Endocannabinoid Mediated Synaptic Plasticity in Fragile X Mice

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 knockout 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.