Pharmacologically Activating mGluR7 as a Novel Therapy for Fragile X Syndrome
Nien-Pei Tsai, PhD
Principal Investigator
Vipendra Kumar, PhD
FRAXA Postdoctoral Fellow
University of Illinois at Urbana-Champaign
Urbana, IL
2023-2024 Grant Funding: $100,000
Summary
Metabotropic glutamate receptors (mGluRs), proteins which help brain cells communicate with each other, come in 8 flavors. Boosting mGluR7 activity with drugs is being studied as a potential treatment approach for many disorders: anxiety, depression, Parkinson’s disease, addition, and epilepsy. This team will investigate activating mGluR7 to treat Fragile X syndrome.
The Results
Dr. Vipendra Kumar and his team at the University of Illinois School of Molecular & Cellular Biology have reported a promising new treatment target! Their research shows that boosting mGluR7 activity can reduce protein synthesis. In Fragile X mice this resulted in improved memory and learning and reduced audiogenic seizures.
The team's findings, mGluR7 allosteric modulator AMN082 corrects protein synthesis and pathological phenotypes in FXS were published in EMBO Molecular Medicide on February 19, 2024.
The Science
Fragile X syndrome (FXS) patients and the disease model of FXS, the Fmr1 knockout (KO) mouse, exhibit multiple symptoms associated with neuronal and circuit hyperexcitability, such as sensory hypersensitivity, seizures, social anxiety, and cognitive and behavioral impairment. Studies have shown that dysregulation in protein synthesis underlies many of these symptoms in FXS. It is also evident from a plethora of reports that reducing basally elevated protein synthesis is able to reduce hyperexcitability and a wide range of behavioral and cognitive defects in Fmr1 KO mice.
However, despite the extensive efforts in the past to ameliorate disease symptoms in Fragile X syndrome, there remains no effective therapy to rectify aberrant protein synthesis and neuronal excitability in FXS. It is therefore imperative to discover effective druggable targets that can alleviate disease symptoms and improve the quality of life of individuals with FXS.
Our research aims to address this issue by investigating one of the understudied metabotropic glutamate receptors (mGluRs), mGluR7. mGluR7 belongs to the group III mGluRs and is predominantly expressed in the presynaptic terminals of both glutamatergic and GABAergic neurons. Activation of mGluR7 has been shown to reduce excitatory neurotransmission, while mutation or loss of function of mGluR7 is associated with increased seizure susceptibility, developmental delay and autism spectrum disorders.
Following these prior findings, our preliminary data confirmed that pharmacologically activating mGluR7 is able to reduce protein synthesis in Fmr1 KO neurons and reverse multiple disease phenotypes in Fmr1 KO mice. Our research is therefore aimed to test the central hypothesis that activating mGluR7 possesses the therapeutic potential to rectify neuronal hyperexcitability and behavioral abnormality in Fragile X syndrome.
We will employ multiple in vitro, ex vivo and in vivo approaches to validate this hypothesis. Successful completion of this project will introduce an understudied metabotropic glutamate receptor mGluR7 as a new therapeutic target for Fragile X syndrome and will set the foundation for future clinical studies on mGluR7.
Grant Post Revisions
- 2024/03 - Added The Results.
- 2023/06 - Original grant post published.
