AUTHOR=Paul Abhik , Nawalpuri Bharti , Shah Devanshi , Sateesh Shruthi , Muddashetty Ravi S. , Clement James P. 

TITLE=Differential Regulation of Syngap1 Translation by FMRP Modulates eEF2 Mediated Response on NMDAR Activity

JOURNAL=Frontiers in Molecular Neuroscience

VOLUME=12

YEAR=2019

URL=https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2019.00097

DOI=10.3389/fnmol.2019.00097

ISSN=1662-5099

ABSTRACT=<p>SYNGAP1, a Synaptic Ras-GTPase activating protein, regulates synapse maturation during a critical developmental window. Heterozygous mutation in <italic>SYNGAP1</italic> (<italic>SYNGAP1</italic><sup>-/+</sup>) has been shown to cause Intellectual Disability (ID) in children. Recent studies have provided evidence for altered neuronal protein synthesis in a mouse model of <italic>Syngap1</italic><sup>-/+</sup>. However, the molecular mechanism behind the same is unclear. Here, we report the reduced expression of a known translation regulator, FMRP, during a specific developmental period in <italic>Syngap1</italic><sup>-/+</sup> mice. Our results demonstrate that FMRP interacts with and regulates the translation of <italic>Syngap1</italic> mRNA. We further show reduced <italic>Fmr1</italic> translation leads to decreased FMRP level during development in <italic>Syngap1</italic><sup>-/+</sup> which results in an increase in <italic>Syngap1</italic> translation. These developmental changes are reflected in the altered response of eEF2 phosphorylation downstream of NMDA Receptor (NMDAR)-mediated signaling. In this study, we propose a cross-talk between FMRP and SYNGAP1 mediated signaling which can also explain the compensatory effect of impaired signaling observed in <italic>Syngap1</italic><sup>-/+</sup> mice.</p>