The Endocannabinoid System in a Mouse Model of Fragile X Syndrome
Bradley Alger, PhD
Principal Investigator
Ai-Hui Tang, PhD
FRAXA Postdoctoral Fellow
University of Maryland
College Park, MD
2011-2013 Grant Funding: $128,500
Summary
With this grant from FRAXA Research Foundation, Drs. Bradley Alger and Ai-Hui Tang at the University of Maryland targeted the endocannabinoid pathways as a treatment strategy for Fragile X syndrome.
The Results
The team's findings, Homer protein-metabotropic glutamate receptor binding regulates endocannabinoid signaling and affects hyperexcitability in a mouse model of Fragile X Syndrome were published in PubMed on March 4, 2015.
The Science
by Bradley Alger
Regulation of synaptic inhibition mediated by the neurotransmitter, GABA, is critical to normal brain development and functioning. Dysregulation of inhibition leads to abnormalities in neuronal migration and circuit formation, synaptic connectivity, excitability control, and synaptic plasticity. Decreases in inhibition can cause seizure disorders and are implicated in neurological diseases, such as autism spectrum disorders, including Fragile X syndrome (FXS). Many studies have shown that inhibitory neurotransmission is abnormal in the Fragile X brain.
We had began to understand that inhibitory circuits in the brain are regulated by the endocannabinoid system. This system makes widespread use of signaling pathways which are also impaired in Fragile X.
The convergence of disparate lines of evidence on dysregulation of the eCB system in the FXS mouse model is striking. Our central hypothesis was that dysregulation of the eCB system is a major contributing factor to the neuronal circuit malfunction in Fmr1-/y and possibly FXS.
We investigated the implications of eCB dysregulation at the level of neuronal circuitry, as well as the possibility of reversing some of the physiological consequences of FMRP deletion by manipulations of the eCB system.