Pharmacological Rescue of Cortical Synaptic and Network Potentiation in a Mouse Model for Fragile X Syndrome

Fragile X syndrome, caused by the mutation of the Fmrl gene, is characterized by deficits of attention and learning ability. In the hippocampus of Fmrl knockout mice (KO), long-term depression is enhanced whereas long-term potentiation (LTP) including late-phase LTP (L-LTP) is reduced or unaffected. Here we examined L-LTP in the anterior cingulate cortex (ACC) in Fmrl KO mice by using a 64-electrode array recording system. In wild-type mice, theta-burst stimulation induced L-LTP that does not occur in all active electrodes/channels within the cingulate circuit and is typically detected in similar to 75% of active channels. Furthermore, L-LTP recruited new responses from previous inactive channels. Both L-LTP and the recruitment of inactive responses were blocked in the ACC slices of Fmrl KO mice. Bath application of metabotropic glutamate receptor 5 (mGluR5) antagonist or glycogen synthase kinase-3 (GSK3) inhibitors rescued the L-LTP and network recruitment. Our results demonstrate that loss of FMRP will greatly impair L-LTP and recruitment of cortical network in the ACC that can be rescued by pharmacological inhibition of mGluR5 or GSK3. This study is the first report of the network properties of L-LTP in the ACC, and provides basic mechanisms for future treatment of cortex-related cognitive defects in fragile X patients.