Protein targets currently known to be affected by the balance of mGluR5-FMRP balance:
- AMPA receptor
- Kc3.1b potassium channels
- Homer (which is a synaptic scaffold protein)
- GSK3 (signaling proteins)
- Matrix metalloproteinase-9 (an extracellular matrix-degrading enzyme)

Changes in any of the above proteins cause the most prominent pathological signs of Fragile X Syndrome: the presence of numerous dendritic spines with elongated shafts and small heads, as well as an increase in dendritic spine density. Loss of FMRP also causes enhanced LTD through alterations in mGluR5 signaling, which leads to excessive internalization of AMPA receptors.


Macalester College

- Enhanced long-term depression (LTD)
- Protein targets affected by the balance of mGluR5-FMRP balance

Neurobiology of Fragile X Syndrome

Sontheimer, H. (2015). Diseases of the Nervous System. Academic Press. 

Diseases of the Nervous System 

Seen in Fragile X Syndrome is highly enhanced LTD. This is because FMRP acts as a negative feedback regulator in the process which couples metabotropic glutamate receptor (mGluR5) with activity-dependent glutamate release with changes in the translation of proteins by suppressing protein biosynthesis at polyribosomes. When FMRP is absent, protein production goes awry and LTD is enhanced as a result of this dysregulation. To go into further detail regarding the pathways that lead to this:
- mGluR5 couples to phospholipase C (PLC) via Gq (a G protein) and signals via extracellular-regulated kinase and mammalian target of rapamycin (mTOR) to regulate protein translation at polyribosomes
- Additionally, since mGluR-mediated LTD is insensitive to changes in intracellular calcium, another pathway is as follows: Homer → Pike-L → phosphoinositide 3-kinase (PI3K)
- PI3K then activates the mTOR extracellular signal-regulated kinase pathway: PI3K→ PIP3 → AKT → mTOR → FMRP

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