Grant reports

2017

Electrophysiological biomarkers of altered brain plasticity in children with Fragile X Syndrome

Dr. Sarah Lippé Ph.D from Université de Montréal/CHU Sainte-Justine university hospital centre, in collaboration with Sébastien Jacquemont, MD, PhD, is leading an extensive research project aimed at defining sensitive outcome measures of learning capacities in patients with fragile X syndrome (FXS). The goal is to define the electrical brain signature of learning alterations measured in FXS patients using non-invasive, reliable, low cost methods.
 
Electroencephalography (EEG) is a non-invasive, painless and sensitive tool to study brain functioning that has been successfully used in several studies, which included moderately and severely affected FXS patients. Lippé and her team have demonstrated a relation between EEG learning signatures and cognitive functioning levels in adolescents and adult patients with FXS. Now, they aim at understanding the developmental trend of these learning brain responses in FXS. The significance of this research lies in the fact that these measures could be used with great sensitivity to test treatment efficacy. It has the potential to be rapidly transferred into clinical practice because it can be repeated as often as needed, before, during and after the introduction of a treatment.
 
Dr. Lippé’s team is recruiting FXS patients of all ages for their study that includes one visit of approximately two hours at the CHU Ste-Justine hospital. If you would like further information, please emailSarah.Lippé@umontreal.ca. You can visit the website of her lab under http://www.ned.umontreal.ca.

Aberrant insulin signaling in a mouse model of Fragile X Syndrome

Insulin signaling is known to be dysregulated in diabetes and cancer, and has lately been described to be implicated in cognitive impairments in neurodegenerative disorders such as Alzheimer’s disease. Also, dysregulation of insulin signaling might be associated with autism. Dr. Sonenberg’s team will systematically investigate the impact of insulin signaling on autistic-like behaviors, synaptic plasticity, spine morphology and mRNA translation (protein production) in the mouse model of Fragile X syndrome. Targeting insulin signaling might uncover novel drug treatment options for Fragile X syndrome.

We are very pleased to announce that this special funding partnership has been arranged between the Fragile X Research Foundation of Canada and our U.S. counterpart, the FRAXA Research Foundation. Since both foundations are dedicated to funding biomedical research for improved treatment, and ultimately a cure for fragile X, this funding partnership will allow your donations to go twice as far.

Role of Basal Forebrain Cholinergic System in the Modulation of Sensory Evoked Neurovascular Coupling Response in Fragile X Syndrome

Blood moving on a second to second basis in the blood vessels of the brain is controlled by a tight relationship between neurons and another cell type called the astrocyte. We will test what happens to the neuron/astrocyte relationship in conditions of fragile X syndrome (FXS). Using a genetically modified / transgenic animal model that is manipulated to express light driven channels in a specific subset of neurons, we will selectively activate or inactivate the neurons known to be impaired in FXS and determine the impact on the blood flow responses to sensory information. In this project, we will target an area of the brain that is involved in learning and memory, called the basal forebrain cholinergic system because it uses acetylcholine as its main neurotransmitter. We will also target the local neurons – GABA interneurons (neurons that use GABA as their neurotransmitter). We aim to study the effects of light stimulation on cholinergic neurons that control blood flow responses. In addition, following cholinergic stimulation, we will use specific inhibitors for GABA interneurons to study their specific contribution to the blood flow response. This study is important because alterations in cerebral blood flow responses seen with several brain imaging techniques have been associated with FXS pathophysiology. However, little is known about the neuron-astrocyte-blood vessel relationships in FXS and our findings should establish if blood flow changes can be established as reliable markers of neuronal activity in FXS.

Fragile X gene therapy using Adeno-Associated Viruses

Fragile X syndrome (FXS), the leading single-gene cause of autism, is caused by a severe down regulation of the fragile X mental retardation protein (FMRP). FXS does not have any pharmaceutical cures and current medication can only address symptoms of the disorder. Recent advances in gene therapies using Adeno-Associated Viruses (AAV) show promise to treat FXS and a number of other neurogenetic disorders. We thus aim to test biopharmaceuticals that use AAV to carry FMRP into brain cells for the long term amelioration of FXS syndrome.  The fragile X knockout mouse model displays a wide range of autism-related behavioural characteristics that we have shown could be corrected with this AAV-FMRP strategy. Neonatal mice who were given injections of AAV-FMRP into the fluid containing areas of the brain showed a widespread forebrain FMRP production pattern using the imaging techniques of  immunohistochemistry and western immunoblotting. The mice were tested for behavioural rescue during adulthood and showed prominent neurological improvement compared to their untreated controls. A new strain of mice, the FVB FMRP KO mice, as well as a Sprague-Dawley rat model of FXS will also be injected with our lead bio-pharmaceutical AAV to monitor behavioural changes in two other model organisms. Injections given directly into the cerebrospinal fluid will also be used to administer the viral vectors in order to maximize FMRP production in the hindbrain.  Correlations between behavioural tests and local neuroanatomical production of the reintroduced FMRP will give insights into brain regions associated behavioural pathologies. These results will help better understand the neuropathological significance of FXS as well as other X-linked neurological disorders, help devise better transgenic approaches and delivery methods, and ultimately, ameliorate the way of life for FXS patients

The effect of oxytocin to rescue of the FMRP- related synaptic plasticity

Fragile X syndrome (FXS) is the most commonly inherited form of mental retardation and is the most common cause of autism. It is caused by the loss of the fragile X mental retardation protein (FMRP). Loss of FMRP contributes to abnormal cognitive behaviors in FXS patients and rodents.

Psychopharmacology plays a very important role in the treatment of developmental disorders in FXS patients. A variety of medications are used in individuals with FXSs for the treatment of comorbid disorders including repetitive and stereotypic behavior, attention deficit hyperactivity Disorder (ADHD), anxiety, irritability, and aggression. Previous studies suggested that some medications such as mGluR5 antagonists, GABA agonists and minocycline play a role in the treatment of some symptoms in the FXS patients. More targeted treatments are either under study in mouse models of FXS or plan to be studied clinically.

Recently, it was shown that neuropeptide oxytocin (OXT) can ameliorate some symptoms of social anxiety in patients with FXS patients. However, little is known about the role that OXT play to the FMRP.  In this study, we will systematically examine the rescue of Fmr1 KO mouse, related learning and memory deficits by OXT treatment. We will focus on fear and memory behavior, synaptic morphology and potential changes of cortical synaptic plasticity in the prefrontal cortex including the anterior cingulate cortex after OXT treatment, using the Fmr1 KO mice. We believe that OXT treatment can be to bring practical treatment into current medical practice in the FXS patients.