glutamate Archives • Fragile X Research - FRAXA Research Foundation

A Day in the Lab with FRAXA Investigator Dr. Tue Banke

Laurie Bowler Banke, Tue • FRAXA Updates June 11, 2019autism, glutamate

Recently Laurie Bowler and her 19-year-old son Casey, who has Fragile X syndrome, visited FRAXA research grant recipient Dr. Tue Banke at his University of Washington laboratory. We hope you enjoy Laurie’s wonderful description of their adventure! FRAXA awarded $90,000 to Dr. Banke to study the Developmental Profile of Glutamatergic Synapses in Fragile X.

Developmental Profile of Glutamatergic Synapses in Fragile X

FRAXA Research Foundation 2019 Grants • Banke, Tue • Current Research Grants • Disease Mechanisms • University of Washington May 2, 2019May 2, 2019glutamate

FRAXA Research Foundation has awarded a $90,000 research fellowship to Dr. Tue Banke. With this award, Dr. Banke is investigating how glutamate receptors at neuronal synapses – essential building blocks of learning and memory – are impacted in Fragile X syndrome. Dr. Banke recently left Aarhus University in Denmark to continue his research first as a visiting scholar and now as an assistant professor at the University of Washington.

Novel Modulators of Potassium Channels to Treat Fragile X

FRAXA Research Foundation 2015 Grants • 2016 Grants • 2017 Grants • Disease Mechanisms • Kaczmarek, Leonard • Research Grant with Results • Treatment Targets • Yale University January 2, 2019April 2, 2019Autifony Therapeutics, autism, glutamate, hypersensitivity, ion channel, mGluR, mGluR5, mRNAs, potassium channels, sound

With funding from FRAXA over 2015-2017, the Yale University team of Leonard Kaczmarek, PhD showed that the firing patterns of auditory neurons in response to repeated stimulation is severely abnormal in Fragile X mice. Based on these results, they are collaborating with the UK-based company Autifony to develop advanced compounds which may reverse these deficits.

Coffee, Tea, and Chocolate: Adenosine Receptors in Fragile X

FRAXA Research Foundation 2018 Grants • Borreca, Antonella • Current Research Grants • Disease Mechanisms • Italian National Institute of Health • Martire, Alberto • Treatment Targets December 11, 2018February 7, 2019AMPAkines, BDNF, cyclic AMP, glutamate, mGluR5, sleep

Caffeine is the most popular smart drug in the world. With a $90,000 grant from FRAXA Research Foundation, Alberto Martire, PhD and Antonella Borreca, PhD in Rome, Italy are investigating adenosine receptors antagonists to treat Fragile X syndrome. Compounds which are able to block adenosine receptors are commonly found in tea, chocolate, and coffee.

Fragile X Clinical Trial of AZD7325 in Adults

FRAXA Research Foundation 2017 Grants • 2018 Grants • Biomarkers • Cincinnati Children's Hospital • Clinical • Clinical Trials • Current Research Grants • Erickson, Craig • Recruiting February 1, 2018February 25, 2019AstraZeneca, AZD7325, GABA, glutamate

With a $51,000 grant from FRAXA Research Foundation, Dr. Craig Erickson will conduct a double-blind, placebo-controlled clinical trial of AZD7325 in adults with Fragile X syndrome at Cincinnati Children’s Hospital. The compound being studied is an investigational new drug from AstraZeneca that targets GABA (A) receptors.

Newly Discovered Regulatory Pathways in Fragile X

J. Dora Levin Kaczmarek, Leonard • Research Updates October 31, 2017July 30, 2018Autifony Therapeutics, BK channel, FDA, glutamate, hyperexcitability, hypersensitivity, mGluR5, potassium channels, seizure

Studies at Yale University and elsewhere are showing that FMRP plays a significant role in the regulation of potassium channels. Looking forward, potassium channel opener drugs could rescue some symptoms of Fragile X in humans.

