A Brief Description of Currently Funded Research Grants 2013 – 2014

A Brief Description of Currently Funded  Research Grants 2013 – 2014


Dr. Brian Chen
Research Institute of the McGill University Health Centre
Department of Neurology, Montreal General Hospital
Montreal, QC

Purpose of the research: We will investigate how the gene Down Syndrome Cell Adhesion Molecule (DSCAM) is involved in neural development. DSCAM has been implicated in Down syndrome and is targeted for protein translation suppression by Fragile X Mental Retardation Protein (FMRP). We propose to investigate how overexpression of DSCAM impairs dendritic development in the neocortex.
Proposed research plan: We will use mouse genetics, biochemistry, molecular biology and fluorescence imaging to examine how FMRP regulates DSCAM protein levels. We will image the dendritic structure of neurons in mouse brains that overexpress DSCAM to examine how excessive DSCAM protein amounts affect dendritic development.
Anticipated outcome: We expect that excessive DSCAM levels due will restrict dendritic growth and impair neural circuit development and function.
Projected benefits and applications of findings: Characterizing the function of DSCAM in neural development will help bridge the gap between how triplication of specific genes on human chromosome 21 or overexpression of FMRP RNA targets causes intellectual disability. Investigating dysregulation of DSCAM protein expression will also give us insight into how it may serve as a common molecular feature underlying a wide variety of neural developmental disorders such as in the dendritic pathologies found in Fragile X, Down, and Rett syndromes.


Dr. Carl Ernst
Douglas Hospital Research Centre
McGill University
Montreal, QC
Introduction: Fifteen to twenty percent of all cases of neurodevelopmental disorders (NDDs) are associated with a known genetic mutation, yet these mutations are individually rare, usually occurring in only a small proportion of subjects. Some genes that are mutated in people with NDDs are master regulators of the cell, meaning they turn many other genes on or off. Some of these mutated genes may have overlapping targets and these overlapping targets might define a common molecular pathway(s) for people with NDDs. In other words, NDDs may be caused not by the mutation in a particular gene itself, but because of the effects a mutated gene has on turning other genes on or off; if mutated genes associated with NDDs turn the same genes on and off, or a proportion of them, this might suggest a common molecular pathway of NDDs.

Objective: This project will identify the molecular targets of three genes fundamentally important to human neurodevelopment. It will also identify how these targets change when the disease is experimentally modeled in human brain cells, and how other molecules in the cell are affected. We suspect that the three genes we are studying might share targets and function, in which case we will identify those targets and molecules that are at the crossroad of each of the three genes. This could identify the fundamental pathways for NDDs, which will pave the way for therapeutic intervention, irrespective of whether or not patients have an identified mutation associated with an NDD. It may be that these threegenes do not share any molecular targets; if that is the case, we will have important information about the function of genes that are profoundly important to human neurodevelopment.
Research plan: We will focus on three master regulator genes, all of which are unambiguously associated with neurodevelopmental disorder, i.e., a mutation in any of the three always leads to an NDD. Because of the overlapping clinical profile across subjects with mutations in any of three genes, it may be that similar molecular pathways are affected. First, we will assess the DNA target of each of the three using adult human brain tissue, and we will re-perform this analysis using human neural stem cells at early and late neurodevelopmental stages. This will reveal the normal DNA target of each in adult brain and during neurodevelopment in healthy human tissue. Next, we will model the patient mutations in each of the three genes in human neural stem cells and determine if the binding targets change and how the mutation affects all other genes in the genome.
Projected benefits and application of findings: Findings from this study will reveal the underlying causes of NDDs and may identify final common pathways for neurodevelopmental disease. These findings can be useful to genetic screening studies and development of therapeutic molecules that target the appropriate cell pathways to alleviate the suffering associated with NDDs, including Autism.


