Drs. Neuhofer and Manzoni focused on two connected areas of the brain called the Nucleus Acumbens and in the Prefrontal Cortex, which are involved in reward processing and regulation of emotional behavior and emotional memory as well as attention, planning and working memory.

With FRAXA Foundation awardee Dr. M. Sepers and in collaboration with the teams of Dr. D. Piomelli and DR. I. Katona, they have found an mGluR5-dependent form of LTD at excitatory synapses that is mediated by an endocannabinoid called 2-AG and is absent in the synapse of FX knock-out mice.

The endocannabinoid system is an attractive potential therapeutic target for Fragile X syndrome because CB1R overlaps with mGluR5 throughout the rat brain with high densities in the striatum, cortex and hippocampus (Tsou et al., 1998; Romano et al., 1996). Drugs that target the enzymes of cannabinoid degradation would affect only endocannabinoid involved in synaptic signaling where they are released and therefore bypass the system wide activation of cannabinoid (and cannabis) receptor CB1R responsible for unwanted psychotropic side effects.

In agreement with their initial hypothesis, they have also found that pharmacological enhancement of 2-AG signaling normalizes endocannabinoid dependent LTD in the FX knock-out mice. This identifies a new target for potential drug therapy for Fragile X.

2013 Project Description

by Olivier Manzoni, 9/6/2013

The first part of our current project follows up on our recent discovery of altered endocannabinoid system in the Nucleus Accumbens and Prefrontal cortex in FMR1 null mice. Practically, we have:

• used the optogenetic toolbox to identify which specific neuronal pathway onto accubens neurons are altered.
• extended our accumbens results to the Prefrontal Cortex, a brain area controlling planning, attention and search/rescue endocannabinoid synaptic plasticity in FMR1 null mice.
• further studied these pathways and test potential new therapeutic agents.

The second part of our research project focused on the possible interaction between the mGluR / endocannabinoids synaptic plasticity pathways and other major forms of synaptic plasticity in the Nucleus Accumbens and the Prefrontal Cortex.

The endocannabinoid system in Fragile X syndrome

FRAXA Funded a Previous $45,000 Fellowship in the Manzoni Lab in 2009

Dysruption of endocannabinoid mediated synaptic plasticity in the NAc of FMR1 null mice

by Olivier Manzoni, 5/1/2009

The study proposed an extension to the mGluR hypothesis since a major function of group I mGluR is to make endocannabinoids. In this regard, it was surprising that the endocannabinoid system had never been studied in the context of Fragile X syndrome. To that end we addressed the following hypothesis.

HYPOTHESIS: Following mGluR5 dysregulation in FMR1 null mice, activity dependent synaptic plasticity in the nucleus accumbens is disrupted due to aberrant endocannabinoid signalling, which can be modulated to rescue synaptic function.

Marijuana has been used medicinally for centuries. The most distressing side effect when used as an antiemetic by patients in chemotherapy has been the “high” or psychotropic effect. The eCB system was an attractive potential therapeutic target for Fragile X syndrome because CB1R overlaps with mGluR5 throughout the rat brain with high densities in the striatum, cortex and hippocampus(Tsou et al., 1998; Romano et al., 1996). Drugs that target the enzymes of cannabinoid degradation would affect only eCBs involved in synaptic signalling where they are released and therefore bypass the system wide activation of CB1R responsible for unwanted psychotropic side effects.