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What is Fragile X ?

The term Fragile X refers to a group of conditions due to defects in a gene on the X chromosome:

  • Fragile X syndrome (FXS)
  • Fragile X-associated Tremor Ataxia Syndrome (FXTAS)
  • Fragile X-associated primary ovarian insufficiency (FXPOI)

Fragile X syndrome (FXS), first known as Martin-Bell syndrome, is the most common inherited form of mental impairment. FXS affects 1 in 4,000 boys and 1 in 6,000 girls of all races and ethnic groups. While Fragile X individuals have a normal life expectancy, most will need support and care for their entire lives.

A single gene in the brain cells shuts down, causing Fragile X syndrome. In 1991, scientists discovered the defect in a gene on the X chromosome (called FMR1) that causes FXS. In affected individuals, this gene is shut down and cannot manufacture the protein it normally makes – a protein vital for normal brain development and functioning.

Large-scale population studies of Fragile X still need to be done, but it is clear that this is one of the most common genetic diseases in humans. Most people with Fragile X are not yet correctly diagnosed.

Research is aimed at developing effective treatments. In addition, this research is leading to better understanding and treatments for other conditions, such as autism, and Alzheimer’s Disease.

Grant reports


Principal Investigator: Dr. Massimo Avoli, Ph.D., Montreal Neurological Institute, McGill University, Montreal, Quebec
Postdoctoral Fellow: Dr. Giulia Curia, Ph.D. 
Amount: $40,000
Start Date: January 1, 2006

Phasic and Tonic Components of the GABAA Current in a Mouse Model of Fragile X syndrome

Fragile X is the most common form of inherited mental impairment and it is caused by the absence of the Fragile X mental retardation protein (FMRP). About 20% of the patients affected by this syndrome experience epileptic seizures. A similar incidence has been observed in the fmr1 knockout (KO) mice (Fragile X mice). Moreover, after several inbred crossing of mice experiencing seizures, we have created a KO seizure-prone colony. The goal of my project is to understand the mechanisms underlying epilepsy in Fragile X patients.

Neurons receive electrical impulses via synapses from many other neurons. Some of these neurons inhibit neighbouring cells while other excite them. Therefore it is the balance between excitatory and inhibitory impulses that determines the overall level of electrical activity in the nerve cells of the brain. γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system. Alteration of this system in the brain has been linked to other forms of epilepsy. The study proposed here will elucidate whether an altered expression of the GABA system causes the neurons to be persistently hyperexcitable and therefore lead to epilepsy in fragile X patients.

Because GABAA receptor impairment could produce neuronal hyperexcitability, the lower expression of the inhibitory GABAA receptor-mediated current in fragile X animals could explain the hyperexcitable EEG profile and the epileptic seizures of the fragile X patients. I am confident that the findings of this project will have great potential to be beneficial for improving the quality of life of Fragile X patients.


Principal Investigator: Dr. Yu Tian Wang, Ph.D., The Brain Research Centre, University of British Columbia
Postdoctoral Fellow: Dr. Nadège Chéry, Ph.D
Amount: $40,000/year in partnership with the CIHR
Start Date: Renewed January 1, 2005 for three years

The role of group I mGluR activation in AMPAR trafficking and enhanced LTD in the Fmr1 knockout mouse

In the brain, certain changes in the strength of neurotransmission at synapses (the sites of neurotransmitter release) are referred to as ‘synaptic plasticity’, a process thought to be involved in learning and memory. The synthesis of specific proteins is considered an important component of synaptic plasticity and FMRP – a protein that is normally abundantly expressed in neurons of the brain, but is absent in the fragile X syndrome – appears to function as a regulator of protein synthesis. FMRP is therefore thought to play an important role in synaptic plasticity.

Certain forms of synaptic plasticity, such as long-term depression (LTD), have been observed in specific regions of the brain at synapses that contain specific types of receptors on the post-synaptic membrane (on the receiving neuron), such as the α-amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid receptor (AMPAR). AMPARs appear to be the components that primarily express the plastic changes. In particular, the trafficking of AMPARs toward and away from the post-synaptic membrane is altered during LTD. In the hippocampus, a part of the brain involved in learning and memory, a form of LTD that is dependent on protein synthesis can be induced by the activation of specific receptors named group I metabotropic glutamate receptors (mGluRs). It has recently been shown that the Fmr1 knockout mouse (an experimental model of the fragile X syndrome) displays enhanced hippocampal LTD induced selectively by the activation of group I mGluRs. Some labs (including ours) have shown that group I mGluR activation with a pharmacological agent named DHPG leads to internalization (endocytosis) of AMPARs in cultured hippocampal neurons (thus, reduced AMPAR function). Endocytosis refers to the uptake of material into a cell by the formation of a membrane bound sac. Interestingly, we have found that blocking AMPAR endocytosis prevented DHPG-induced LTD.

We therefore hypothesize that, in the absence of FMRP, group I mGluR activation causes enhanced LTD and may lead to enhanced AMPAR endocytosis. The purpose of this project is to test this hypothesis in the Fmr1 knockout mouse.

Our study will help improve the current understanding of the molecular mechanisms underlying the fragile X syndrome and will potentially suggest appropriate molecular targets towards which novel therapies can be designed to efficaciously treat patients affected with this syndrome.

