The Endocannabinoid System in a Mouse Model of Fragile X Syndrome

With a $128,500 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.

$128,500 Grant
Bradley Alger, PhD
Principal Investigator
Aihui Tang

Ai-Hui Tang, PhD
Research Associate

University of Maryland
2011-2013 FRAXA Research Grant
$128,500 over 3 Years

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, such as epilepsy, 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.

Results can be found at:

Tang AH and Alger BE (2015) Homer protein-metabotropic glutamate receptor binding regulates endocannabinoid signaling and affects hyperexcitability in a mouse model of Fragile X Syndrome.

These results connect nicely with work from Dr. Kim Huber’s lab: J Neurosci. 35(9):3938-45.  J Neurosci. 2016 Feb 17.  Selective Disruption of Metabotropic Glutamate Receptor 5-Homer Interactions Mimics Phenotypes of Fragile X Syndrome in Mice.

Explore Current Fragile X Research

FRAXA-funded researchers around the world are leading the way towards effective treatments and ultimately a cure.