Fig. 4. Altered eCS in a FXS model.

Hyperactive mGlu5 signalling in FMRP-KO mice leads to increased 2-AG-mediated suppression of GABA release in neurons within the striatum and the hippocampus. Desensitized CB1R receptor function is observed at glutamatergic synapses possibly due to excess 2-AG release and receptor overactivation. Additionally, mGlu5-mediated eCB-LTD is impaired in prefrontal cortex and ventral striatum of FMRP-KO mice. These impairments are associated with targeting of DAGLα away from the postsynaptic density, caused by reduction in the scaffold protein Homer, selectively enhancing 2-AG-mediated heterosynaptic suppression of GABA release. Ultimately, these eCB signaling adaptations shift excitation/inhibition balance toward excess synaptic excitation.