A Brief Description of Currently Funded  Research Grants 2016 – 2017


Dr. Pushpal Desarkar
Centre for Addiction and Mental Health
Toronto, ON
Co-applicants:
Dr. Zafiris Daskalakis
Dr. Tarek Rajji
Dr. Daniel Blumberger
Dr. Stephanie Ameis
Dr. Meng-Chuan Lai

Introduction: Autism Spectrum Disorder (ASD) is the most common neurodevelopmental disorder, affecting about 1% of Canadians. Since the cause of ASD is still unknown and there are no satisfactory treatments, there is an urgent need to explore novel and effective treatment options for ASD population. Previous research using theta burst stimulation (TBS), a type of non-invasive magnetic brain stimulation, indicates that the brain in ASD is abnormally responsive to modifying stimulation i.e. has greater neuroplasticity or ‘hyperplasticity’, compared to healthy controls. Further, it has been proposed that such neuroplasticity abnormalities could underlie autistic behaviours. Repetitive magnetic brain stimulation or rTMS is safe, well-tolerated, and its sophisticated ability to influence target brain networks sets it apart from other therapies. rTMS has the potential to improve core deficits of ASD. Since abnormal neuroplasticity has been linked with autistic behaviours, one key line of potentially curative therapeutic inquiry would be to test if such neuroplasticity abnormalities can be `reversed’.
Objective: Building upon our team’s expertise, in this innovative study we aim to a) show that the brain in ASD has excessive neuroplasticity or `hyperplasticity’ and b) study if such hyperplasticity can be stabilized with rTMS. The ultimate goal of this project is to promote a new line of potentially curative therapeutic intervention for people with autism.
Outline of Research: In this randomized study, we will recruit 60 adult subjects with ASD and 60 control subjects. Using TBS, we will first assess neuroplasticity changes in the ASD subjects and compare them to the controls. Then, we will randomize the ASD subjects to receive a single session of active (n=30) or sham (n=30) rTMS. We will then reassess neuroplasticity changes on the next day following single session of rTMS. We anticipate that, compared to controls, ASD brain will show abnormally excessive neuroplasticity and active, but not sham, rTMS will be able to stabilize it.
Projected benefits and applications of findings: To our knowledge, this is the first study investigating if rTMS can stabilize hyperplasticity in ASD. This is an innovative attempt to lay the groundwork for developing a potentially curative therapeutic intervention in ASD, based on causative mechanism. Optimal level of neuroplasticity is related to optimal performance; therefore, a key next step will be to relate stabilizing neuroplasticity to facilitating behavioural and cognitive performance in ASD. Given that successful treatment of ASD is still elusive, a novel and effective treatment for ASD will be transformative for the field. In the future, this information and safety data will act as a springboard for similar trials involving lower functioning adults and children with ASD. Finally, this information will also enrich current understanding of the neurophysiological underpinnings of ASD.


Dr. Julie Lefebvre
Hospital for Sick Children
Toronto, ON

Introduction: Autism spectrum disorder (ASD) are complex disorders of brain development that affects ~ 1% of children, and pose significant challenges to affected individuals, their families and communities. ASD is characterized by core deficits in social interactions, language, repetitive movements, and restricted interests. Other symptoms include epilepsy, intellectual disabilities, anxiety, and sensory abnormalities. As a result of the significant gains in human genetic and imaging studies, we have learned that ASD is primarily a genetic disorder of early brain development involving multiple risk genes, and that abnormal neural connectivity patterns underlie widespread deficits in sensorimotor, cognitive and affective function. Moreover, risk genes and symptoms overlap greatly those of other neurodevelopmental disorders (NDD), such as schizophrenia and bipolar disorders. Investigating common deficits is an important strategy to understand how these disorders arise. One idea that is gaining much support is that defects in the development of inhibitory nerve cells, and consequently, imbalances in excitation and inhibition (E/I) causes long-lasting effects on brain function. These disruptions might be responsible for clinical features of NDDs. Inhibitory nerve cells are crucial as they modulate the electrical activities of other nerve cells and coordinate the activities of brain networks; during development, they refine neural circuitry during critical periods of learning. Mouse models based on human disease-causing mutations are powerful research tools to discover ASD causes and cures.
The root causes and long-term consequences of inhibitory dysfunction in the developing brain are unknown. We discovered an essential role for a set of genes called clustered Protocadherins (Pcdh) in regulating the development and final number of inhibitory nerve cells in many regions of the brain and central nervous system. Building on our expertise and mouse genetic models, we will investigate how inhibitory nerve cells use these molecules to develop and first establish an E/I balance. We will also study how defects cause brain network dysfunction and behavioral deficits. Pcdh genes are susceptibility genes for ASDs and other NDDs such as schizophrenia, bipolar and Tourette’s syndrome. Therefore our studies will lead to a better understanding of inhibitory dysfunction and potential treatment strategies for ASD/NDDs.

Objective: The objective of our study is to test our hypothesis that developmental loss of inhibitory nerve cells caused by Protocadherin mutations causes brain network dysfunction and behavioural deficits consistent with autistic phenotypes.

Outline of Research: Using mouse models, our first aim is to identify which populations of inhibitory nerve cells (interneurons) are vulnerable to mutations in Protocadherin genes. We will determine how Protocadherins regulate inhibitory interneuron development, number, and precise connectivity into neural circuits in the cortex and hippocampus. We expect to learn how Protocadherins molecules help to assemble inhibitory interneurons into larger circuits. Our second aim is to take advantage of this model to learn what happens to brain function when there are fewer, and possibly improperly connected inhibitory cells. We will use EEGs (electroencephalography) to record brain activities to test for abnormal patterns. We will also test if defects cause seizure predisposition, which is common in ASD children who don’t develop apparent epilepsy. We will test mice in behavioural assays that report on autistic-like deficits in cognitive, social, and repetitive behaviours.

