Assessment of Glutamatergic Neurosystem in Fragile X Syndrome for Targeted Therapy
Abstract
Fragile X syndrome (FXS) is the most common single gene disorder and is characterized by mild to severe mental retardation. In the majority of cases, it is caused by silencing of the FMR1 gene, which encodes the fragile X mental retardation protein. In patients with FXS, the defective gene cannot produce normal levels of the FMRP protein, and this leads to learning disability and other neurological symptoms. FXS is characterized by a variety of behavioral deficits; as such, there is no specific medication but rather it draws on treatments designed for other disorders that have also been beneficial for some features observed in FXS. There are presently 19 clinical trials in Fragile X using three different drugs that were originally designed for other disorders. The drugs in the clinical trials are used to alleviate behavioral symptoms of FXS. In this proposal, we aim to focus on mechanisms and ?drugs? that function directly or indirectly on the impaired glutamatergic neurosystem underlying the syndrome. Findings from genetic reduction of mGluR5 expression in the FMR1 knockout mice as well as pharmacological studies using short-acting mGluR5 inhibitors such as MPEP and fenobam have revealed a reduction in a broad range of fragile X phenotypes, clearly pointing to the role of overactive mGlu5 receptors in the disorder. There are a number of Fragile X phenotypes associated with the implicated glutamatergic system. The cognitive phenotype usually includes moderate to severe intellectual disability, deficits in executive function, short-term memory, attentional control, and visuospatial processing. The behavioral phenotype may include anxiety, hyperactivity, motor, and social interaction deficits. In keeping with these characteristics, neuroimaging studies in individuals with Fragile X have found reduced grey matter volume in a number of brain regions including the cerebellum, amygdala, hippocampus, caudate nucleus, and the parietal lobe. Importantly, some neuroanatomical differences are evident from a very young age (e.g., caudate, posterior vermis) whereas other regions like the thalamus emerge as being different in later years, providing clues about the circuits and transmitter systems involved at different time points in the progression of the disorder. In the face of recent failures of mGluR-based clinical trials in FXS, which may be potentially related to dosing and drug tolerance issues, the current project persists in its search for a better understanding of the mGluR mechanism in the hope of positive treatment outcomes for this condition. Specifically, the proposed multimodal approach, PET (positron emission tomography), MRI/DTI (magnetic resonance imaging/diffusion tensor imaging), MEG (magnetoencephalography) incorporating both human patients and mouse models with FXS, to identify structural and functional networks of impacted brain regions, along with longitudinal tracking of the progression of the disorder as well as response to the drugs targeting the mGluR5 system presents a powerful opportunity to drill deeper into the underlying mechanism for a fuller understanding of the disorder. To this end, the team brings invaluable experience in terms of developing mGluR5-targeted ligands, imaging difficult-to-test human populations, and expertise in learning disabilities (e.g., dyslexia, specific language impairment relevant to the project. The proposal aims to (a) find correlates between regional mGluR5 expression in the brain and different behavioral measures including anxiety, learning, memory, and locomotor activity using genetically modified mice (FMR1 Knock Out); (b) use PET imaging to identify affected brain areas in adults between age of 18 and 24 years with FXS, and correlates in genetically modified mice; (c) use DTI and MEG to examine disruptions in structural and functional connections within the network of impaired brain areas; (d) evaluate the outcomes of a therapeutic drugs in FMR1 knock
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710228
Entities
People
- Anna-Liisa Brownell
Organizations
- Massachusetts General Hospital
- United States Army