New Roles for FMRP and p53 Proteins in Fragile X Identified in Mouse Study

New interactions involving the FMRP and p53 proteins were found to play an important part in neural defects associated with fragile X syndrome, a new mouse study shows.

The study, “Dysregulation and restoration of homeostatic network plasticity in fragile X syndrome mice,” was published in the journal Neuropharmacology.

Homeostatic plasticity is a natural response of our nerve cells that counteracts disturbances in their activity and allows them to maintain electrical impulses (excitability) within a physiological range.

Neurons carry out homeostatic plasticity through specific mechanisms that can modulate the proteins involved in the regulation of excitability, like ion channels, vesicle trafficking proteins, and synaptic proteins.

As a result, synaptic plasticity is adjusted. Synapses are the junctions between two nerve cells that allow them to communicate; synaptic plasticity refers to the ability of synapses to strengthen or weaken over time.

The molecular mechanisms underlying homeostatic plasticity in neuronal networks — the large scale intertwined circuits that connect nerve cells to one another — are not well understood. 

Understanding them could help explain the molecular mechanisms of some neurological diseases like autism spectrum disorders, of which fragile X is the most common inherited form, where neural plasticity is altered or insufficient to keep the excitability of nerve cells in check.

To address this question, researchers investigated nerve cell impulses and the proteins involved in the neural networks of mice with fragile X syndrome. These mice were genetically engineered to lack the FMR1 gene (and, consequently, the FMRP protein) which is also the defective gene in fragile X patients.

The team recorded the electrical impulses of lab-cultured mouse neurons and saw that FMR1, which provides instructions for making the FMRP protein, is crucial to maintaining a series of important neural network properties.

A deficiency of FMR1 made the network stop synchronizing as it should when nerve cells were chronically stimulated to be continuously active. Also, spontaneous nerve spikes increased when the cells were stimulated in this manner. 

Nerve spikes happen when the membrane potential — the electrical voltage across the cell’s plasma membrane — of a specific neuron rapidly rises and falls, causing a shift in electric charge distribution of adjacent cells.

A protein called p53 was found to pay a major role in these FMR1-related impairments. Blocking this protein restored or partially corrected the properties of neural networks in fragile X models.

The roles played by FMRP and p53 add to the current understanding of why neural networks stop working properly in people with fragile X syndrome.

Because related neuronal imbalances are a common finding in many autism spectrum disorders (ASDs), these results “may provide mechanistic insights into the excitability imbalances observed in  [fragile X] and other [autism spectrum disorders],” researchers wrote.