FIGURE 3.

Pathways in the cortex and hippocampus thought to be involved in the mGluR mechanism of mental retardation in FXS and expected effects of lithium, 2-methyl-6-(phenylethynyl)pyridine (MPEP)/mGluR blockers, and CX516/ampakines. In the normal state, mGluR activation by glutamate (glu) results in activation of dendritic translation through the phospholipase C (PLC) cascade. FMRP levels increase with translational activation, and FMRP then inhibits translation, acting as the negative feedback or “brake” on the translational mechanism. When FMRP is missing in FXS, mGluR-mediated translation lacks the negative feedback balance normally provided by FMRP and is activated excessively and constitutively, leading to excessive synthesis of specific synaptic proteins, internalization of AMPA receptors, and other synaptic changes that result in excessive long-term depression and persistently weak and immature synapses. Treatment with 2-methyl-6-(phenylethynyl)pyridine or other mGluR5 negative modulators would block excessive mGluR-mediated translation directly. Lithium, which blocks inositol phosphate (IP) turnover, thus depleting phospholipase C substrate and blocking phospholipase C-mediated signal transduction, also inhibits glycogen synthase kinase 3β (GSK3β) activity, thus downregulating translation of FMRP target proteins, and would be expected to block in part excessively activated mGluR-mediated translation in FXS. In either case, the system would then move toward the normal level of translational activity, resulting in normalization of synaptic activity and maturation. Treatment with CX516 or other ampakines would be expected to increase AMPA activity directly, as well as redistributing AMPA receptors to the synaptic membrane through activation of BDNF. PKC indicates protein kinase C.