neuron needs to properly process,store and send information in the brain.
Projected benefits and applications of findings: I expect that these finding will shed light on spine function in information processing, learningand memory in health and disease. These findings will allow the development of novel therapeutical approaches for Fragile-X mental retardation syndrome.

 

Dr. Sarah Lippé
Dr. Anthony McIntosh
Ste-Justine Hospital
>Montreal, QC

Purpose of the research:The most common form of X-linked mental retardation is the Fragile X Syndrome (FXS),which affects about 2% of male with intellectual disability. Over the past decades, insights into the biochemical causes of this disease have increased tremendously. We now understand that synaptic plasticity is disrupted in FXS. This has led to recent human patient clinical trials targeting the biological mechanisms of FXS. So far, results on 30 patients have suggested improvements on stereotyped behaviors, hyperactivity and inappropriate speech. Unfortunately, learning, the crucial deficit of FXS has not been investigated. One possibility is that new sensitive methods for short-term learning investigations have never been used in FXS. The purpose of this research program is to provide sophisticated but efficient tools to test neurophysiological learning mechanisms. Short-term learning is not only important for acquisition of new information, but also for brain network development further supporting learning capacities. Cellular plasticity underlying perceptual tuning is at the base of large-scale network formations. In fact, inefficient perceptual learning caused by altered plasticity mechanisms may not only explain reduced knowledge acquired by FXS, but also in adaptive behaviours since it may impact on brain network development.

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.

Dr. Hong-Shou Sun
University of Toronto
Toronto, ON

Purpose of the research: Human infant brain damage due to lack of oxygen is known to cause cerebral palsy, which in layman’s terms is “brain weakness”. Cerebral palsy is a group of disorders that can involve brain and nervous system functions such as learning, thinking, hearing, seeing and movement. Statistically, the incidence of asphyxia (literally suffocating) is up to 2% (20 per 1000) in full-term infants and approaches 60% inpremature infants. From 20 to 50% of asphyxiated newborns who have hypoxic-ischemic brain damage actually terminate shortly after birth. Among the survivors, up to 25% of asphyxiated newborns show permanent brain functional handicaps in the form of cerebral palsy with or without associated epilepsy, learning disability or mental retardation. The disabilities in afflicted survivors of infant hypoxic-ischemia injury also have significant social and economic impacts on our society. The lifetime costs of hypoxic-ischemic brain damage to the healthcare system have been estimated at about 11.5 billion dollars, according to 2003 US statistics. Thus, finding the causes and eventual cure of intellectual impairment for this childhood disease is important goal for our medical researchers.
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.

 

Dr. Mark Woodbury-Smith
Dr. Peter Szatmari
Dr. Andrew Paterson
St. Joseph’s Healthcare
Hamilton, ON

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.