Fragile X syndrome is the most common heritable form of intellectual disability and a leading genetic cause of autism. The disorder results from loss of a key regulatory protein known as FMRP, but how the absence of this protein causes the cognitive impairments associated with fragile X syndrome is still unclear. Suzanne Zukin and her colleagues at Albert Einstein College of Medicine in New York, as well as others, have identified hyperactivation of a key cellular signaling pathway — the PI3K-mTOR signaling pathway — as a key feature of the syndrome.

Synaptic plasticity refers to changes in the strength of synapses — the connections between neurons — that underlie learning and memory. A specific form of synaptic plasticity that involves metabotropic glutamate receptors (mGluRs) is altered in fragile X. Zukin’s team has been studying a small signaling molecule called PI3 kinase enhancer (PIKE). PIKE is linked to mGluRs and is required for activation of PI3K and mTOR in response to mGluR stimulation. PIKE is directly regulated by FMRP, and altered levels of PIKE have been observed in a mouse model of fragile X syndrome.

These findings support a model in which FMRP represses PIKE and thereby suppresses mTOR signaling in normal mice. Upon activation, mGluRs act via PIKE to engage PI3K signaling, which activates mTOR and drives the local synthesis of synaptic proteins critical to learning and memory. In mice lacking FMRP, PIKE is unrepressed, resulting in over-activation of mTOR, and disrupted synapses. Zukin’s lab is using a combination of genetic approaches to correct excessive PIKE protein levels in mice with the fragile X mutation. They have generated fragile X mice that are missing either one or both PIKE alleles, resulting in reduced or absent PIKE expression, respectively. Experiments are ongoing to assess whether altered PIKE expression is sufficient to correct elevated mTOR signaling and synaptic plasticity deficits in the fragile X mice.