In Their Own Words: Reports From the International Fragile X Workshop

FRAXA Research Foundation Cogram, Patricia • Contractor, Anis • Events Recap • Kooy, Frank • Lee, Jeannie • McGill University • Moine, Herve • Razak, Khaleel • Research Updates • Smith, Carolyn B. • Sonenberg, Nahum • Todd, Peter • Vanderklish, Peter October 29, 2017June 18, 2018amygdala, autism, bumetanide, DgkK, EEG, ERK, FDA, Fragile X Meeting, GABA, ganaxolone, glutamate, hyperexcitability, hypersensitivity, metformin, mGluR5, minocycline, mRNAs, Rett syndrome, seizure, sleep, sound

The 18th International Fragile X and Related Neurodevelopmental Disorders Workshop in Quebec, Canada, was a great success, featuring Fragile X much more heavily than any previous meeting in this series! We asked our speakers to summarize their work in their own words. These brief updates from researchers investigating Fragile X.

Brain Imbalance Target of Dr. Erickson’s New Clinical Trial

Theodore Coutilish Biomarkers • Cincinnati Children's Hospital • Clinical • Erickson, Craig • Research Updates October 25, 2017June 15, 2018Abilify, AstraZeneca, autism, AZD7325, EEG, GABA, glutamate

According to Dr. Erickson, AZD7325 is a drug that selectively boosts GABA neurotransmission in the brain. GABA is the primary neurochemical in the brain that blocks brain activation. GABA activity is in balance in the brain with Glutamate activity, which is the primary neurochemical that causes brain activation. In Fragile X, GABA activity is insufficient and glutamate activity is excessive, likely causing brain activity to be out of balance. AZD7325 attempts to correct parts of this imbalance by boosting the insufficient GABA activity in the brains of people with Fragile X

MicroRNA Mediated Astroglial GLT1 Dysregulation in Fragile X

FRAXA Research Foundation 2017 Grants • 2018 Grants • Current Research Grants • Disease Mechanisms • Higashimori, Haruki • Men, Yuqin • Treatment Targets • Tufts University • Yang, Yongjie September 30, 2017August 22, 2018astrocytes, autism, glutamate, Pierce Family Fragile X Foundation

Almost all brain research focuses on neurons – nerve cells. However, the brain has many more glial cells which support, nourish, and protect the neurons. FRAXA Research Foundation awarded a 2017 grant $90,000 to support Dr. Yang’s studies of how changes in glial cells contribute to Fragile X syndrome. This grant is funded by a grant from the Pierce Family Fragile X Foundation.

Defining Subcellular Specificity of Metabotropic Glutamate Receptor (mGluR5) Antagonists

FRAXA Research Foundation 2006-2010 Grants • 2011 Grants • 2012 Grants • Biomarkers • FRAXA Research Grants • Hogan, Carolyn Ann • Kumar, Vikas • O'Malley, Karen • Research Grant with Results • Treatment Targets • Washington University September 22, 2017March 27, 2019glutamate, mGluR5

With $217,500 in grants from FRAXA Research Foundation, Dr. Karen O’Malley and team studied the function of mGluR5 when it is inside cells. Many of the symptoms of Fragile X Syndrome (FXS) are thought to arise due to overactive metabotropic glutamate receptor 5 (mGluR5) signaling, which is normally opposed by the protein missing in FXS, Fragile X Protein (FMRP).

Mechanisms of Tolerance to Chronic mGluR5 Inhibition

FRAXA Research Foundation 2015 Grants • 2016 Grants • 2017 Grants • Bear, Mark • Disease Mechanisms • Massachusetts Institute of Technology (MIT) • Osterweil, Emily • Research Grant with Results • Senter, Rebecca • Treatment Targets September 19, 2017August 29, 2018AFQ056, drug tolerance, glutamate, lovastatin, mGluR5, Novartis, Roche

Over the past few years, both Novartis and Roche sponsored large-scale clinical trials of metabotropic glutamate receptor 5 (mGlu5) negative allosteric modulators (NAMs) to treat Fragile X syndrome (FXS). With a $90,000 grant from FRAXA Research Foundation in 2015-2017, Dr. Mark Bear’s team will explore if mGlu5 NAMs dosed chronically causes tolerance, and if so, how it develops and to probe new avenues to prevent or circumvent it.

