Dysruption of Endocannabinoid Mediated Synaptic Plasticity in the Nac of FMR1 Null Mice
Olivier Manzoni, PhD
Principal Investigator
Marja Sepers, PhD
FRAXA Postdoctoral Fellow
INMED INSERM
Marseille, France
2009 Grant Funding: $45,000
Summary
This project was among the first to investigate the endocannabinoid (eCB) system in Fragile X syndrome. Building on the mGluR theory of Fragile X, the study proposed that abnormal mGluR5 signaling in FMR1-deficient mice disrupts synaptic plasticity in the nucleus accumbens, through altered endocannabinoid signaling. The work highlighted the eCB system as a promising therapeutic target, suggesting that drugs that modulate enzymes controlling endocannabinoid degradation could restore synaptic function while avoiding the widespread CB1 receptor activation responsible for the psychotropic effects of cannabis.
The Results
The team was able to establish the endocannabinoid system as a therapeutic target:
• Fragile X disrupts endocannabinoid-dependent synaptic plasticity
• The pathway can be pharmacologically modulated
• Correcting the pathway can improve Fragile X phenotypes in animal models
This study showed that endocannabinoid-dependent synaptic plasticity is impaired in FMR1 knockout mice, supporting the idea that Fragile X disrupts retrograde cannabinoid signaling at synapses.
Jung KM et al., 2012 — Nature Neuroscience
Endocannabinoid signaling and synaptic plasticity are disrupted in Fragile X mouse models.
In a follow-up translational study, the researchers demonstrated that enhancing endocannabinoid signaling restored synaptic function and improved behavioral abnormalities in Fragile X mice, suggesting the pathway could be therapeutically targeted.
Busquets-Garcia A et al., 2013 — Nature Medicine
Manipulating the endocannabinoid system can rescue Fragile X phenotypes.
The Science
by Olivier Manzoni, 5/1/2009
This study proposed an extension of the mGluR hypothesis of Fragile X syndrome. One important consequence of activating group I mGluRs is the production of endocannabinoids, signaling molecules that regulate communication between neurons. Surprisingly, despite this connection, the endocannabinoid system had not yet been studied in the context of Fragile X syndrome.
We therefore tested the following hypothesis:
Hypothesis: Dysregulation of mGluR5 signaling in FMR1 knockout mice disrupts activity-dependent synaptic plasticity in the nucleus accumbens through abnormal endocannabinoid signaling. Modulating this pathway may restore normal synaptic function.
The endocannabinoid (eCB) system represents a promising therapeutic target. Cannabinoid receptors (CB1R) overlap extensively with mGluR5 throughout the brain, particularly in regions such as the striatum, cortex, and hippocampus (Tsou et al., 1998; Romano et al., 1996). Rather than activating cannabinoid receptors directly—which can produce unwanted psychoactive effects—therapies that target the enzymes responsible for endocannabinoid degradation may enhance signaling only at synapses where endocannabinoids are naturally released. This approach could potentially restore normal synaptic regulation while avoiding the widespread receptor activation responsible for the psychotropic effects associated with cannabis.