Principal Investigator: Dr. Mathew Lorincz Ph.D, Department of Medical Genetics, University of British Columbia
Postdoctoral Fellow: Dr. Margaret Rush, Ph.D.
Amount: $40,000
Start Date: April 1, 2006

The role of knockout mouse

Fragile X syndrome is a very common genetically inherited form of mental disability, affecting 1 in 4000 births, ranging from mild learning disabilities to severe mental retardation. The Fragile X mental retardation protein (FMRP), the loss of which causes Fragile X syndrome, is important for neuronal cells to develop correctly and for normal learning ability. Prior to birth, changes in the structure of the gene required to produce FMRP occurs in Fragile X patients. This change, known as DNA methylation, prevents FMRP from being made in Fragile X individuals, and is initiated due to the presence of an altered form of the DNA sequence encoding the FMRP. The extent of DNA methylation has been linked to both the level of FMRP produced and the severity of Fragile X syndrome. Currently, no therapy exists that prevents Fragile X syndrome.

Using a novel molecular approach, researchers at the University of British Columbia aim to develop an efficient system to facilitate the process of identifying potential new drugs for the treatment of Fragile X syndrome. In collaboration with the Ordway Research Institute in Albany, NY, a library of over 100,000 medicinal compounds will be tested for their potential to reactivate production of the important FMRP protein, despite DNA methylation of the gene encoding the FMRP. Successful compounds will be further investigated and may eventually be used to treat Fragile X patients. Simultaneously, using molecular tools to study DNA structure, the researchers at UBC will investigate what physical characteristics in the inheritable, mutated DNA sequence are associated with DNA methylation of the Fragile X mutation. Understanding how the mutated sequence is packaged prior to DNA methylation, which subsequently inhibits FMRP protein production, may open new avenues for treatment.

Principal Investigator: Dr. Peter Carlen Ph.D., MD, Toronto Western Research Institute, University of Toronto
Postdoctoral Fellow: Dr. Chris Feeney
Amount: $42,500
Start Date: Awarded March 1, 2004, $48,000 for one year
Renewed June 1, 2005, $40,000 for one year
Renewed June 1, 2006 for one year, $42,500

The Role of FMRP (Fragile Mental Retardation Protein) in Central Nervous System Synaptogenesis and Development 

2006 Update
The genetic abnormality causing Fragile X syndrome has been identified. The mutation of the FMR1 gene shuts down the production of the Fragile X Mental Retardation Protein – FMRP, and mice deficient in this protein have been created. We are studying the cellular electrophysiological factors underlying the cause of seizure activity in the brain tissue of FMRP gene knockout mice, with the aim of targeting potential therapies for the seizure disorder associated with the fragile X syndrome. We are particularly interested in the interaction(s) between excitatory (glutaminergic) and inhibitory (GABA) networks of the Fmr1 knock-out hippocampus (a key part of the brain used in learning). In addition we are interested in understanding how alterations in rhythmicity of electrical activity in the brain may contribute to the cognitive impairments occurring in the FX condition. We hope that a better understanding of the pathophysiology of FX syndrome will aid in the development of novel treatments for those who suffer with this syndrome.

Principal Investigator: Dr. Min Zhuo Ph.D., Department of Physiology, Faculty of Medicine, University of Toronto
Postdoctoral Fellow: Dr. Long-Jun Wu, Ph.D
Amount: $40,000
Start Date: January 1, 2006

Inhibitory synaptic transmission and plasticity in the anterior cingulate cortex of FMR1 knockout mice

Fragile X syndrome is an inherited cause of mental impairment. The disease is a result of a loss of function of the Fragile X mental retardation gene, FMR1, and its encoded protein, FMRP. This results in impaired communicaton at the synapses (the connections between neurons). Synapses that are heavily used get built up, while those that are not used wither away. This is what neuroscientists mean when they speak of the synaptic plasticity and is generally thought to be the basis for most of our learning and memory.

Previous studies showed that there is a change in excitatory synaptic plasticity in the cortex of the brain in FMR1 knockout mice. However, little is known about inhibitory synaptic transmission and plasticity in these knockout mice. GABA is a major inhibitory neurotransmitter and the fast synaptic inhibition is largely mediated by GABAA  receptors in the adult brain. The level of activity of GABA mediated neurotransmission modulates the excitability of target neurons, thereby shaping the activity of neuronal networks in relation to the behavior. Here, we will examine the potential changes in GABA mediated synaptic transmission and plasticity, as well as the cellular mechanisms underlying these changes in the anterior cingulate cortex (ACC), a cortical region of the brain related to memory and emotion, of FMR1 knockout mice. This study will reveal the potential role of FMRP in GABA mediated transmission and plasticity and the subsequent balance of inhibition and excitation. Therefore, we will characterize the inhibitory synaptic mechanisms of FMRP on the symptoms of Fragile X syndrome-like seizure, anxiety, or autism, which are believed to be related to the GABA system in the central nervous system. These studies will lead to a better understanding of Fragile X neuropathophysiology, and provide new molecular targets for treating patients who suffer from Fragile X syndrome.