Clinical Trial of Ganaxolone in Patients with Fragile X Syndrome

FRAXA Research Foundation 2014 Grants • 2015 Grants • Clinical • Dijck, Anke Van • Kooy, Frank • Research Grant with Results • Treatment Targets • University of Antwerp, Belgium September 2, 2017March 27, 2019GABA, GABA-A, ganaxolone, glutamate, seizure, sleep

With a $90,000 grant from FRAXA Research Foundation funded during 2014-2015, Dr. Frank Kooy and colleagues at the University of Antwerp are conducting a double blind crossover trial of ganaxolone in patients with Fragile X syndrome. Results of this study were mixed (see Marinus: Results from Phase 2 Exploratory Clinical Study Support Continued Development of Ganaxolone in Fragile X Syndrome.

Did Tolerance Result in Fragile X mGluR5 Clinical Trial Failures?

Theodore Coutilish Bear, Mark • Massachusetts Institute of Technology (MIT) • Research Updates • Senter, Rebecca March 15, 2017June 14, 2018AFQ056, drug tolerance, glutamate, mGluR, mGluR5, Novartis, Roche

Although the clinical trials failed to show efficacy in the patient population and Novartis and Roche discontinued their Fragile X development programs, Dr. Senter has worked with Mark Bear, PhD to carefully review parent observations. Those caregiver reports suggested tolerance to mGlu5 antagonists antagonists developed quickly, consistent with some preclinical findings in the mouse model.

Repurposing Available Drugs to Treat Fragile X Syndrome – FRAXA Initiatives

Michael Tranfaglia, MD Drug Repurposing • Research Updates February 10, 2017July 26, 2018arbaclofen, autism, baclofen, FRAXA-DVI, glutamate, GSK3, Healx, hypersensitivity, lithium, lovastatin, MAP1b, matrix metalloproteinase, metformin, mGluR, minocycline

FRAXA Research Foundation was founded in 1994 to fund biomedical research aimed at finding a cure for Fragile X syndrome and, ultimately, autism. We prioritize translational research with the potential to lead to improved treatments for Fragile X in the near term. Our early efforts involved supporting a great deal of basic neuroscience to understand the cause of Fragile X. By 1996, these efforts had already begun to yield results useful for drug repurposing. To date, FRAXA has funded well over $25 million in research, with over $3 million of that for repurposing existing drugs for Fragile X. Here are some examples of FRAXA-funded work on repurposing available drugs for Fragile X syndrome: Lithium In the mid-1990s, the Greenough lab at the University of Illinois discovered that FMRP, the protein missing in Fragile X, is rapidly translated in dendrites in response to stimulation of glutamate receptors. FRAXA funded preclinical validation of this discovery in theRead more

Enhancement of NMDA Receptor Signaling for the Treatment of Fragile X Syndrome

Theodore Coutilish 2016 Grants • 2017 Grants • 2018 Grants • Barnes, Stephanie • Completed Research Grant • Osterweil, Emily • Research Updates • Treatment Targets • University of Edinburgh, Scotland August 15, 2016March 26, 2019ERK, glutamate, lovastatin, mGluR, NMDA, seizure

FRAXA Research Foundation funded a 2016-2017 Fellowship for Dr. Stephanie Barnes in the University of Edinburgh lab of Dr. Emily Osterweil. With this $90,000 award, the team is investigating NMDA signaling in fragile X syndrome mice.

Fruit Flies to Model and Test Fragile X Treatments

FRAXA Research Foundation 2001-2005 Grants • 2006-2010 Grants • 2012 Grants • 2013 Grants • 2014 Grants • 2015 Grants • Choi, Catherine • Completed Research Grant • Drug Repurposing • Jongens, Tom • McBride, Sean • Pepper, Anita • Treatment Targets • University of Pennsylvania September 13, 2015April 25, 2018ERK, FDA, fruit fly, glutamate, lithium, metformin, mGluR, mTOR

Dr. Jongens and his collaborators have found an insulin-like protein in the fly brain that is overexpressed in the Fragile X mutant fly, leading to increased activity of the insulin signaling pathway. Furthermore, they found that certain behavioral patterns in the Fragile X flies can be rescued by expressing the FX gene just in insulin producing neurons in the fly brain. In the mutant, there are other changes in the signaling pathways, including a decrease in cAMP and elevation in PI3K, mTOR, Akt and ERK activity. They now propose to study 2 medicines used for diabetes: pioglitazone (increases cAMP and decreases Akt and ERK) and metformin (inhibits mTOR), in flies and mice to validate the potential efficacy of these novel therapeutics for Fragile X.