Dr. Karun Singh
McMaster University
Hamilton, ON

Purpose of the Research: Autism spectrum disorders (ASDs) are neurodevelopmental disorders in which individuals have disrupted social communication and repetitive stereotyped behaviors, which lead to life-long difficulties. Approximately 1 in 88 individuals in North America have an ASD, which demonstrate the need to better understand these disorders, and find effective treatments to improve quality of life. In this regard, recent studies have identified over 2000 genes that are risk factors for ASDs. Given this large information, it is very difficult to determine which genes are the most important and should be the focus of further investigation and drug development. Many labs have attempted to simplify thisinformation by finding “hubs”, called common signaling pathways, which converge the actions of multiple genetic risk factors. The discovery of signaling hubs would makes it possible to develop drugs that target it specifically instead of the many individuals genes that contribute to ASD. In the current proposal, we will study a new “hub” named Wnt/GSK3 signaling in animal models. Our goal is to test whether multiple ASD-linked genes converge and disrupt Wnt/GSK3 signaling, and contribute to the  risk of ASDs by causing abnormal fetal brain development. Finally, we will test the exciting possibility that drugs used to treat high cholesterol, which are safe for use in humans, could be used to correct abnormalities in the Wnt/GSK3 hub, and be developed as new ASD therapeutics.
Proposed Research Plan: Aim 1. We will determine whether 3 specific ASD-linked genes (FMRP, DISC1 and CHD8) converge to regulate Wnt/GSK3 signaling. We will accomplish this by altering the amounts of FMR1, DISC1 or CHD8 proteins in mouse brain stem cells, followed by use of a fluorescent indicator to measure changes in Wnt/GSK3 signaling.
Aim 2. We will determine whether the FMRP/DISC1/CHD8 signaling network impacts the growth of
developing mouse brain stem cells, since this may be disrupted in individuals with ASD.
Aim 3. Lastly, we will attempt to correct the reduction in Wnt signaling that we believe is driving many of developmental brain defects in ASDs. We will accomplish this by testing FDA-approved cholesterol reducing drugs in mice for their ability to stimulate the activity of Wnt/GSK3 signaling and correct brain stem cell growth.
Anticipated Outcome: We predict the FMRP/DISC1/CHD8 gene network will be a critical regulator of the Wnt/GSK3 signaling hub. Furthermore, our studies will reveal that inhibiting the FMRP/DISC1/CHD8 network will cause abnormalities in the growth and behavior of mouse brain neural stem cells, which will cause defects in brain development and risk for ASDs. Finally, we anticipate FDA-approved cholesterol lowering drugs will reverse these effects by stimulating Wnt/GSK3 signaling and restoring normal mouse brain stem cell development.
Project Benefits and Applications of Findings: Our proposed studies will have a number of benefits for ASDs. First, our experiments will uncover a new and important autism signaling “hub” that converges the actions of multiple ASD-linked genes, and will provide greater insight into the causes of ASDs. Most important, identifying the Wnt/GSK3 signaling hub will provide a new target to develop drugs. To this end, our initial studies will repurpose FDA-approved cholesterol-reducing drugs to correct abnormalities in the hub’s activity within brain stem cells of animal models, as a potential novel therapy for ASDs. Since our studies will reveal how cholesterol-reducing drugs produce their beneficial effects in brain cells, this will give us the opportunity to minimize their side-effects and improve safety in future studies. Lastly, because the statin drugs are well characterized in humans, and have low toxicity, we can rapidly move into ASD clinical trials if our animal model studies reveal they stimulate the Wnt/GSK3 hub and restore normal brain development.

Dr. Marie-Eve Tremblay
CHU de Québec
Quebec, QC

Purpose of research: A series of discoveries spanning the last 5 years have challenged our view of microglia, the brain immune cells, showing unexpected roles in the active maintenance and structural remodeling of neuronal circuits throughout the lifespan. In particular, microglia were found to continuously contact and eliminate –by means of phagocytosis most notably– subsets of healthy synaptic elements (pre-synaptic axon terminals and post-synaptic dendritic spines) along the changes in sensory and behavioural experience. Contributing to this nascent field of investigation, my project aims at exploring the relevance of these new roles of microglia in Alzheimer’s disease (AD), the most prevalent form of dementia affecting over 35 million people worldwide. Although the neurofibrillary Tangles and plaques of amyloid-β are the most prominent hallmarks of AD, it is the loss of synapses that best correlates with the progressive impairment of learning, memory and other essential cognitivefunctions. Several lines of evidence suggest that microglial phagocytosis is dysregulated in AD, and pharmacological treatments promoting microglial phagocytosis (of amyloid-β) were lately shown to ameliorate learning and memory in a spectacular manner in several mouse models.To generate novel insights into the mechanisms underlying this devastating loss of synapses, I will characterize the changes in microglia-synapse interactions that occur during disease progression and phagocytosis-promoting treatment in the APP-PS1 mouse model of amyloid-β deposition.
Proposed research plan: Using state-of-the-art imaging approaches, my aims are to:
1) Measure the prevalence of microglial contacts (both phagocytic and non-phagocytic) with dendritic spines and axon terminals.
2) Categorize the contacted synaptic elements into particular subsets based on their healthy, stressed (but viable) or degenerating nature, considering that phagocytosis of such elements could serve distinct roles. Primary phagocytosis of viable neurons and synapses could induce neurodegeneration in AD by causing cell death, while secondary phagocytosis, or clearance of degenerating neurons and synapses following their death, could have beneficial effects on the maintenance of neuronal circuits.
3) Measure the formation and elimination rates of these contacted elements (healthy, stressed or
degenerating) with relation to amyloid-β plaques deposition.
Anticipated outcome: An increased phagocytosis of either healthy, stressed or degenerating synaptic elements during disease progression in the APP-PS1 mice could indicate microglial implication in the devastating loss of synapses in AD. In particular, an increased phagocytosis of predominantly healthy or stressed synaptic elements during disease could reveal detrimental roles of microglia in inducing neurodegeneration by primary phagocytosis in AD. During treatment, an increased phagocytosis of mainly degenerating synaptic elements observed in the APP-PS1 mice could indicate beneficial roles of microglia in the cognitive amelioration by secondary phagocytosis of degenerating neurons and synapses. Also, an increased formation of healthy elements in the treated APP-PS1 mice could reveal beneficial effects of Aβ clearance on the maintenance and structural remodeling of neuronal circuits.
Projected benefits and applications of findings: Overall, this project will provide:
a) Basic insights into the possible roles of microglia-synapse interactions in AD;
b) Better understanding of the mechanisms by which phagocytosis-promoting treatments ameliorate learning and memory –irrespective of microglial intervention;
c) Novel reference measurements to help evaluating additional treatments in clinical development for AD with respect to their consequences on synapses and neuronal circuits.
Such insights will contribute to enrich, orient and refine current working hypotheses on the complex pathogenesis of AD by including the brain immune cells as a novel, potentially important player.