PIKE as critical regulator of mTOR signaling and synaptic dysfunction in Fragile X syndrome
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Fragile X syndrome, the most common form of inherited intellectual disability and leading genetic cause of autism, is caused by transcriptional silencing of the Fmr1 gene, which encodes the F&barbelow;ragile X M&barbelow;ental R&barbelow;etardation P&barbelow;rotein (FMRP). FMRP is an RNA binding protein that negatively regulates translation. The Fmr1 knockout mouse, a well-established model of fragile X syndrome, exhibits cognitive deficits and exaggerated m&barbelow;etabotropic glutamate r&barbelow;eceptor-dependent l&barbelow;ong-t&barbelow;erm d&barbelow;epression (mGluR-LTD) at hippocampal CA1 synapses. However, the molecular mechanisms that link loss of FMRP to aberrant synaptic plasticity remain unclear.;The m&barbelow;ammalian T&barbelow;arget O&barbelow;f R&barbelow;apamycin (mTOR) signaling cascade controls initiation of cap-dependent translation and is required for mGluR-LTD. Here I showed that mTOR phosphorylation and activity are elevated in the hippocampus of Fmr1 Knockout mice by a number of functional readouts. Consistent with this, mGluR-LTD at CA1 synapses of FMRP-deficient mice is exaggerated and rapamycin-insensitive. In addition, my data suggest overactivation of PI3K/Akt. The PI3K inhibitor LY294002 corrects p-mTOR and restores sensitivity to the group I agonist DHPG. I further show that PI3K&barbelow; E&barbelow;nhancer (PIKE), an upstream activator of PI3K and mTOR signaling and identified target of FMRP, is elevated in Fmr1 Knockout mice. I further examined the effects of acute genetic manipulation of FMRP on PIKE expression and mTOR signaling. RNAi-mediated depletion of FMRP increased PIKE, p-mTOR and p-Akt in wild-type neurons. Conversely, hFMRP overexpression rescued elevated PIKE, p-Akt and p-S6K in FMRP-deficient neurons.;Collectively, these findings suggest that elevated PIKE and mTOR signaling serve as a functional link between overactivation of mGluRs and aberrant synaptic plasticity in fragile X mice. According to my model, in wild-type mice, FMRP represses PIKE translation and exerts a negative regulatory effect on mTOR signaling. Activation of group I mGluRs stimulates PIKE via mGluR-Homer-PIKE complex and thereby activates PI3K/Akt/mTOR signaling, dendritic cap-dependent translation, and mGluR-LTD. In FMRP-deficient mice, PIKE is elevated and mTOR signaling is overactivated and DHPG-insensitive, leading to aberrant synthesis of synaptic proteins and exaggerated protein synthesis-independent mGluR-LTD. Thus, I predict that dysregulation of mTOR signaling and aberrant protein translation contribute to the cognitive and social interaction deficits observed in humans with fragile X syndrome.
Source: Dissertation Abstracts International, Volume: 72-08, Section: B, page: 4467.;Advisors: R. Suzanne Zukin.