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

Enhanced LTD in Fragile X Syndrome

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.


Protein Targets Affected by the Balance of mGluR5-FMRP in Fragile X Syndrome

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

Macalester College

Fragile X syndrome is perhaps the most common genetic form of intellectual disability. It results when the trinucleotide repeats (i.e., CGG repeats) in the long arm of the X chromosome number more than 200 repeats, as opposed to the normal 6-50 repeats. This extension of repeats leaves this region of DNA fragile, or prone to breakage. Specifically, the overexpansion causes methylation and transcriptional repression of the Fragile X Mental Retardation 1 gene (*FMR1*), which encodes an important RNA-binding protein that inhibits RNA translation into proteins known as fragile X retardation protein (FMRP). The condition affects 1 in 3600 males and 1 in 8000 females. The reason for this large discrepancy between incidences in biological sexes is due to the fact that genetic females have two X chromosomes rather than one X like genetic males do. Generally speaking, females have one normally functioning *FMR1* on the non-mutated chromosome in each cell, which allows their symptoms to be milder since the amount of abnormal *FMR1* is more variable than in males.

Fragile X Syndrome

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

Diseases of the Nervous System 

Sleep problems and seizures are common comorbidities seen in Fragile X Syndrome.

Comorbidities of Fragile X Syndrome

In these mice, mGLUR5 proteins are reduced by 50% and thus symptoms of Fragile X Syndrome are seen. However, when you cross a *FMR1* knockout mouse with a mouse that has a heterozygous deletion of mGLUR5, it leads to expression of only 1 intact mGLUR5 allele and this led to the reversal of all Fragile X symptoms except for enlarged testes. Additionally, this transgenic mouse model is being used to look at pharmacological treatments of Fragile X Syndrome.


Mouse Model: *FMR1* Knockout

Currently, there are no clinically proven treatments that directly affect the disease. Most proven treatments are for the comorbidities seen with Fragile X rather than the condition itself. However, there are many pharmacological treatments being tested for treatment of Fragile X - and many of these are already approved for treatment of other mental or physical conditions:
- Fenobam 
- Baclofen 
- Arbaclofen
- Acamprosate 
- Minocycline
- Lithium 
- MPEP
- CTEP
Some studies that use animal models have found ways to reduce the severity of symptoms like impaired cognition and seizures by conducting trials with metabotropic glutamate receptor 5 pathway antagonists. The severity of these symptoms correlate with the severity of the FMRP (fragile X mental retardation protein) deficit (Hagerman et al., 2009). Further research into this deficit and the methylation needed to prevent it may reveal more about possible treatments in the future.  

Emerging Treatments for Fragile X Syndrome

- Anatomical signs
- Cognitive and behavioral symptoms

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