Projected Benefits and Applications of Findings: These studies will lead to a better understanding on how inhibitory circuits are established in the developing brain, and link ASD-risk Protocadherin genes to brain function deficits. Importantly, because multiple gene defects can lead to loss of inhibitory cells, our approach will lead to a better understanding of how defects in inhibition has long-lasting consequences on brain circuit function. Together, this knowledge can inform the development of therapeutics to restore inhibitory nerve cells or function in the brain. In particular, a strategy promoting the survival and integration of nerve cells into an existing circuitry could have applications for emerging regenerative/replacement therapies aimed to restore inhibitory cells, such as childhood ASD and epilepsies.

Dr. Lisa Münter
McGill University
Montreal, QC

Alzheimer disease is the most common form of dementia and currently affects more than 20 million people worldwide. First molecular changes indicative of Alzheimer disease occur as early as 15 – 30 years before the onset of clinical symptoms. It is therefore necessary to understand all molecular changes during this early phase of the disease to identify new drug targets that may help effectively to halt Alzheimer disease. On the molecular level, it is widely believed that amyloid-beta peptides cause the degeneration in the brain responsible for the memory loss. Amyloid-beta peptides are cut out from a larger ‘amyloid precursor protein’ (APP) by two different enzymes, two well understood molecular scissors.

My laboratory has discovered that a different molecular scissor, a so called rhomboid enzyme, cleaves APP as well and directs it into an alternative cellular pathway. Instead of amyloid-beta peptides, the rhomboid scissors generate different, larger fragments. These novel APP fragments may play a significant role in Alzheimer disease as it was recently suggested by a publication in the renowned scientific Journal Nature. Such fragments seem to be 5 times more present in human brain liquid as compared to classic amyloid-beta peptides. We propose that our rhomboid enzyme generates these novel fragments and may therefore contribute to Alzheimer disease progression, either with beneficial or detrimental effects, which we will determine in this project. We suggest to analyze the effects of the rhomboid scissors on their impact on Alzheimer disease. Our research may reveal if rhomboids may serve as a potential drug target in Alzheimer disease.

Dr. Jing Wang
Ottawa Hospital Research Institute
Ottawa, ON

Introduction: Alzheimer’s disease (AD) is a neurodegenerative disease that is associated with progressive deterioration of cognitive function. In Canada, approximately 1 in 7 elderly individuals (over 65 years) live with AD. As the aging population rises, the number of Canadians with AD will increase rapidly, causing huge economic burdens and decreased quality of life for caregivers and patients. There is an urgent need to develop medical breakthroughs to prevent and/ or cure AD. Increasing evidence shows that the reduced hippocampal neurogenesis in AD animal models is associated with the early onset of cognitive impairments far before the occurrence of AD pathology Thus, dysfunctional neurogenesis may exacerbate hippocampal vulnerability to AD and eventually account for cognitive impairments. Until now, there is still a knowledge gap with regards to molecular mechanisms underlying dysfunctional neurogenesis in AD. Excitingly, my lab recently identified a signaling-induced epigenetic pathway, atypical protein kinase C (aPKC)-mediated CBP (histone acetyltransferase) activation, acting as a homeostatic mechanism to maintain the stable rate of hippocampal neuronal differentiation during early adulthood brain development. In addition, we observed that this pathway was impaired in the hippocampi of an animal AD model. These research findings prompt us to ask whether the impaired signaling-induced epigenetic pathway in the animal AD model leads to perturbations in homeostatic hippocampal neurogenesis. And this dysfunctional neurogenesis may mediate the early-onset cognitive decline in AD. A better understanding of the underlying molecular mechanisms that regulate homeostatic hippocampal neurogenesis will reveal insights into the pathogenesis of AD and provide the basis for the development of neurogenesis-based therapeutic strategies for AD.
Objective: The objectives of the research proposal are to determine 1) whether the newly-identified homeostatic epigenetic pathway plays a pathogenic role for the early-onset dysfunctional neurogenesis and cognitive decline in AD far before the occurrence of AD pathology, 2) and whether this pathway is a valid therapeutic target for the treatment of AD.
Outline of Research: To determine whether the homeostatic molecular process is impaired in AD, we will use a well-characterized AD mouse model named 3xTg carrying 3 human mutations for AD (APP KM670/671NL, MAPT (Tau) P301L and PS1M146V) as its name implies. We will also use multidisciplinary techniques including BrdU in vivo labeling, lentiviral injection and cognitive behavioral tests to assess and manipulate adult neurogenesis and cognition in the animal model of AD. We will pursue the following three aims:
aim1: determine the association between impaired epigenetic pathway and early-onset dysfunctional neurogenesis and cognitive decline in the animal model of AD
aim2: determine therapeutic outcomes of constitutive activation of the signaling-induced epigenetic pathway in the animal model of AD.
aim3: determine therapeutic outcomes of an FDA-approved drug, metformin, in the treatment of AD by activating the signaling-induced epigenetic pathway.
Projected benefits and application of findings: Completion of the proposed project will elucidate underlying molecular mechanism that is responsible for pathogenesis of AD in regards to the early-onset of dysfunctional hippocampal neurogenesis and cognitive impairments. This underlying molecular mechanism could be used as a potential therapeutic target to treat AD. Importantly, we previously showed that an FDA-approved diabetes drug, metformin, enhances hippocampal neurogenesis and improves spatial memory formation in the normal mice. This proposal will provide insightful molecular mechanisms to support future clinical trials of metformin in the treatment of AD and give us the opportunity to minimize its off-target effects and improve safety in the future.