Fragile X Treatment: New Research Directions

Michael Tranfaglia, MD Research Updates March 12, 2015July 11, 2018astrocytes, BK channel, glutamate, hyperexcitability, mGluR, mGluR5, seizure, sound

Re-examining the Nature of Fragile X In the wake of negative results from several high-profile clinical trials in Fragile X, we find ourselves questioning many of our previous assumptions about the nature of this disorder. After all, understanding the basic pathology of disease is critical to development of new treatments — this is true across the board, in all branches of medicine. In the early days of Fragile X research, shortly after the FMR1 gene was discovered and the normal protein product of the gene (FMRP) was identified, it was noted that FMRP is an RNA binding protein. Whatever the normal function of this single protein which Fragile X patients lack, it had something to do with RNA metabolism. Since RNA is the template used to make new proteins, this meant that the Fragile X protein is involved in regulating protein synthesis. A synapse showing the axon of neuron 1,Read more

Inhibitors of STEP as a Novel Treatment of Fragile X Syndrome

FRAXA Research Foundation 2006-2010 Grants • 2011 Grants • 2014 Grants • 2015 Grants • Completed Research Grant • Disease Mechanisms • Lombroso, Paul • Research Grant with Results • Treatment Targets • Yale University February 26, 2015May 16, 2018AMPA, AMPAkines, autism, glutamate, LTD (Long-term depression), mRNAs, STEP (STriatal-Enriched protein tyrosine Phosphatase)

With a $349,000 grant from FRAXA Research Foundation from 2008-2015, Dr. Paul Lombroso and his team at Yale University researched if inhibiting STEP could reduce behavioral abnormalities in Fragile X syndrome. Results published.

Cellular-Specific Therapeutic Targeting of Inhibitory Circuits in Fragile X Syndrome

FRAXA Research Foundation 2013 Grants • 2014 Grants • Cea-Del Rio, Christian • Completed Research Grant • Disease Mechanisms • Huntsman, Molly • Treatment Targets • University of Colorado September 13, 2014April 25, 2018endocannabinoid, glutamate, mGluR, seizure, somatostatin

Studies have shown that the function of inhibitory networks is disturbed in Fragile X. This abnormality is not well understood but appears to be secondary to abnormalities in metabotropic glutamate and endocannabinoid systems. With a $90,000 grant from FRAXA in 2013-2014, Dr. Molly Huntsman’s team examined how these networks interact and how inhibitory deficits can best be remedied.

Seizures in Fragile X Syndrome and Therapeutic Potential of NMDA Receptor Antagonists

FRAXA Research Foundation 2013 Grants • 2014 Grants • Completed Research Grant • Disease Mechanisms • Drug Repurposing • State University of New York • Treatment Targets • Wong, Robert September 8, 2014April 28, 2018autism, glutamate, mGluR, NMDA, seizure

With a $90,000 grant from the FRAXA Research Foundation, Dr. Robert Wong is investigating how seizures are generated in Fragile X neurons. More generally, he is looking at how synapses are modified to enable learning and memory and how this process is impaired in Fragile X. $90,000 Grant Robert Wong, PhD Principal Investigator State University of New York 2013-2014 FRAXA Research Grant $90,000 over 2 Years Abnormal increases in sensitivity of a type of glutamate receptor (group I mGluR) cause brain malfunction, including epilepsy, in Fragile X syndrome (FXS). We are examining a newly uncovered regulation of this increased group I mGluR sensitivity by a second type of glutamate receptor, the NMDA receptor. By looking at audiogenic seizures in FXS model mice, NMDA receptor blockers were found to robustly suppress these seizures at the young developmental stage. In contrast, the same antagonists activated seizure activities, normally dormant, in adult FXS model mice and in a CGGRead more

What Treatments Work for FXTAS?

Michael Tranfaglia, MD Community March 25, 2014June 21, 2018Alzheimer's, FXTAS, glutamate

Many older family members in the Fragile X community are affected by FXTAS (Fragile X-associated Tremor/Ataxia Syndrome). We all hope that knowing the underlying cause of neurodegenerative symptoms in FXTAS will help in the development of specific treatments over the long term. In the short term, we would also hope that having a specific diagnosis would help us to identify particular available treatments which might be more effective than others. One of the available treatments for Alzheimer's Disease is a glutamate receptor blocker called memantine (Namenda), and dementia specialists think this drug could be effective in treating a wide range of neurodegenerative diseases. It has been found to be effective in treating Lewy Body Dementia, a disorder which causes parkinsonism and cognitive decline, with features rather similar to FXTAS. This led researchers to think that this drug could also be useful in treating FXTAS, and initial open-label experience with it wasRead more

Lovastatin Discovery in Fragile X Mice Leads FRAXA to Fund Clinical Trials

FRAXA Research Foundation Bear, Mark • Massachusetts Institute of Technology (MIT) • Osterweil, Emily • Research Updates • Treatment Targets June 11, 2013July 30, 2018autism, ERK, Fragile X Meeting, glutamate, lovastatin, mGluR, minocycline

Available Medication Lovastatin Corrects Excess Protein Synthesis in Fragile X Mice Dr. Emily Osterweil At the opening dinner of the 2011 FRAXA Investigators Meeting in Southbridge, MA, Dr. Emily Osterweil was awarded the FRAXA Pioneer Award for work demonstrating that Lovastatin could treat Fragile X. Dr. Osterweil conducted her experiments in the MIT laboratory of Dr. Mark Bear; she has since established her own laboratory at the University of Edinburgh. The team discovered that lovastatin, a drug widely prescribed for high cholesterol, can correct excess hippocampal protein synthesis in the mouse model of FXS and can prevent epileptogenesis. The work is published in the prestigious neuroscience journal Neuron: Lovastatin Corrects Excess Protein Synthesis and Prevents Epileptogenesis in a Mouse Model of Fragile X Syndrome. One implication of the mGluR theory of Fragile X is that there are exaggerated consequences of activation of signaling pathways which link metabotropic glutamate receptors (mGluRs) to the cellular machinery ofRead more

Justin Cowan, PhD — University of Chile

FRAXA Research Foundation Uncategorized June 2, 2013January 24, 2018dopamine, glutamate

Treatment of Fragile X Syndrome via Dopamine Enhancers and Glutamate Inhibitors with Patricia Cogram, PhD FRAXA Awards: $50,000 in 2011 $50,000 in 2010 Project Description by Justin Cowan, 4/1/2010 Dopamine Enhancers and Glutamate Inhibitors This project aims to follow up our and others observations that the dopamine receptor is under expressed in the Fragile X syndrome and thus determine the effectiveness of targeted pharmacological treatments in Fragile X syndrome. We hope to increase our understanding of the mechanism of under expression of dopamine in fmr1 knockout mice and to test whether drugs that activate dopamine release and glutamate inhibition can alleviate the clinical symptoms of Fragile X syndrome. For the purpose of this project, we are investigating two compounds, Safinamide and Kuvan (BH4). We are using human cortical cells fmr1-/- to analyze the direct effects of these compounds on the neuronal phenotype and also to help

Is There a Developmental Switch in the Effects of FMRP?

FRAXA Research Foundation 1994-2000 Grants • 2001-2005 Grants • 2006-2010 Grants • 2011 Grants • 2012 Grants • Completed Research Grant • Disease Mechanisms • Huber, Kimberly • University of Texas at Southwestern March 12, 2013January 21, 2019glutamate, mGluR, mGluR5

With a $474,300 grant from FRAXA Research Foundation from 2000-2013, Dr. Kimberly Huber and her team at the University of Texas conducted several studies on the relationship between mGluR5 and Fragile X syndrome. Dr. Huber made the original discovery of the mGluR Theory of Fragile X when she was a postdoctoral fellow in the lab of Dr. Mark Bear, with her first FRAXA grant in 2000.

Preclinical Evaluation of Serotonin Receptor Agonists as Novel Pharmacological Tools in Fragile X Syndrome

FRAXA Research Foundation 2013 Grants • Ciranna, Lucia • Completed Research Grant • Disease Mechanisms • Treatment Targets • Universita di Catania, Italy February 22, 2013August 9, 2018glutamate, LTD (Long-term depression), mGluR, seizure, serotonin

With a $66,000 grant from FRAXA Research Foundation in 2013, Dr. Lucia Ciranna and her team from the Universita di Catania tested if specific serotonins could reverse abnormal phentotypes found in Fragile X syndrome.

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